Regulation of chicken haemopoiesis by cytokines

Regulation of chicken haemopoiesis by cytokines

Developmental and Comparative Immunology 24 (2000) 37±59 www.elsevier.com/locate/devcompimm Review Regulation of chicken haemopoiesis by cytokines C...

332KB Sizes 0 Downloads 83 Views

Developmental and Comparative Immunology 24 (2000) 37±59 www.elsevier.com/locate/devcompimm

Review

Regulation of chicken haemopoiesis by cytokines Christopher Siatskas*, Richard Boyd Department of Pathology and Immunology, Monash University Medical School, Commercial Road, Prahran, 3181, Melbourne, Australia Received 14 January 1999; received in revised form 25 August 1999; accepted 27 August 1999

Abstract The continuous production, control and functional activation of blood cells involves a complex series of cellular events in which a small population of stem cells generates large numbers of mature cells. The survival, proliferation and development of these cells is strictly dependent on extracellular signals, among these are polypeptide regulators generally known as cytokines. While a large number of mammalian cytokines with proliferative and inhibitory e€ects have been described in detail, it is surprising that comparatively little is known of the avian system. Given the success of human cytokines as a model, the ability to manipulate the chicken haemopoietic and lymphopoietic systems by precise application of puri®ed cytokines provides a rational approach to defence against disease. As a general caveat, an increased awareness of the existence of regulatory networks and the likelihood that these regulators were designed to function most e€ectively when acting in combination, will provide an understanding into the regulation of haemopoiesis and hence ®nd application in both clinical and agricultural research. # 2000 Elsevier Science Ltd. All rights reserved. Keywords: Cytokines; Haemopoiesis; Stem/progenitor cells; Chicken; Ontogeny

Abbreviations: Ab, antibody; AEV, avian erythroblastosis virus; AGM, aorta-gonad-mesonepheros; ATH, avian thymic hormone; BM, bone marrow; CD, cluster of determination; Ch, chicken; ChIFN-I, chicken type I interferon; CFC, colony forming cell; CFU-M, colony forming unit-marrow; CFU-S, colony forming unit-spleen; cMGF, chicken myelomonocytic growth factor; CSF, colony stimulating factor; D, diversity region; E, days of embryogenesis; EGF, epidermal growth factor; eq, equine; G-CSF, granulocyte-colony stimulating factor; GM-CSF, granulocyte-macrophage-colony stimulating factor; H, heavy chain immunoglobulin gene; h, human; HSC, haemopoietic stem cell; IFN, interferon; Ig, immunoglobulin; IL, interleukin; J, joining region; m, mouse; ma, mammalian; LPL, lipoprotein lipase; mAb, monoclonal antibody;

MIF, migration inhibitory factor; M-CSF, macrophage colony stimulating factor; ND, not determined; NK, natural killer cell; PAS, para-aortic-splanchnopleura; PBL, peripheral blood lymphocyte; PDGF, platelet derived growth factor; PNA, peanut agglutinin; R, receptor; r, recombinant; Ra, receptor antagonist; SCF, stem cell factor; TGF, transforming growth factor; TH, thymic hormone; TNF, tumour necrosis factor; V, variable region; l, lambda light chain. * Corresponding author: Present address: University of Illinois, Section of Hematology/Oncology, Department of Medicine, Room 3256 MBRB, 900 South Ashland Avenue, Chicago, IL 60607-7173, USA. Tel.: +1-312-355-3974; fax: +1-312-413-7963. E-mail address: [email protected] (C. Siatskas).

0145-305X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 3 0 5 X ( 9 9 ) 0 0 0 5 1 - 8

38

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

Contents 1.

Haemopoiesis during avian ontogeny 1.1. Yolksac . . . . . . . . . . . . . . . . 1.2. Intraembryonic sites . . . . . . . 1.3. Spleen . . . . . . . . . . . . . . . . . 1.4. Blood . . . . . . . . . . . . . . . . . . 1.5. Liver . . . . . . . . . . . . . . . . . . 1.6. Bursa . . . . . . . . . . . . . . . . . . 1.7. Pre-bursal stem cells . . . . . . . 1.8. Bursal stem cells . . . . . . . . . . 1.9. Post-bursal stem cells. . . . . . . 1.10. Thymus . . . . . . . . . . . . . . . . 1.11. BM . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

. . . . . . . . . . . .

38 38 39 40 41 41 41 41 42 42 43 43

2.

Chicken cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Chicken myelomonocytic growth factor (cMGF) 2.2. Interferon (IFN) . . . . . . . . . . . . . . . . . . . . . . . 2.3. Stem cell factor (SCF) . . . . . . . . . . . . . . . . . . . 2.4. TGF-a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. TGF-b . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. 9E3/CEF-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7. IL-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8. IL-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9. Other cytokine-like activities . . . . . . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

44 45 45 48 49 49 49 50 50 51

3.

Summary and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

1. Haemopoiesis during avian ontogeny Whilst the phenotypic and functional characterisation of avian stem/progenitor cells is not as advanced as in mammals, investigations into the ontogenic origins of stem cells has been resolved in the avian haemopoietic system and has provided a paradigm for delineating the homologous processes in mammals. Hence the current review will focus on avian haemopoietic cell development during ontogeny. 1.1. Yolksac The avian yolksac contains precursors for Tand B-lymphocyte, erythroid and myeloid cells [1±4]. Evidence suggesting that it was the initial

site of haemopoietic stem cell production was based on the observations of a number of groups who showed that: (a) the blood islands of the yolksac are the ®rst haemopoietic sites detectable in the avian embryo at the four somite stage of development (26±29 h) [5]; (b) in vitro colony formation of myeloid cells could be established using embryonic day 6 (E6) yolksac stem cells [6]; (c) E7 yolksac stem cells successfully reconstituted both lymphoid and myeloid systems in irradiated E14 recipients [1,3]. Similarly, murine E7 yolksac stem cells have been demonstrated to contain day 7±8 CFU-S stem cells [7] and can induce in vitro colony formation of myeloid cells, while E8 yolksac cells are able to reconstitute both lymphoid and myeloid haemopoietic compartments in irradiated recipients [8±9].

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

Furthermore, DJH rearrangements (a putative marker for chicken B-cell progenitors) ®rst appear in the yolksac between E5-6 of incubation [10]. This result supports earlier reports which demonstrated that B-lymphoid cell progenitors were present in both the avian and mammalian yolksac [1,3,8,11]. Inasmuch as the these observations suggested that the yolksac was the initial site of haemopoiesis, data presented by Martin et al. [12] indicated the contrary. Analysis of the haemo/ lymphopoietic reconstituting ability of E2 yolksac-derived HSCs revealed that this stem cell source was unable to reconstitute the haemopoietic system in sublethally irradiated recipients. Considering that the chicken circulatory system is not established until E2 of development [5], the haemopoietic stem cells present in the yolksac in the above mentioned experiments are most likely secondary immigrants originating intraembryonically [13]. Data arguing against this hypothesis, at least for T-cell development, was presented by Jotereau and Houssaint [14] who demonstrated that E2 quail yolksac stem cells were able to colonise an E6 chick thymus when transplanted together in the somatopleure of a 3 day chick host. The most logical explanation for this is that the surgical translocation of the thymus facilitated the uptake of haemopoietic stem cells which would otherwise not occur in the normal situation. 1.2. Intraembryonic sites Moore and Owen [1±3], utilising sex chromosomes as donor cell markers, demonstrated by vascular anastomosis or injecting haemopoietic cells from various embryonic sites into irradiated recipients, that stem cells are indeed blood borne upon colonisation of haemopoietic tissues. Histological studies have revealed that haemopoietic cells, identi®able as basophilic cells, and most probably devoted to the production of red blood cells (de®nitive series), appear in the E3 ventrolateral wall of the aorta and protrude into the lumen and into the mesentery. At E5, these cells become frequent but scattered in the dorsal mesentery. From E6 to E8, clusters of basophilic

39

cells greatly increase outside the aorta, forming the para-aortic foci and coincide before the ®rst wave a thymic colonisation and the beginning of bursal colonisation. By E9, intramesodermal haemopoiesis has almost ceased, although a few scattered pockets of haemopoietic foci can be found in the dorsal mesentery [15]. Stimulated E4 aortic wall-derived haemopoietic stem cells form in vitro haemopoietic colonies consisting of either macrophages, granulocytes, granulocytes/macrophages or erythroid burst forming units [16]. The importance of the aortic wall as a site of haemopoiesis was further demonstrated in experiments where cells from whole embryos, which were reassociated after removal of the aorta, and subsequently seeded in growth/di€erentiation inducing conditions, did not form in vitro colonies after stimulation, thus substantiating the role of the aorta and paraaortic regions in generating stem cells (reviewed in [17]). Furthermore, Lassila et al. [13,18] were able to demonstrate functional B- and T-cell activity in cyclophosphamide-treated and irradiated embryos transplanted with E7 intraembryonic mesenchymal cells. Arguably some of the most important data on stem cell origins and migrations stemmed from the use of heterospeci®c grafting of E1-2 quail embryo onto an age-match chick yolksac, taking advantage of the di€erent nuclear structure between chick and quail cells. These studies demonstrated that myelopoiesis in the BM and lymphopoiesis in the thymus and bursa were initiated by cells that originated intraembryonically [12,19]. This was subsequently con®rmed by Lassila et al. [4,20], utilising a similar experimental design but opting to transplant embryos of di€erent sex, and homospeci®c chick±chick chimaeras di€ering at the B-complex locus. Analysis of avian erythrocyte development has revealed primitive (embryonic) and de®nitive (adult) types. They di€er morphologically and by the types of haemoglobin they synthesise [21±22]. Utilising these di€erences, Beaupain et al. [22] demonstrated that yolksac stem cells provide the entire primitive series and contribute initially to the de®nitive series, which after E6, are derived from intrambryonic stem cells. This suggests that

40

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

primitive and de®nitive haemopoietic cells are derived from two distinct precursor populations, as also recently suggested by Nakano et al. [23]. By co-culturing murine embryonic stem cells on the M-CSF de®cient OP9 stromal cell line, they demonstrated, using limiting dilution, that primitive erythrocytes develop prior to de®nitive erythrocytes and from distinct di€erentiation pathways. The concept of an intraembryonic origin for stem cells is not restricted in the chicken. HSCs are present in mice from E7.5 in the para-aortic splanchnopleura (PAS) and aorta-gonad-mesonepheros (AGM) region [7,24±26]. The PAS region at E8.5 contains B-cell progenitors [26,27] and at E9, PAS/AGM cells harbour signi®cantly higher numbers of CFU-S in comparison to yolk-sac stem cells [25]. Similarly, the E10 AGM region is the initial intraembryonic source capable of repopulating both lymphoid and myeloid cell lineages, while age-match yolksac or liver transplants can not [7,25]. In humans, CD34+ haemopoietic precursor cells accumulate on the ventral wall of the aorta in 3 to 7 week foetuses which have the potential to generate high numbers of haemopoietic colonies in vitro when co-cultured with BM stroma [28]. In summary, the current body of evidence indicates that at early stages of development (E2±5), circulating haemopoietic cells are derived from the yolksac and are committed primarily to primitive erythropoiesis, while stem cells emerging from the embryo proper seed the de®nitive haemopoietic organ rudiments and subsequently become the dominant cell types. The apparently distinct fate of the di€erent precursors may not be so much cell autonomous, but rather a re¯ection of the haemopoietic cytokines expressed at di€erent locations. 1.3. Spleen Coincident with the decline in para-aortic haemopoiesis, the splenic mesenchymal rudiment is in®ltrated by a sinusoid network supplying stem cells of intraembryonic origin at around E8±10 which supports erythropoiesis up to E15 and granulopoiesis until 3±4 days post-hatching

[29,30]. Furthermore, erythropoietic stem cells from the yolksac have also been found to transiently colonise the spleen at E11±12 [31]. The ®rst T-cells can be identi®ed at approximately E16, while B-cells are present by E12 [32]. Embryonic spleen progenitors capable of colony formation in vitro, can be detected by E9 [6], and can form in vivo colonies on the chorioallantoic membrane by E11 [33] (in vivo colony formation on the chorioallantoic membrane has been described as an assay for stem cells in the chicken that is comparable to the CFU-S spleen cell assay of Till and McCulloch [34]). Both assays types determined peak splenic haemopoietic activity as occurring between E15±17/18 with granulocyte-CFC, macrophage-CFC, granulocyte-macrophage-CFC and ®broblast-CFC all being present [35]. Reynaud et al. [10] monitored the development of B-cells analysing the rearrangement events of their V, D and J genes during embryogenesis in a number of tissues including the embryonic spleen. Initially, heavy chain immunoglobulin DJH rearrangements in the embryonic spleen was demonstrated at E6±7 with the second wave of rearrangement (VHDJH, VlJl ) appearing at E8± 9. Despite a peak accumulation 6±7 days after the appearance of the ®rst VlJl/VHDJH-positive cell, no B-cell proliferation or selection for inframe sequences occurred, suggesting that the embryonic spleen is not a site that supports the further di€erentiation of precursor B-cells, a function that is ful®lled by the bursa. This conclusion is supported by the lack of B-cell reconstituting capability of embryonic spleen cells in embryos or newly hatched chicks rendered immunode®cient by cyclophosphamide treatment [36,37]. Although the phenotype of these cells was not de®ned, Houssaint et al. [38] showed that the Bu-1 antigen is a marker which de®nes B-cell precursors with pre-bursal stem cell activity. GoÈbel et al. [39] identi®ed NK-cells that are detectable in E8 spleen reaching peak numbers by E14. They express cytoplasmic CD3 and, while expressing surface CD8, CD45, HNK-1 and receptors for IgG, they do not express surface CD3/T-cell receptor complex (designated

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

41

TCR0 cells). Although surface T-cell receptor expression clearly di€erentiates T-cells from NKcells, the presence of the CD3 complex, responsiveness to IL-2 and cytotoxic capabilities, suggests a common T/NK precursor. Although the embryonic spleen has been hypothesised as a site for stem cells ampli®cation in transit from the para-aortic regions to the BM [35] and is initially committed to erythro/myelopoiesis, its function is altered post-hatching, where it becomes a secondary lymphoid organ. The switch from haemopoietic to lymphoid function in the embryo most likely depends on the nature of colonising cells as well as a change in the stromal architecture as shown by the development of specialised vascular-associated regions appearing between E15±18 [30]. This phenomenon could also be associated with the di€erential expression of cytokines.

contain higher frequencies of primitive haemopoietic progenitors than does adult BM [41].

1.4. Blood

Ontogenically, the bursa of Fabricius is ®rst observed as an outgrowth of the urodeal membrane at about E4, with the bursal epithelial anlage subsequently developing and forming a hollow, sac-like structure (reviewed in [46]). Chimaeric studies have demonstrated that, unlike the thymus which is seeded by 3 successive waves of precursors (reviewed in [47]), the bursa is colonised by blood borne extra-bursal stem cells [3] during a single distinct receptive period in embryonic development between E8±14 [48]. The nature of stem cells that give rise to B-cells has been investigated by cell transfer studies or reconstitution of bursal organs from chemically bursectomized embryonic/neonatal chicks with stem cells from various organs during ontogeny. On the basis of these assays, three categories of precursor B-cells have been identi®ed.

Evidence for blood-derived precursors initially came from Moore and Owen [3] who demonstrated that E13 blood could colonise thymic, BM and bursal rudiments in E14 irradiated chick embryo hosts. A similar ®nding was demonstrated by Samarut and Nigon [40] who transplanted embryonic blood from various ages into irradiated hosts and scored the number of initiating colonies present in the recipient marrow (CFU-M). They demonstrated that E6 blood contained approximately three times the number of CFU-M in comparison to the yolksac, which expanded exponentially with a doubling time of 20 h reaching peak levels (8000 CFU-M) by E13. Additional studies by Reynaud et al. [10] demonstrated that precursor B-cells initially appear by E10 and represent 0.5±1% of total blood cells, with their numbers and proportions increasing by E13 (proportions [1±2%] and absolute numbers [2.5  105ÿ5  105]), and subsiding thereafter. Hence embryonic blood appears to be a very rich source of progenitors, which most likely expand before seeding their microenvironmental niches (reviewed in [17]). Similarly, mammalian umbilical cord blood has been demonstrated to

1.5. Liver The mammalian fetal liver is the primary site of haemopoiesis before birth (reviewed in [42]). This was determined by in vitro cultures of E9 liver which demonstrated multi-lineage progenitors for erythroid and myeloid cell lineages [8]. Furthermore, the fetal liver contains precursors for both T- and B-cell lineages [43,44]. In contrast, the avian liver plays only a minor role in maintaining haemopoiesis in the embryo. It is involved solely with erythropoiesis by E7 and eosinophilic granulopoiesis by E9±10. Haemopoietic activity peaks by E14 and subsequently diminishes by hatching [45]. 1.6. Bursa

1.7. Pre-bursal stem cells Pre-bursal stem cells ®rst appear in the E7 yolksac and intraembryonic mesenchyme [3,13]. Later, they are found in E14 spleen [38], blood [49], E16±18 BM [3,50] and E16 yolksac [49]. Le Douarin and Jotereau [51] hypothesised that a chemoattractant secreted by bursal stromal cells

42

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

was responsible for the seeding of stem cells to the bursa, the secretion of which may be regulated by the degree of precursor input. Cell surface expression of Bu-1 and IgM has been demonstrated on pre-bursal stem cells [38,46]. While all B-cell precursors in the E14 spleen express the Bu-1 antigen, the function for this antigen has not been deciphered [38,52], however, IgM appears to be involved in stem cell seeding of the bursa as antibodies (Ab) speci®c for IgM prevents E16 BM cells from reconstituting the Bcell compartment of cyclophosphamide-treated chicks [53,54]. 1.8. Bursal stem cells Bursal stem cells have an absolute requirement for the bursal microenvironment in order to fully di€erentiate [36,37,55,56]. They are immunologically incompetent and are detectable from late in embryonic development until 4±6 weeks posthatching. 1.9. Post-bursal stem cells Post-bursal stem cells are the major cell type in the bursa and BM, and are detected ten weeks post-hatching. Their characteristic feature is their inability to colonise the bursae of cyclophosphamide-treated recipients, however, they are able to provide humoral immunity as judged by Ab responses to sheep red blood cells and Brucella abortis [56,57]. Whilst it is generally accepted that these three categories of precursor B-cells exist, there are inconsistencies in the data between various models. For example, Eskola and Toivanen [36], and Toivanen et al. [37] demonstrated that reconstitution of functional B-cells in E18 cyclophosphamide-treated embryos results following E18 bursal cell transplants but not with E15 or E18 BM or yolksac cells derived from various stages of development. In contrast, Moore and Owen [3] demonstrated that donor E16±18 BM and E7 yolksac cells contributed to the cellular make-up of irradiated recipient E14 bursae, whilst Weber and Mausner [50] demonstrated that functional reconstitution of both T- and B-cell lineages

occurs upon transfer of E14 BM into irradiated E14 hosts. The possible reasons for these discrepancies could be due to the inherent nature of the irradiation treatment. Studies on the sensitivity of precursors to cytotoxic agents such as gamma rays have demonstrated that there are radioresistant precursors in both the thymus [58] and the BM [59]. Hence radioresistant precursors could contribute to the reconstitution of functional B-cells while such precursors are eradicated following cyclophosphamide treatment. Furthermore, cyclophosphamide could damage the stromal compartment, thus preventing the support of B-cell development, whereas irradiation primarily a€ects dividing cells. Alternatively, the lack of reconstituting capability of BM and yolksac in the cyclophosphamide model might re¯ect the importance of the compatibility (age and MHC) between the transferred stem cell and its new microenvironment. Although principally dedicated to the generation of functional B-cells, the embryonic bursa also serves as a site for granulopoiesis. Granulocyte development is observed within the mesenchymal shaft of the plicae with the ®rst granuloblasts being observed by E11, which peak by E12±13 and subsequently disappear around the time of hatching (reviewed in [60]). Whether the bursa is colonised by a single bipotential precursor, or by two precursor subsets is unknown. It could be hypothesised that precursors that are retained in the mesenchyme di€erentiate to granulocytes, while those that are in close contact with epithelial cells di€erentiate into lymphocytes. Identi®cation and phenotypic characterisation of a bi-potential B-cell/macrophage pre-bursal stem cell, has been substantiated. Using the allotypic marker Bu-1, Houssaint et al. (38) demonstrated that sorted Bu-1a+ cells derived from E14 spleen could functionally reconstitute both macrophage and B-cell compartments in irradiated Bu-1b congenic embryonic hosts. These precursor cells may also potentially contribute to the bursal microenvironment as dendritic/macrophages. These latter cell types are responsible for the formation of the epithelial buds, which assist in creating the necessary microenvironment for

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

B-cell development [48,61]. Precursors with Blymphoid/myeloid-cell potentialities have also been reported in a number of mammalian models [62±70]. 1.10. Thymus Using the chick/quail chimaeric model and in cell transfer experiments, thymocyte precursors have been identi®ed in the E3 aorta, E7 intraembryonic mesenchyme [13,47,60] and later in the yolksac [49], spleen [38,52] and BM [50]. The earliest de®ned T-cell precursor in the murine thymus is distinguished by low levels of CD4 and expression of Sca-2/TSA-1 (CD4low precursors) [71]. They also generate peripheral B-cells and thymic dendritic cells, but not all of the myeloid or erythroid cell lineages [71,72]. In contrast to the mouse, chicken precursor cells rapidly commit exclusively to the T-cell lineage after thymic entry as no reconstitution of donor type B-cells, T-cells or BM cells have been reported with donor embryonic thymocytes [3,37]. Similarly, Houssaint et al. [52], demonstrated that T-cell precursors present in E14 spleen do not possess B-cell potential, suggesting that lymphoid precursors segregate early in embryogenesis. This is probably also the case for E14 BM where, both T- and B-cell precursors are present, however by E16±17, B-cell precursors progressively diminish in number and are no longer present by two days after hatching [50]. 1.11. BM The avian BM, like its mammalian counterpart, is the primary site of haemopoiesis in the post-hatch period. Haemopoietic precursors of extrinsic origin [1,3] begin seeding the BM rudiment at around E10 [73]. By E12 the marrow contains cells of multiple haemopoietic cell lineages, and is distinguished from adult marrow by having fewer cells and comparatively more blasts. Recently two phenotypically distinct BM-derived stem cells have been identi®ed. BEN+ myeloid precursors give rise to macrophage, granulocyte, thrombocyte and erythrocyte colo-

43

nies and have been identi®ed in E15±18 BM [74]. Vainio et al. [75] showed that E13.5 HEMCAM+ Bm cells which co-express c-kit produce in vitro myeloid and erythroid colonies and reconstitute T-cells in irradiated congenic hosts. Although not as clearly de®ned as in the mammalian system, restricted precursors for lymphoid cells have been tentatively identi®ed in chick BM [3,50,56,76,77]. Interestingly, in both embryonic and posthatch periods, specialised haemopoietic niches have been demonstrated to develop in the BM, which in turn, compartmentalise erythropoiesis, granulopoiesis and lymphopoiesis (reviewed in [78]). This suggests that discrete microenvironments have been created either by local secretion of growth factors that interact within a speci®ed cell lineage and/or the expression of speci®c stromal cell molecules. The latter may function by either capturing precursors and presenting them to the pool of cytokines or by directly orchestrating the development of incoming precursors. In contrast to which adult BM-derived stem cells give rise to precursors, and precursors generate the various di€erentiated cell types, in the mammalian embryo, di€erentiated cells appear in the mouse yolksac at E7.5 while the ®rst colony forming cell at E8 and CFU-S at day 9. This sequential pattern of di€erentiation is identical in the liver but occurs at a later point in ontogeny [8]. These observations indicate that embryonic haemopoietic stem cells are intrinsically programmed to generate large numbers of di€erentiated cells, then committed precursors, and ®nally transplantable stem cells [7]. Alternatively, speci®c microenvironmental niches that direct the di€erentiation of the various haemopoietic pools may also di€er in their developmental sequence. In synopsis, the capacity to generate a functional haemopoietic system is reliant on a small population of stem cells that vary in their origin (Fig. 1). Although a functional stromal microenvironment is paramount in the development of stem cells to mature cells, questions regarding the continuous shift in haemopoietic sites during ontogeny are still unanswered. What are the factors associated with this phenomenon? Why do precursors localise to certain organs? Is there a

44

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

Fig. 1. Schematic representation of the sequence of haemopoiesis in the developing chicken embryo. The relative levels of activities in the yolksac, spleen, and liver are given with haemopoietic activity indicated by the degree of tinting (white=high; black=none). The presence of di€erent types of cells produced de novo are indicated. The yolksac is the main erythropoietic organ (primary series) during development. Haemopoietic activity in the embryo proper occurs initially in the intra-aortic clusters, then in the para-aortic foci which are an irregular group of cells that occupy the whole dorsal mesentery. The entry of extrinsic progenitors in the thymus is cyclical, with periods of receptivity and non-receptivity, whilst a single receptive colonisation period exists for the bursa of Fabricius. The spleen receives the ®rst incoming HSC as early as E4, and carries out transient erythropoietic and granulopoietic functions before becoming a secondary lymphoid organ at the time of hatch. Unlike the mammalian liver, the chicken liver plays a minor role in haemopoiesis, with erythrocytes and myeloid cells predominating. The bone marrow is the last haemopoietic organ to develop and become colonised (adapted from Dieterlen-LieÂvre, 1993 [17]).

correlation with the cell surface expression of adhesion molecules and cytokine receptors in di€erentiating stem cells and stromal cells? How does this e€ect the migration of mature cells out of the primary haemopoietic organ and into the circulation? What factors in¯uence the commitment of stem cells into lineage speci®c cells? Are these factors intrinsically programmed within stem cells, or are they derived from the microenvironment? Future studies addressing the expression of adhesion molecules, transcription factors and

cytokines that are known at present to be associated in the growth and di€erentiation of haemopoietic cells should provide insight to these issues. 2. Chicken cytokines Comparative analysis of cytokines between mammalian and avian species has indicated some striking similarities, with some avian cytokines

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

demonstrating more primordial forms. However, unlike the large number of cloned and fully characterised mammalian haemopoietic cytokines, which exceed 20 in number, far fewer avian cytokines have been described, which have been characterised primarily on functional activities of culture supernatants (refer to Table 1) with only eight characterised at the nucleotide level (refer to Table 2). 2.1. Chicken myelomonocytic growth factor (cMGF) cMGF is a glycoprotein which induces the in vitro proliferation and di€erentiation of granulocytes and macrophages from normal chick BM and myeloblasts transformed by the myb containing retroviruses E26 and AMV [79]. cMGF activity was originally identi®ed in the culture supernatants of ConA activated spleen cells (Con A SCM) which could replace the feeder cell requirements of chicken transformed myeloblasts or macrophages [80]. Subsequent identi®cation of cMGF-like activities in serum free CM derived from LPS stimulation of the HD11 macrophage cell line greatly facilitated its puri®cation. Puri®cation by sequential chromatography of concentrated HD11 CM revealed that cMGF is a remarkably stable 27 kDa single chain protein, withstanding treatments such as heat, organic solvents or SDS [79]. In its native state, cMGF exists as a glycosylated protein of 23 to 200 kDa [81]. Despite its heterogeneity in size, Ab raised against puri®ed 27 kDa cMGF abrogates the activity of puri®ed cMGF as well as Con A-SCM or LPS-treated HD11 cells. cMGF is encoded by a single copy gene and nucleotide and amino acid sequence analysis indicates that it shares homology to both murine and human interleukin (IL)-6 and granulocyte-colony stimulating factor (G-CSF). The positions of cysteine and leucine residues are highly conserved [82], all three factors having the same number of exons, similar exon size and encode proteins of similar molecular weight. Despite its sequence homology to G-CSF and IL-6, cMGF manifests activities more closely related to GM-CSF and M-CSF as determined by

45

in vivo [83,84] and in vitro studies [79]. Evidence that the mammalian equivalent of cMGF exists was provided by the observation that cMGF speci®c probes reveal bands in both murine and human DNA which do not correspond to bands detected by G-CSF and IL-6 probes [82]. The receptor for cMGF has been identi®ed as a 120 kDa cell surface protein detected on myeloblasts, but not on erythroblasts or lymphoid cells (cited in [79] as unpublished results). Binding kinetic analysis revealed the presence of 60±100 cMGF receptors per cell, a ®gure which is comparable to that for the murine G-CSF, granulocyte/macrophage-colony stimulating factor (GMCSF) and IL-3 receptors [85]. Cytokine signalling via this receptor employs the STAT 5 transcription factor [86], hence this receptor type is likely to be homologous to both mammalian class I cytokine receptors or receptor tyrosine kinases as both activate STAT 5 in myelomonocytic cells [87±89]. 2.2. Interferon (IFN) IFN activity was ®rst described in the chick by Isaacs and Lindenmann [90]. More recently, the chicken homologues to type I (IFN-a/b ) and type II (IFN-g ) have been cloned [91,92]. As in the mammal, chicken interferons have been categorised by virtue of their synthesis in response to viral challenge or stimulation with plant lectins (reviewed in [93]). Type I interferons (ChIFN I), of which there are four (IFN-a, b, o, t), are produced by virally infected chick embryo cells and lymphocytes [94,95], whilst type II interferon, which is solely represented by IFN-g, (ChIFN-g) is produced by lectin- or parasite-stimulated lymphocytes [96±98]. Biochemical analysis of semipuri®ed chick interferon demonstrated that this molecule is heterogeneous in molecular weight, ranging from 17 to 36 kDa [99±102], which is comparable to human IFN-g [103]. The gene for ChIFN I has been cloned and the cDNA expressed in both E. coli and COS cells [91,104,105]. The open reading frame codes for a mature protein of 162 amino acids with a predicted molecular weight of approximately 19 kDa. The ChIFN I gene shares

HD11 cells serum Anaemic serum Macrophage Splenocytes PBL, spleen rHuman Macrophage Fibroblast rHuman Fibroblasts Fibroblasts rHuman Lymphocyte Spleen Spleen rHuman Brain, bursa, heart, kidney, ovary, spleen, thymus and testis Mammalian Fibroblasts rHuman Macrophage Macrophage Macrophage Neurons Thymus Thymus

CSF

EPO189 IL-1

BM T-cells

Fibroblasts RP9 adipocytes mL929

Maturation Maturation

Cytolysis Inhibited LPL Increased cytolysis

Chemotaxis Inhibit migration Antiviral Antiviral Mitogen Proliferation and di€erentiation Self renewal of stem cells Mitogen

Heterophils PBL Spleen Embryo Fibroblasts Haemopoietic, melanogenic and neural progenitors Erythroid progenitors

Lymphocyte Intestine Hepatocyte Hepatocyte Hepatocyte Heterophils

Increased in colony formation Increased in colony formation Proliferation and di€erentiation Co-mitogen Increased cortisone synthesis Mitogen Anion secretion Increased ®brinogen synthesis Increased ®bronectin synthesis Increased ®brinogen synthesis Chemotaxis

Activity

Myeloblasts BM Erythroid progenitors Thymocyte

Target (chicken)

Abbreviations: CSF: colony stimulating factor; h: human; IL: interleukin; IFN: interferon; LPL: lipoprotein lipase; m: mouse; MIF: migration inhibitory factor; PBL: peripheral blood lymphocyte; PDGF: platelet derived growth factor; r: recombinant; SCF: stem cell factor; TGF: transforming growth factor; TH: thymic hormone; TNF: tumor necrosis factor. b Unless otherwise indicated source cells are of chicken origin.

a

TH Thymulin

TNF-a

PDGF SCF TGF-a114 TGF-b

MIF IFN

IL-8

IL-2 IL-3 IL-6

Sourceb

Cytokinea

Table 1 Avian haemopoietic cytokines that have mammalian equivalents based on bioactivity (adapted from Klasing, [194])

46 C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

15±16 tripeptide 24±28

267 amino acids 121 amino acids 25±40 11 19

16.8 29±52 15±29 69 amino acids 287 amino acids 112 amino acids 9 amino acids

ATH Bursin cMGF

IL-1b

IL-2

IL-6 IL-8 ChIFN-a/b (Type I)

ChIFN-g (Type II)

MIF

MIP-1b

SCF TGF-b3 Thymulin

YES YES ND

YES

ND

YES

ND YES YES

YES

YES

ND ND YES

cDNA cloned

with with with with

hIL-6 hG-CSF mIL-6 mG-CSF

ND 79% with hTGF-b2 ND

75±85% h+mMIP-1b

No signi®cant homologies with mammalian IL-2 ND 51% with hIL-8 23% with maIFN-a 24% with maIFN-b 43% with maIFN-o 43% with maIFN-t 31% with maIFN-g ND ND ND

ND ND 41% 56% 37% 54% ND

Nucleotide sequence homology with mammalian cytokines

0100% with hThymulin

Chemokine characteristic amino acids are conserved 52% with hSCF, 53% with mSCF

24% with maIFN-a 20% with maIFN-b 23% with maIFN-o 20% with maIFN-t 3% with maIFN-g 35% with eqIFN-g 32% with hIFN-g

080% with ha-parvalbumin ND 41% with hIL-6 56% with hG-CSF 39% with mIL-6 52% with mG-CSF 25% with hIL-b, 30% with hIL-1Ra, 13% with hIL-1a 46 and 44% amino acid similarity to both bovine IL-15 and IL-2

Amino acid sequence homology with mammalian cytokines

110 131 199

195

169

92

172, 198 142 91

161

149

196 197 79, 81±82

Reference

Abbreviations: ATH: avian thymic hormone; Ch: Chicken; cMGF: chicken myelomonocytic growth factor; CSF: colony stimulating factor; eq: equine; G: granulocyte; h: human; IFN: interferon; IL: interleukin; m: mouse; ma: mammalian; MIF: migration inhibitory factor; ND: not determined; Ra: receptor antagonist; SCF: stem cell factor; TGF: transforming growth factor; TNF: tumor necrosis factor.

a

Molecular weight (kDa)

Cytokinea

Table 2 Chicken cytokines characterised at the protein and nucleotide levels (adapted from Klasing [194]) C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59 47

48

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

homologies with mammalian type I IFN genes [91]. The functional spectrum of ChIFN I also resembles that of mammalian type I IFN. For example, ChIFN I protects cells against viral cytolysis [105], but has a reduced speci®c activity to induce nitric oxide from stimulated macrophages when compared to ChIFN-g [106,107]. The gene for ChIFN-g has also been cloned and functionally expressed in COS cells, chicken CEC-®broblast cell lines, Spodoptera frugiperda (SF9) insect cells and in E. coli [92,106,108,109]. Like mammalian IFN-g, the ChIFN-g gene product is sensitive to heat and low pH and induces nitrate production by chicken macrophages. The ChIFN-g gene encodes for a mature protein of 145 amino acids with a molecular mass of 16.8 kDa. Modi®cation of the protein core by the addition of sugar moieties is possible as two potential N-glycosylation sites have been identi®ed [92], and is probably the reason for the increase in molecular weight (26±27 and 22± 23 kDa) when ChIFN-g was derived from COS cells and SF9 insect cells respectively [108,109]. The amino acid sequence homology of ChIFN-g exhibits 35 and 32% identity with equine and human IFN-g respectively, and is 15% homologous to ChIFN I [92]. Functionally, ChIFN-g shares a number of characteristics with its mammalian counterpart, such as an increase in MHC class I and II expression on macrophages, and anti-viral protection of ®broblasts against virusmediated lysis [84,108]. Furthermore, in vitro studies demonstrate that CHCC-OU2 chicken cells, which are prone to Eimeria tenella infection, showed signi®cant reductions in intracellular sporozoite development when treated with ChIFN-g. In vivo experiments demonstrated that animals developed an enhanced resistance to Eimeria acervulina challenge when pre-treated with ChIFN-g [109]. Furthermore an increase in body weight gain followed disease challenge [84,109], and an improved humoral immune response developed against sheep red blood cells [84]. These results provide a solid foundation for the development of ChIFN-g as a vaccine and/or adjuvant against infection.

2.3. Stem cell factor (SCF) Chicken SCF, is 287 amino acid polypeptide and was cloned from a chicken brain cDNA library [110]. The protein shares 53 and 52% sequence homology to murine [111] and human [112] SCF respectively. All four cysteine residues in the extracellular portion of mammalian SCF are also conserved in chicken SCF, indicating the tertiary conformation of the molecule has been conserved between species. Northern hybridisation studies demonstrate that SCF is present in a wide variety of tissues including, brain, bursa, heart, kidney, spleen, thymus, ovary and testis [110]. Chicken SCF has been produced in recombinant form in bacteria [113] and shares many properties with its mammalian counterpart. It is involved in the proliferation of normal haemopoietic cells [114±116], proliferation and di€erentiation of neural crest-derived melanocytes [117] di€erentiation and functional activation of osteoclasts [118] and survival of dorsal root ganglia neurons in vitro [119]. Because of its mitogenic ability, SCF has been implicated in the transformation of haemopoietic progenitors infected with the v-ski oncogene [115]. Transient self-renewing progenitors expressing c±kit (the receptor for SCF) [120], which represent approximately 1:300±500 BM cells, [116] have been demonstrated to be maintained only by SCF. Nevertheless these precursors have been demonstrated to undergo a process of programmed cell death. Long-term maintenance of c-kit bearing precursors has been achieved using a combination of cytokines, namely, SCF, transforming growth factor-a (TGF-a), estradiol and chick serum. This cocktail of growth factors was found to upregulate the TGF-a tyrosine kinase receptor (TGF-aR) on c-kit positive progenitors which in turn induced the long-term self-renewal phenotype [114,116]. Based on these observations it has been postulated that SCF suppresses apoptosis until TGF-aR cell surface expression is at the level required to maintain self-renewal [116]. This hypothesis is consistent with the anti-apoptotic/survival properties of mammalian SCF (reviewed in [121]).

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

2.4. TGF-a TGF-a is a polypeptide growth factor structurally related to epidermal growth factor (EGF). Although the EGF receptor is recognised on a wide variety of normal and neoplastic cells [122], it has only recently been demonstrated to be present on mammalian haemopoietic cells [123]. A mutated form of this growth factor receptor was ®rst recognised in the v-erbB oncogene of the avian erythroblastosis (AEV) retrovirus [124]. The c-erbB protooncogene which recognises TGF-a as a ligand, encodes for a membrane tyrosine kinase receptor present on normal chicken progenitors [125]. The mutated form lacks the ligand binding domain, thus generating constitutive tyrosine kinase activity and uncontrolled mitogenic stimulation of cells [124,126]. Initially identi®ed as inducing the proliferation of erythrocytic progenitors in a dose-dependent fashion [125], mammalian TGF-a was found to act in synergy with estradiol to induce a supraadditive proliferative response in BM cells [127]. Although erythroid progenitors can be maintained with combinations of SCF, estradiol, TGF-a and chick serum, the expression of the TGF-aR/c-erbB enables sustained self-renewal [114,116] as opposed to cells that express other tyrosine kinases (e.g. c-kit ) which do not maintain long-term self-renewal [116]. The reasons for this are unclear, although it may be related to a quantitative di€erence in the type of signal emitted from the two receptors. Alternatively, ckit and TGF-aR/c-erbB may transduce signals using two di€erent pathways, with the activated TGFaR/c-erbB pathway leading to gene expression essential for long-term self-renewal [116]. 2.5. TGF-b TGF-b is a multifunctional molecule which regulates both proliferation and di€erentiation [128]. The prototypical structure of all TGF-b molecules, which number ®ve in total, is of a 390 amino-acid precursor molecule corresponding to the monomeric form [129]. After post-translational modi®cations, the mature protein exists as

49

a homodimer with a molecular weight of 25 kDa, although heterodimers have also been identi®ed [130]. Of the ®ve TGF-b molecules described to date, avian homologues to TGF-b2±4 isoforms have been cloned and their functions in avian development investigated. These functions include cellular di€erentiation, wound repair, bone metabolism and growth [131±135]. It has been demonstrated by two independent studies that the avian homologue to mammalian homologue TGF-b1 does not exist [135,136]. Although mammalian TGF-b has been shown to have haemopoietic modulatory activities [137], these have not yet been described in the chicken. 2.6. 9E3/CEF-4 The chicken growth factor 9E3/CEF-4 is a small inducible cytokine (11 kDa) that is homologous to human connective tissue activating peptide III, b-thromboglobulin platelet factor 4, IL-8 and gro a [138±140]. 9E3/CEF-4 was initially characterised in transformed chick embryonic ®broblasts (CEF) transformed by Rous sarcoma virus (RSV) [138]. Although constitutively expressed by non-transformed CEF, 9E3/CEF-4 expression is increased in cells transformed by a variety of oncogenes, however the level of expression di€ers among transformed cells with maximal expression appearing in cells transformed with v-src, v-yes and v-fps [141]. Along with CEF, stimulated and non-stimulated peripheral blood monocytes express this protein [142]. Its high amino acid sequence homology to human IL-8 (51%) is suggestive that this molecule acts as a chemotactic factor. This assumption is supported by functional data that demonstrate that 9E3/CEF-4 is chemotactic for chicken peripheral blood monocytes, heterophils and transformed and nontransformed CEF and is mitogenic for CEF [142]. Although human IL-8 is chemotactic for granulocytes [143], it nevertheless is not chemotactic for monocytes as is 9E3/CEF-4. Because of its broader spectrum of target cells, it could be hypothesised that 9E3/CEF-4 represents an archetypal version of mammalian IL-8. Biochemical characterisation of this molecule

50

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

has shown that it is synthesised and secreted rapidly (<10 min) as a 9 kDa precursor, and is further processed to 6±7 kDa by plasmin. Furthermore, the smaller form binds to interstitial collagen, laminin and proteoglycan, but not to collagen IV or ®bronectin. These interactions with ECM molecules suggest that 9E3/CEF-4 is presented in the context of the ECM to receptor bearing cells in the lumen (140). It is hypothesised that this type of interaction acts to tether receptor bearing cells at the site of the cytokine, or, the ECM molecule(s) are protecting the factor from degradation. 2.7. IL-1 Initially identi®ed in adherent spleen cell cultures stimulated with LPS [144], IL-1 production has since been reported in wide variety of stimulated tissue macrophages isolated from peripheral blood, peritoneum, spleen and by the macrophage cell line HD11 [145]. Chicken IL-1-like activity puri®ed from the sera of LPS-stimulated birds has been demonstrated to have a molecular weight of 30 kDa [146], while chromatographic separation of CM derived from a transformed macrophage cell line revealed two peaks with lymphocyte co-activating activity [147]. Injection of sheep red blood cells (SRBC) in conjunction with CM containing IL-1 activity, was reported to increase the titre of circulating anti-SRBC Ab, suggesting a role for IL1 in the humoral immune response [146]. In the context of mediating an in¯ammatory response, chicken IL-1 appears to function like its mammalian counterpart. Studies have shown that the in vivo levels of IL-1 increase upon administration of LPS [148], while the in vitro culture of macrophages secreting IL-1 is enhanced by increasing incubation temperatures from 398C to 428C [145]. Furthermore, chicken IL-1 has been shown to induce fever [148]. Chicken IL-1 appears to act cross-species as it co-stimulates with lectins to induce mouse thymocyte proliferation [145] while stimulating murine LM cells to be cytotoxic [147]. Recently the gene for chicken IL-1b has been cloned using COS cell expression cloning [149].

The isolated cDNA gene codes for a 267 amino acid protein which shares 25, 30 and 13% identity to human IL-b, IL-1 receptor agonist (Ra) and IL-1a, respectively. Northern blot analysis indicated that the gene is quickly induced (within one hour) in LPS-treated blood monocytes. Functionally, chicken IL-1b shares many biological characteristics of its mammalian counterpart including its ability to increase corticosterone levels, when introduced in vivo, and to induce RNA transcription of the CXC cytokine, K60, from CEC 32 ®broblasts. A cDNA clone for the chicken IL-1 receptor has been isolated, of which the predicted amino acid sequence shares 60% homology with the human counterpart [150]. 2.8. IL-2 Chicken IL-2-like activity has been identi®ed in a number of culture supernatants derived from either lectin-stimulated spleen or peripheral blood lymphocytes [151,152]. Although functional Th1 and Th2 subsets [153] have not been demonstrated in the chicken, Schauenstein and Hayari [154] demonstrated that higher IL-2 production was attributable to stimulated splenic lymphocytes which bound peanut agglutinin (PNA) in comparison to cells that did not bind. Such discrimination may de®ne functional T-cell subsets. Production and assay of chicken IL-2 has been investigated extensively [93,155], which initially led to partial physicochemical characterisation of this molecule. KroÈmer et al. [155] demonstrated that chicken IL-2 in CM has a much lower half life (10 h) in comparison to murine IL-2 (53 h). There has been some dispute as to the molecular weight of IL-2 with Vainio et al. [156] and Schnetzler et al. [152] reporting 13 kDa, Fredericksen and Sharma [101] reported a molecular weight of 30 kDa and Myers et al. [157] reported an apparent molecular weight of 17.5 kDa. Reasons for these discrepancies could be due to IL-2 forming homodimers or aggregates with other proteins [101] or di€erential glycosylation. Although quanti®cation of IL-2 has relied primarily on the culture of IL-2-dependent short-

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

term blasts, equivalents of the murine CTL L/2 IL-2-dependent cell line [158] has been developed in the chicken [156,159,160]. Chicken IL-2 has recently been cloned using COS cell expression cloning [161]. Cloned chicken IL-2 gene encodes a mature protein of 121 amino acids of which there is 46 and 44% amino acid sequence similarity to bovine IL-15 and IL-2 respectively, however homologous sequences only account for 25% between mammalian factors. Although the DNA sequence revealed no signi®cant nucleotide homology between mammalian IL-2 and IL-15, similarities between chicken IL-2 and mammalian IL-2 and IL-15 include their expression by activated T-cells, mRNAs have a short 5 ' region preceding its open reading frame, short leader sequence, and four conserved cysteine residues which is commonly shared with IL-15 [161]. Although the genomic organisations and amino acid sequence homologies di€er considerably between mammalian IL-2 and IL-15 [162,163] both factors utilise common b and g chains when transducing their actions in Tand NK-cells [164]. This fact, coupled with the distant homology with chicken IL-2, suggest that the chicken gene is ancestral to both mammalian IL-2 and IL-15 genes, having duplicated and mutated before the separation of birds and mammals [161]. Evidence for an IL-2 receptor was demonstrated using the monoclonal antibody (mAb) INN-CH16 [165,166] which identi®es an epitope of 48±50 kDa present on stimulated T-cells. This mAb competitively inhibited IL-2-dependent proliferation of stimulated lymphocytes, and dramatically reduced the proliferative capacity of pretreated lymphoblasts. Similarly, Lee and Tempelis [167] have characterised the reactivity of the mAb E12 which also inhibits IL-2-dependent proliferation of lymphoblasts. However, immunoprecipitation and electrophoretic analysis of the antigen recognised by this mAb identi®ed a 110 kDa protein. Based on a similar molecular weight to mouse and human IL-2 receptor g chain, and the functional ability of the mAb to prevent lymphoblast proliferation, Lee and

51

Tempelis [167] postulate that the mAb E12 recognises the homologue of the IL-2 receptor g chain. 2.9. Other cytokine-like activities Although relatively few chicken cytokines have been characterised at the molecular level, several reports of growth factor activities in cell CM exist. Sensitised T- and B-cells derived from chickens immunised with Mycobacterium tuberculosis secrete lymphokines ranging in molecular weight from 10±50 kDa which mediate both inhibitory and chemotactic activities and inhibitory factors respectively [168,169]. Macrophages have been shown to be essential for the secretion of these factors by T-cells although the underlying mechanism for this is unknown [170]. A similar macrophage requirement for the secretion of mammalian macrophage inhibitory factor has been reported by Landolfo et al. [171]. Ascites ¯uid from chickens has been identi®ed as a source of TGF-b and IL-6. By the addition of mAb speci®c for human TGF-b or IL-6, Rath et al. [172] were able to block TGF-b and IL-6 activity respectively in TGF-b and IL-6 speci®c assays. It was also demonstrated that the molecular weight of IL-6 following size exclusion high pressure liquid chromatography of ascites ¯uid, was 35 kDa. With the exception of cMGF, no other CSFlike avian growth factor has been characterised at the nucleotide level. However, CSF-like activities in¯uencing granulocyte and macrophage development have been reported to be secreted from a number of sources, including ®broblasts [16,173±175] macrophages [175±177] and epithelium [178]. Furthermore, colony stimulating and inhibiting activities have been detected in both normal and leukemic sera [179±184]. Macrophages have also demonstrated the ability to secrete a factor with TNF-a-like activity which has been attributed in causing the pathological manifestations of coccidial infection [185±187]. Activities from CM derived from the chicken liver cell line LMH, or co-culture on chicken embryonic ®broblasts, have been shown to maintain mouse embryonic stem cells in an undi€eren-

52

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

tiated state. These ®ndings suggest an avian homologue to mammalian LIF exist in these sources [188]. Additionally, activities corresponding to erythropoietin have been described in the sera from anaemic chickens [189]. 3. Summary and future perspectives Apart from its suitability for studying lymphoid development due to discrete T- and B-cell organs, and, accessibility during embryonic development, the chicken provides an ideal model system to study haemopoietic cell migration and to de®ne the regulatory elements involved in the self-renewal and di€erentiation of haemopoietic cells [190,191]. From a commercial perspective, chickens are important because they provide a vital food source. Surprisingly, little research has been directed to the elucidation of cytokines regulating haemopoiesis in the chicken. While eight chicken haemopoietic cytokines have been cloned and their in vitro functions partially characterised, a paucity of their actions still remains. In vitro data clearly indicates that cytokines, when acting alone, induce the proliferation and di€erentiation of precursor cells, however, increasing evidence suggests that combinations are required to achieve a maximal response [175,192]. Further detailed characterisations of these combinations is required, which hence, will provide valuable data towards mapping the avian cytokine network. There is little doubt that the ability to manipulate the chicken haemopoietic system by precise application of cytokines should facilitate a marked improvement in their health status. Implementing the newly developed INOVOJECT system [193], has provided a vehicle for the mass introduction of cytokines for possible therapeutic regimes in disease resistance. For example, as a means to maintain the high quality of animal husbandary required in the poultry industry, selective treatment with chicken haemopoietic cytokines could be applied. Alternatively, administration of cytokines could be implemented as adjuvants to increase the ecacy of deliberate immunisation programs in adult birds. Further-

more, these haemopoietic cytokines alone or in combination with de®ned peptides, could provide a potentially valuable approach to improving disease resistance in chickens, particularly in the newly hatched period where immune capacity is limited. Added note: it should be noted that during the revision of this manuscript details describing the molecular and functional characterization of the chicken homologue to IL-15 were published by Choi et al. [200].

Acknowledgements This work was supported by a grant from the Rural Industries Research and Developmental Corporation. References [1] Moore MAS, Owen JJT. Chromosome marker studies on the development of the haemopoietic system in the chick embryo. Nature 1965;208:989±90. [2] Moore MAS, Owen JJT. Stem cell migration in developing myeloid and lymphoid systems. Lancet 1967;23:658±9. [3] Moore MAS, Owen JJT. Chromosome marker studies in the irradiated chick embryo. Nature 1967;215:1081± 2. [4] Lassila O, Martin C, Toivanen P, Dieterlen-LieÂvre F. Erythropoiesis and lymphopoiesis in the chick yolk sac embyro chimaeras: contribution of yolk sac and intraembryonic stem cells. Blood 1982;59:377±81. [5] Hamburger V, Hamilton HL. A series of normal stages in the development of the chick embryo. J Morphol 1951;88:49±92. [6] Szenberg A. Ontogeny of myelopoietic precursor cells in the chicken embryo. In: Benedict AA, editor. Avian immunobiology Advances in experimental medical biology, vol. 88. New York, London: Plenum Press, 1977. p. 3±11. [7] MuÈller AM, Medvinski AL, Strouboulis J, Grosveld F, Dzierzak EA. Development of hematopoietic stem cell activity in the mouse embryo. Immunity 1994;1:291± 301. [8] Moore MAS, Metcalf D. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol 1970;18:279±96. [9] Huang H, Auerbach R. Identi®cation and characterisation of hematopoietic stem cells from the yolk sac of the early mouse embryo. Proc Natl Acad Sci USA 1993;90:10,110±4.

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59 [10] Reynaud CA, Imhof BA, Anquez V, Weill JC. Emergence of committed B lymphoid progenitors in the developing chicken embryo. EMBO J 1992;11:4349±58. [11] Cumano A, Furlonger C, Paige CJ. Di€erentiation and characterization of B-cell precursors detected in the yolk sac and embryo body of embryos beginning at the 10- to 12-somite stage. Proc Natl Acad Sci USA 1993;90:6429±33. [12] Martin C, Beaupain D, Dieterlen-LieÂvre F. Developmental relationships between vitelline intra-embryonic haemopoiesis studied in the avian ``yolk sac chimaeras''. Cell Di€erentiation 1987;7:115±30. [13] Lassila O, Eskola J, Toivanen P, Dieterlen-LieÂvre F. Lymphoid stem cells in the intra-embryonic mesenchyme of the chicken. Scand J Immunol 1980;11:445±8. [14] Jotereau FV, Houssaint E. Experimental studies in the migration and di€erentiation of primary lymphoid stem cells in the avian embryo. In: Solomon JB, Horton JD, editors. Developmental immunobiology. Amsterdam: Elsevier North Holland Biomedical Press, 1977. p. 123± 30. [15] Dieterlen-LieÂvre F, Martin C. Di€use intra-embryonic haemopoiesis in normal and chimeric avian development. Dev Biol 1981;88:180±91. [16] Cormier F, Dieterlen-LieÂvre F. The wall of the chick embryo aorta harbours M-CFC, G-CFC, GM-CFC and BFU-E. Development 1988;102:279±85. [17] Dieterlen-LieÂvre F. Haemopoiesis during avian ontogeny. Poult Sci Rev 1993;5:273±305. [18] Lassila O, Eskola J, Toivanen P. Pre-bursal stem cells in the intra-embryonic mesenchyme of the chick embryo at 7 days of incubation. J Immunol 1979;123:2091±4. [19] Dieterlen-LieÂvre F. On the origin of haemopoietic stem cells in the avian embryo: an experimental approach. J Embryol Exp Morphol 1975;33:607±19. [20] Lassila O, Eskola J, Toivanen P, Martin C, DieterlenLieÂvre F. The origin of lymphoid stem cells studied in chick yolk sac-embryo chimaeras. Nature 1978;272:353± 4. [21] Ramano€ AL. The avian embryo. New York: Macmillan Company, 1960. [22] Beaupain D, Martin C, Dieterlen-LieÂvre F. Are developmental hemoglobin changes related to the origin of stem cells and the site of erythropoiesis? Blood 1979;53:212±25. [23] Nakano T, Kodama H, Honjo T. In vitro development of primitive and de®nitive erythrocytes from di€erent precursors. Science 1996;272:722±4. [24] Godin IE, Garcia-Porrero JA, Coutinho A, DieterlenLieÂvre F, Marcos MA. Para-aortic splanchnopleura from early mouse embryos contains B1a progenitors. Nature 1993;364:67±70. [25] Medvinski AL, Samoylina NL, MuÈller AM, Dzierzak EA. An early pre-liver intra-embryonic source of CFUS in the developing mouse. Nature 1993;364:64±6. [26] Godin I, Dieterlen-LieÂvre F, Cumano, A. Emergence of

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

53

multipotential hemopoietic cells in the yolksac paraaortic splanchnopleura in mouse embryos, beginning at 8.5 days postcoitus. Proc Natl Acad Sci USA 1995;92:737± 77. Cumano A, Dieterlen-LieÂvre F, Godin I. Lymphoid potential probed before circulation in mouse is restricted to caudal intraembryonic splanchnopleura. Cell 1996;86:907±16. Tavian M, Coulombel L, Luton D, Clemente HS, Dieterlen-LieÂvre F, PeÂault B. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 1996;87:67±72. Delanney LE, Ebert JD. On the chick spleen: origin, patterns of normal development and their experimental modi®cation. Contrib Embryol 1962;255:57±86. Yassine F, Fedecka-Bruner B, Dieterlen-LieÂvre F. Ontogeny of the chick embryo spleen Ð a cytological study. Cell Di€er Dev 1989;27:29±45. Dieterlen-LieÂvre F, Beaupain D, Martin C. Origin of erythropoietic stem cells in avian development: shift from the yolk sac to an intraembryonic site. Ann Immunol 1976;127C:857±63. Payne LM, Powell PC. The lymphoid system. In: Freeman BM, editor. Physiology and biochemistry of the domestic fowl. Florida: Academic Press, 1984. p. 278±321. Keller G, Havele C, Longenecker M, Diener E. Ontogeny of hemopoietic colony forming units in the chicken embryo spleen. In: Benedict AA, editor. Avian immunobiology Advances in experimental medical biology, vol. 88. New York, London: Plenum Press, 1977. p. 13±27. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961;14:213±22. Nicolas-Bolnet C, Yassine F, Cormier F, DieterlenLieÂvre F. Developmental kinetics of hemopoietic progenitors in the avian embryo spleen. Exp Cell Res 1991;196:294±301. Eskola J, Toivanen A. Cell transplantation into immunode®cient chicken embryos. Reconstituting capacity of cells from the bursa of Fabricius, spleen, bone marrow, thymus liver of 18 day old embryos. Cell Immunol 1976;26:68±77. Toivanen A, Eskola J, Toivanen P. Restorative e€ects of di€erent embryonic cells transplanted into immunode®cient chick embryos. Ann Immunol 1976;127C:923± 9. Houssaint E, Lassila O, Vainio O. Bu-1 antigen expression as a marker for B cell precursors in chicken embryos. Eur J Immunol 1989;19:239±43. GoÈbel TWF, Chen CLH, Shrimpf J, Grossi CE, Bernot A, Bucy RP, et al. Characterization of avian natural killer cells and their intracellular CD3 protein complex. Eur J Immunol 1994;24:1685±91. Samarut J, Nigon V. Properties and development of

54

[41]

[42] [43]

[44]

[45]

[46] [47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59 erythropoietic stem cells in the chick embryo. J Embryol Exp Morphol 1976;36:247±60. Broxmeyer HE, Cooper S, Lu L, Hangoc G, Anderson D, Cosman D, et al. E€ect of murine mast cell growth factor (c-kit proto-oncogene ligand) on colony formation by human marrow hematopoietic progenitor cells. Blood 1991;77:2142±9. Tavassoli M. Embryonic fetal hemopoiesis: an overview. Blood Cells 1991;1:269±81. Bell SE, Zamoyska D. Identi®cation of thymocyte precursors in murine fetal liver. Eur J Immuol 1991;21:2931±6. Kantor AB, Stall AM, Adams S, Herzenberg LA. Di€erential development of progenitor activity for three B-cell lineages. Proc Natl Acad Sci USA 1992;89:3320± 4. Wong GK, Cavey MJ. Development of the liver in the chicken embryo. Erythropoietic and granulopoietic cells. Anat Rec 1993;235:131±43. Ratcli€e MJH. Development of the avian B lymphocyte lineage. Crit Rev Poult Biol 1989;2:207±34. Le Douarin NM, Dieterlen-LieÂvre F, Oliver PD. Ontogeny of primary lymphoid organs and lymphoid stem cells. Am J Anat 1984;170:261±99. Houssaint E, Belo M, Le Douarin NM. Investigations on cell lineage tissue interactions in the developing bursa of Fabricius through interspeci®c chimaeras. Dev Biol 1976;53:250±64. Hemmingsson EJ, Alm GV. Migration of stem cells from the yolksac to the thymus and bursa of Fabricius in the chicken embryo. Acta Pathol Microbiol Scand Section A 1973;81:79±84. Weber WT, Mausner R. Migration patterns of avian embryonic bone marrow cells and their di€erentiation to functional T- and B-cells. In: Benedict AA, editor. Avian immunobiology Advances in experimental medical biology, vol. 88. New York, London: Plenum Press, 1977. p. 47±59. Le Douarin NM, Jotereau FV. The homing of lymphoid stem cells to the thymus and bursa of Fabricius as studied in avian embryo chimaeras. CongeÁs Paris Juillet 1980. In: Fougereau M, Dausset J, editors. Immunology. London: Academic Press, 1980. p. 285± 302. Houssaint E, Mansikka A, Vainio O. Early separation of B and T lymphocyte precursors in chick embryo. J Exp Med 1991;174:397±406. Ratcli€e MJH, Lassila O, Pink JRL, Vainio O. Avian B cell precursors: surface immunoglobulin expression is an early, possibly bursa-independent event. Eur J Immunol 1991;16:129±33. Palojoki E, Lassila O, Jalkanen S, Toivanen P. Involvement of the avian m heavy chain in recolonisation of the bursa of Fabricius. Scand J Immunol 1992;36:251±9. Toivanen P, Toivanen A, Good RA. Ontogeny of bur-

[56] [57]

[58] [59]

[60] [61] [62]

[63] [64]

[65] [66] [67]

[68] [69]

[70] [71]

[72]

sal function in chicken. Embryonic stem cell for humoral immunity. J Immunol 1972;109:1058±70. Toivanen P, Toivanen A. Bursal and post bursal stem cells in chicken. Functional characteristics. Eur J Immunol 1973;3:585±95. Toivanen P, Toivanen A, Linna TJ, Good RA. Ontogeny of bursal function in chicken. Post embryonic stem cell for humoral immunity. J Immunol 1972;109:1071±80. Kadish JL, Basch RS. Thymic regeneration after lethal irradiation: evidence for an intra-thymic radioresistant T cell precursor. J Immunol 1975;114:452±8. Meijne EJM, Ria JM, Groenewegen WDWV, Ploemacher RE, Vos O, David JAG, et al. The e€ects of x-irradiation on hematopoietic stem cell compartments in the mouse. Exp Hematol 1991;19:617±23. Dieterlen-LieÂvre F, Pardanaud L, Yassine F, Cormier F. Early haemopoietic stem cells in the avian embryo. J Cell Sci 1988;10(Suppl.):29±44. Houssaint E. Cell lineage segregation during bursa of Fabricius ontogeny. J Immunol 1987;138:3626±34. Davidson WF, Pierce JH, Rudiko€ S, Morse HC. Relationships between B cell and myeloid di€erentiation. Studies with a B lymphocyte progenitor line, HAFTL-1. J Exp Med 1988;168:389±407. Boyd AW, Schrader JW. Derivation of macrophage like lines from the pre-B lymphoma ABLS 8.1 using 5azacytidine. Nature 1982;297:691±3. Martin M, Strasser A, Baumgarth N, Cicuttini FM, Welch K, Salvaris E, Boyd AW. A novel cellular model (SPGM 1) of switching between the pre-B cell and myelomonocytic lineages. J Immunol 1993;150:4395±406. Klinken SP, Alexander WS, Adams JM. Hemopoietic lineage switch: v-raf oncogene converts Em-myc transgenic B cells into macrophages. Cell 1988;53:857±67. Cumano A, Paige CJ, Iscove NN, Brady G. Bipotential precursors of B cells and macrophages in murine fetal liver. Nature 1992;356:612±4. Borrello MA, Phipps RP. Fibroblasts support outgrowth of splenocytes simultaneously expressing B lymphocyte and macrophage characteristics. J Immunol 1995;155:4155±61. Lindemann GJ, Adams JM, Cory S, Harris AW. Blymphoid to granulocytic switch during hematopoiesis in a transgenic mouse strain. Immunity 1994;1:517±27. Metcalf D, Lindemann GJ, Nicola N. Analysis of hematopoiesis in max 41 transgenic mice that exhibit sustained elevations of blood granulocytes and monocytes. Blood 1995;85:2364±70. Langdon WY, Harris AW, Cory S, Adams JM. The cmyc oncogene perturbs B lymphocyte development in Em-myc transgenic mice. Cell 1986;47:11±8. Wu L, Antica M, Johnson GR, Scollay R, Shortman K. Developmental potential of the earliest precursor cells from the adult mouse thymus. J Exp Med 1991;174:1617±27. Ardavin C, Wu L, Shortman K. Thymic dendritic cells

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

[73]

[74]

[75]

[76]

[77]

[78] [79] [80]

[81] [82]

[83]

[84] [85] [86]

and T cells develop simultaneously in the thymus from a common precursor population. Nature 1993;362:761± 3. Jotereau FV, Le Douarin NM. The developmental relationship between osteocytes and osteoclasts: a study using the quail-chick nuclear marker in endochondral ossi®cation. Dev Biol 1978;63:253±65. Corbel C, Pouquie O, Cormier F, Vaigot P, LeDouarin NM. BEN/SCI/DM-GRASP, a homophilic adhesion molecule, is required for in vitro myeloid colony formation in avian haemopoietic progenitors. Proc Natl Acad Sci USA 1996;93:2844±9. Vainio O, Dunon D, Aissi F, Dangy J-P, McNagny KM, Imhof BA. HEMCAM, an adhesion molecule expressed by c-kit+ hemopoietic progenitors. J Cell Biol 1996;135:1655±68. BaÈck O, BaÈck E, Hemmingsson EJ, Liden S, Linna TJ. Migration of bone marrow cells to the bursa of Fabricius and the spleen in the chicken. Scand J Immunol 1973;2:357±65. Dunon D, Kaufman J, Salomonsen J, Skjoedt K, Vainio O, Thiery JP, et al. T-cell precurors migration towards b2-microglobulin is involved in thymus colonization of the chicken embryos. EMBO J 1990;9:3315± 52. Dieterlen-LieÂvre F. Birds. In: Rowley AF, Ratcli€e NA, editors. Invertebrate blood cells. New York: Cambridge University Press, 1988. p. 257±336. Leutz A, Beug H, Graf T. Puri®cation and characterization of cMGF, a novel chicken myelomonocytic growth factor. EMBO J 1984;3:3191±7. Beug H, Hayman MJ, Graf T. Myeloblasts transformed by the avian acute leukemia virus E26 are hormonedependent for growth and for expression of a putative myb containing protein, p35 E26. EMBO J 1982;1:1069±73. Leutz A, Beug H, Walter C, Graf T. Hematopoietic growth factor glycosylation. J Biol Chem 1988;263:3905±11. Leutz A, Damm K, Sterneck E, Kowenz E, Ness S, Frank R, et al. Molecular cloning of the chicken myelomonocytic growth factor (cMGF) reveals relationship to interleukin 6 and granulocyte colony stimulating factor. EMBO J 1989;8:175±81. York JJ, Strom ADG, Connick TE, McWaters PG, Boyle DB, Lowenthal JW. In vivo e€ects of chicken myelomonocytic growth factor. Delivery via a viral vector. J Immunol 1996;156:2991±7. Lowenthal JW, York JJ, O'Neil TE, Steven RA, Strom DG, Digby MR. Potential use of cytokine therapy in poultry. Vet Immunol Immunopathol 1998;63:191±8. Nicola NA. Why do hemopoietic growth factor receptors interact with each other? Immunol Today 1987;8:134±40. Woldman I, Mellitzer G, Kieslinger M, Buchhart D, Meinke A, Beug H, et al. STAT 5 involvement in the di€erentiation reponse of primary chicken myeloid cell

[87] [88]

[89]

[90] [91] [92] [93]

[94] [95] [96]

[97] [98]

[99]

[100] [101]

55

progenitors to myelomonocytic growth factor. J Immunol 1997;159:877±86. Azam M, Erdjument-Bromage HE, Kreider BL, Xia M, Quelle F, Basu R, et al. Interleukin-3 signals through multiple isoforms of Stat5. EMBO J 1995;14:1402±11. Baramand-Pour F, Meinke A, Eilers A, Gouilleux F, Groner B, Decker T. Colony stimulating factors and interferon-g activate a protein related to MGF-STAT 5 to cause formation of the di€erentiation-induced factor in myeloid cells. FEBS Lett 1995;360:29±33. Gouilleux F, Pallard C, Dusanter-Fourt I, Wakao H, Haldosen LA, Norstedt G, et al. Prolactin, growth hormone, erythropoietin and granulocyte-macrophage colony stimulating factor induce MGF-STAT 5 binding activity. EMBO J 1995;14:2005±13. Issacs A, Lindenmann J. Virus intereference. I. The Interferon. Proc R Soc Lond [Biol] 1957;147:258±67. Sekellick MJ, Ferrino AF, Hopkins DA, Marcus PI. Chicken interferon gene: cloning, expression, and analysis. J Interferon Res 1994;14:71±9. Digby RM, Lowenthal JM. Cloning expression of the chicken interferon-g gene. J Interferon Cytokine Res 1995;15:939±45. Lillehoj HS, Kaspers B, Jenkins MC, Lillehoj EP. Avian interferon and interleukin-2. A review by comparison with mammalian homologues. Poultry Sci Rev 1992;4:67±85. Kohase M, Moriya H, Sato TA, Kohno S, Yamazaki S. Puri®cation and characterization of chicken interferon induced by viruses. J Gen Virol 1986;67:215±8. Sekellick MJ, Marcus PI. Induction of high titer chicken interferon. Methods Enzymol 1986;119:115±25. Onaga H, Tajima M, Ishii T. Activation of macrophages by culture ¯uid of antigen-stimulated spleen cells collected from chickens immunised with Eimeria tenella. Vet Parasitol 1983;13:1±11. von BuÈlow V, Weiler H, Klasen A. Activating e€ects of interferons, lymphokines and viruses on cultured chicken macrophages. Avian Pathol 1984;13:621±37. Lillehoj HS, Kang SY, Keller L, Sevoian M. Eimeria tenella and Eimeria acervulina: lymphokines secreted by an avian T cell lymphoma or by sporozoite-stimulated immune lymphocytes protect chickens against avian coccidiosis. Exp Parasitol 1989;69:54±64. Krempien U, Redmann I, Jungwirth C. Puri®cation of chick interferon by zinc chelate anity chromatography and sodium dodecylsulphate-polyacrylamide gel electrophoresis. J Interferon Res 1985;5:209±14. Pusztai R, Tarodi B, Beladi I. Production and characterization of interferon induced in chicken leukocytes by concanavalin A. Acta Virol 1986;30:131±6. Fredericksen TL, Sharma JM. Puri®cation of avian T cell growth factor and immune interferon using gel ®ltration high resolution chromatography. In: Weber WT, Ewert DL, editors. Avian immunology Progress in clinical biological research, vol. 238. New York: Alan R. Liss, 1987. p. 145±56.

56

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

[102] Dijmans R, Creemers J, Billiau A. Chicken macrophage activation by interferon: do birds lack the molecular homologue of mammalian interferon-g? Vet Immunol Immunopathol 1990;26:319±32. [103] Yip YK, Barrowclough B, Urban C, Vilcek J. Puri®cation of two subspecies of human g (immune) interferon. Proc Natl Acad Sci USA 1982;78:1820±4. [104] Schultz U, Kaspers B, Rinderle C, Sekellick MJ, Markus PI, Staeheli P. Recombinant chicken interferon: a potent antiviral agent that lacks intrinsic macrophage activating factor activity. Eur J Immunol 1995;25:847± 51. [105] Schultz U, Rinderle C, Sekellick MJ, Markus PI, Staeheli P. Recombinant chicken interferon from Escherichia coli and transfected COS cells is biologically active. Eur J Biochem 1995;229:73±6. [106] Lowenthal JW, Digby MR, York JJ. Production of interferon-g by chicken T cells. J Interferon Cytokine Res 1995;15:933±8. [107] Sekellick MJ, Lowenthal JW, O'Nell TE, Markus PI. Chicken interferon types I and II enhance synergistically the antiviral state and nitric oxide secretion. J Interferon Cytokine Res 1998;18:407±14. [108] Song KD, Lillehoj HS, Choi KD, Zarlenga D, Han JY. Expression and functional characterisation of recombinant chicken interferon-gamma. Vet Immunol Immunopathol 1997;58:321±33. [109] Lillehoj HS, Choi KD. Recombinant chicken interferon-gamma-mediated inhibition of Eimeria tenalla development in vitro and reduction of oocyst production and body weight loss following Eimeria acervulina infection. Avian Dis 1998;42:307±14. [110] Zhou J-H, Ohtaki M, Sakurai M. Sequence of a cDNA encoding chicken stem cell factor. Gene 1993;127:269± 70. [111] Anderson DM, Williams DE, Tushinski R, Gimpel S, Eisenman J, Cannizzaro LA, et al. Alternative splicing of mRNAs encoding human mast cell growth factor localization of the gene to chromosome 12q22-q24. Cell Growth Di€er 1991;2:373±8. [112] Martin FH, Suggs SV, Langley KE, Lu HS, Ting J, Okino KH, et al. Primary structure and functional expression of rat and human stem cell factors DNAs. Cell 1990;63:203±11. [113] Bartunek P, Pichlikova L, Stengl G, Boehmelt G, Martin FH, Beug H, et al. Avian stem cell factor (SCF): production and characterization of the recombinant his-tagged SCF of chicken and its neutralizing antibody. Cytokine 1996;8:14±20. [114] Hayman MJ, Meyer S, Martin F, Steinlein P, Beug H. Self-renewal and di€erentiation of normal avian erythroid progenitor cells: regulatory roles of the TGF-a/cErbB and SCF/c-kit receptors. Cell 1993;74:157±69. [115] Larsen J, Meyer S, Steinlein P, Beug H, Hayman MJ. Transformation of chicken bone marrow cells by the vski oncogene. Oncogene 1993;8:3221±8. [116] Steinlein P, Wessely O, Meyer S, Deiner E-M, Hayman

[117]

[118] [119] [120]

[121] [122]

[123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

M, Beug H. Primary, self-renewing erythroid progenitors develop through activation of both tyrosine kinase and steroid hormone receptors. Curr Biol 1995;5:191± 204. Lahav R, Lecoin L, Ziller C, Nataf V, Carnahan JF, Martin FH, et al. E€ect of the steel gene product on melanogenesis in avian neural crest cell cultures. Di€erentiation 1994;58:133±9. Van't Hof RJ, von Lindern M, Nijweide PJ, Beug H. Stem cell factor stimulates chicken osteoclast activity in vitro. FASEB J 1997;11:287±93. Carnahan JF, Patel DR, Miller JA. Stem cell factor is a neurotrophic factor for neural crest-derived chick sensory neurons. J Neurosci 1994;14:1433±40. Sasaki E, Okamura HH, Chikamune T, Kanai Y, Watanabe A, Mitsuru N, et al. Cloning and expression of the chicken c-kit proto-oncogene. Gene 1993;128:257±61. Galli SJ, Zsebo KM, Geissler EN. The kit ligand, stem cell factor. Adv Immunol 1994;55:1±98. Soler C, Carpenter G. Transforming growth factor-a (TGF-a). In: Nicola NA, editor. Guidebook to cytokines and their receptors. Oxford, New York, Tokyo: Oxford University Press, 1994. p. 194±7. Waltz TM, Malm C, Nishikawa BK, Wasteson A. Transforming growth factor-a (TGF-a) in human marrow: demonstration of TGF-a in erythroblasts and eosinophilic precursors and of epidermal growth factor receptors in blastlike cells of myelomonocytic origin. Blood 1995;85:2385±92. Ullrich A, Coussens L, Hay¯ick JS, Dull TJ, Gray A, Tam AW, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the ampli®ed gene in A431 epidermoid carcinoma cells. Nature 1984;309:418±25. Pain B, Woods CM, Saez J, Flickinger T, Raines M, Peyrol S, et al. EGF-R as a hemopoietic growth factor receptor: the c-erbB product is present in chicken erythrocytic progenitors and controls their self-renewal. Cell 1991;65:37±46. Downward J, Yarden Y, Mayes E, Scrace G, Totty N, Stockwell P, et al. Close similarity of epidermal growth factor receptor and v-erbB oncogene protein sequences. Nature 1984;307:521±6. Schroeder C, Gibson L, NordstroÈm C, Beug H. The estrogen receptor co-operates with the TGF-a receptor (c-erbB ) in regulation of chicken erythroid progenitor self-renewal. EMBO J 1993;12:951±60. Roberts AB, Sporn MB. The transforming growth factor b's. In: Sporn MB, Roberts AB, editors. Peptide growth factors their receptors. Berlin, New York: Springer-Verlag, 1990. p. 419±72. Gitelman SE, Derynck R. Transfoming growth factor b (TGF-b). In: Nicola NA, editor. Guidebook to cytokines and their receptors. Oxford, New York, Tokyo: Oxford University Press, 1994. p. 223±6. Cheifetz S, Weatherbee JA, Tsang ML, Andersen JK,

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

[131]

[132]

[133]

[134]

[135]

[136]

[137]

[138]

[139] [140]

[141]

[142]

[143] [144]

Mole JE, Lucas R, Massague J. The transforming growth factor-beta system, a complex pattern of cross reactive ligands and receptors. Cell 1987;48:409±15. Jakowlew SB, Dillard PJ, Kondaiah P, Sporn MB, Roberts AB. Complementary deoxyribonucleic acid cloning of a novel transforming growth factor-b, messenger ribonucleic acid from chick embryo chondrocytes. Molec Endocrinol 1988;2:747±55. Jakowlew SB, Dillard PJ, Sporn MB, Roberts AB. Complementary deoxyribonucleic acid cloning of a messenger ribonucleic acid encoding transforming growth factor b4 from chicken embryo chondrocytes. Molec Endocrinol 1988;2:1186±95. Jakowlew SB, Dillard PJ, Sporn MB, Roberts AB. Complementary deoxyribonucleic acid cloning of an mRNA encoding transforming growth factor-b2 from chicken embryo chondrocytes. Growth Factors 1990;2:123±33. Jakowlew SB, Dillard PJ, Winokur TS, Flanders KC, Sporn MB, Roberts AB. Expression of transforming growth factors-b's 1±4 in chicken embryo chondrocytes myocytes. Dev Biol 1991;143:135±48. Jakowlew SB, Ciment G, Tuan RS, Sporn MB, Roberts AB. Expression of transforming growth factor-b2 and b3 mRNAs proteins in the developing chicken embryo. Di€erentiation 1994;55:105±18. Kondaiah P, van Obberghen-Schilling E, Ludwig R, Dhar R, Sporn MB, Melton DA. cDNA cloning of porcine TGF-beta: evidence for alternative splicing. J Biol Chem 1988;263:18,313±7. Keller JR, Sing GK, Ellingsworth LR, Ruscetti FW. Transforming growth factor-b: possible roles in the regulation of normal and leukemia hematopoietic cell growth. J Cell Biochem 1989;39:79±84. Sugano S, Stoeckle MY, Hanufusa H. Transformation by Rous-sarcoma virus induces a novel gene with homology to a mitogenic platelet protein. Cell 1987;49:321± 8. Stoeckle MY, Barker KA. Two burgeoning families of platelet factor 4-related proteins: mediators of the in¯ammatory response. New Biol 1990;22:313±23. Martins-Green M, Stoeckle M, Hampe A, Wimberly S, Hanafusa H. The 9E3/CEF4 cytokine: kinetics of secretion, processing by plasmin, and interaction with extracellular matrix. Cytokine 1996;8:448±59. Gonneville L, Martins TJ, BeÂrard P-A. Complex expression pattern of the CEF-4 cytokine in transformed and mitogenically stimulated cells. Oncogene 1991;6:1825±33. Barker KA, Hampe A, Stoeckle MY, Hanafusa H. Transformation associated cytokine 9E3/CEF4 is chemotactic for chicken peripheral blood mononuclear cells. J Virol 1993;67:3528±33. Bagglioni MA, Walz A, Kunkel SL. NAP/IL-8, a novel cytokine that activates neutrophils. J Clin Invest 1989;84:1045±9. Hayari Y, Schauenstein K, Globerson A. Avian lym-

[145]

[146]

[147] [148]

[149]

[150] [151]

[152] [153] [154] [155]

[156]

[157] [158] [159] [160]

57

phokines, II: interleukin-1 activity in supernatants of stimulated adherent splenocytes of chickens. Dev Comp Immunol 1982;6:785±9. Klasing KC, Peng RK. In¯uence of cell sources, stimulating agents, and incubation conditions on release of interleukin-1 from chicken marocrophages. Dev Comp Immunol 1987;11:385±94. Klasing KC. Avian interleukin-1: immunological and physiological functions. In: Proceedings of the Thirtysixth Western Poultry Disease Conference. Cooperative extension, University of California, Davis, CA, 1987. p. 82±4. Klasing KC, Peng RK. Monokine-like activities released from a chicken macrophage line. Anim Biotech 1990;1:107±20. Klasing KC, Laurin DE, Peng RK, Fry DM. Immunologically mediated growth depression in chicks: in¯uence of feed intake, corticosterone, and interleukin1. J Nutr 1987;117:1629±37. Weining KC, Sick C, Kaspers B, Staheli P. A chicken homologue of mammalian interleukin-1b: cDNA cloning and puri®cation of active recombinant protein. Eur J Biochem 1998;258:994±1000. Guida S, Heguy A, Melli M. The chicken IL-1 receptor: di€erential evolution of the cytoplasmic extracellular domains. Gene 1992;111:239±43. Schauenstein K, Globerson A, Wick G. Avian lymphokines: I. Thymic cell growth factor in supernatants of mitogen stimulated chicken spleen cells. Dev Comp Immunol 1982;6:533±40. Schnetzler M, Oommen A, Nowak JS, Franklin RM. Characterization of chicken T cell growth factor. Eur J Immunol 1983;13:560±8. Mossman TR, Co€man RL. TH1 TH2 cells: di€erential patterns of lymphokine secretion lead to di€erent functional properties. Ann Rev Immunol 1989;7:145±73. Schauenstein K, Hayari Y. Avian lymphokines. Dev Comp Immunol 1982;7:767±8. KroÈmer G, Schauenstein K, Wick G. Avian lymphokines: an improved method for chicken IL-2 production and assay. A con A-erythrocyte complex induces higher T cell proliferation IL-2 production than does free mitogen. J Immunol Methods 1984;73:273±81. Vainio O, Ratcli€e MJH, Leerson T. Chicken T-cell growth factor: use in the generation of a long-term cultured T-cell line and biochemical characterization. Scand J Immunol 1986;23:135±42. Myers TJ, Lillehoj HS, Fetterer RH. Partial puri®cation and characterisation of chicken interleukin-2. Vet Immunol Immunopathol 1992;34:97±114. Gillis S, Ferm MM, Smith KA. T cell growth factor: parameters of production and a quantitative mircoassay for activity. J Immunol 1978;120:2027±32. Corbel C, Thomas JL. Establishment of an IL-2 dependent, antigen nonspeci®c chicken T-cell line. Dev Comp Immunol 1990;14:439±46. Kaplan MH, Dhai A, Brown TR, Sundick RS. Marek's

58

[161]

[162]

[163]

[164]

[165]

[166]

[167]

[168]

[169]

[170]

[171]

[172]

[173]

[174]

[175]

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59 disease virus transformed cell lines respond to lymphokines. Vet Immunol Immunopathol 1992;34:63±79. Sundick RS, Gill-Dixon C. A cloned chicken lymphokine homologous to both mammalian IL-2 and IL-15. J Immunol 1997;159:720±5. Anderson DM, Jonson L, Glaccum MB, Copel NG, Gilbert DJ, Jenkins NA, et al. Chromosomal assignment and genomic structure of IL-15. Genomics 1995;25:701±6. Tagaya Y, Bamford R, DeFilippis AP, Waldmann TA. IL-15: a pleiotropic cytokine with diverse receptor/signal pathways whose expression is controlled at multiple levels. Immunity 1996;4:329±36. Bamford RN, Grant AJ, Burton JD, Peters C, Kurys G, Goldman CK, et al. The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci USA 1994;91:4940±4. Hala K, Schauenstein K, Neu N, KroÈmer G, Wolf H, Beck G, et al. A monoclonal antibody reacting with a membrane determinant on activated chicken T lymphocytes. Eur J Immunol 1986;16:1331±6. Schauenstein K, KroÈmer G, Hala K, Bock G, Wick G. Chicken activated T lymphocyte antigen (CATLA) recognized by the monoclonal antibody INN-CH16 represents the IL-2 receptor. Dev Comp Immunol 1988;12:823±31. Lee T-H, Tempelis CH. Possible 110 kDa receptor for interleukin 2 in the chicken. Dev Comp Immunol 1992;16:463±72. Martin DE, Glick B. Physiochemical characterization of lymphocyte inhibitory factor (LyIF) isolated from avian B and T cells. Cell Immunol 1983;79:383±8. Joshi P, Glick B. Characterization of lymphocyte inhibitory factor from avian bursal and thymic lymphocytes and a chemotactic factor from thymic lymphocytes. Poultry Sci 1990;69:249±58. Joshi P, Glick B. The role of avian macrophages in the production of avian lymphokines. Dev Comp Immunol 1990;90:319±25. Landolfo S, Herberman B, Holden MT. Macrophage lymphocyte interaction in MIF production. J Immunol 1977;118:1244±8. Rath NC, Hu€ WE, Bayyari GR, Balog JM. Identi®cation of transformation growth factor-b and interleukin-6 in chicken ascites ¯uid. Avian Diseases 1995;39:382±9. Dodge WH, Moscovici C. Colony formation by normal chick hematopoietic cells and leukaemic myeloblasts. J Cell Physiol 1973;30:371±86. Sharma S, Dodge WH. Induction of colony-stimulating factor from quiescent ®broblasts by avian macrophages and monocytic leukemic cells. Leuk Res 1985;9:1507± 10. Nicolas-Bolnet C, Qureshi MA, Cieszynski JA, Taylor

[176] [177]

[178] [179]

[180]

[181] [182]

[183]

[184]

[185]

[186]

[187] [188] [189] [190] [191]

RL. Avian hematopoiesis in response to avian cytokines. Poultry Sci 1995;74:1970±4. Klasing KC. Avian in¯ammatory response: mediation by macrophages. Poultry Sci 1991;70:1176±86. Siatskas C, McWaters PG, Digby M, Lowenthal JW, Boyd RL. In vitro characterization of a novel avian haemopoietic growth factor derived from stromal cells. Dev Comp Immnunol 1996;20:139±56. Obranovich TD, Boyd RL. A bursal stromal derived cytokine induces proliferation of MHC class II bearing cells. Dev Comp Immnunol 1996;20:61±75. Silva RF, Dodge WH, Moscovici C. The role of humoral factors in the regression of leukemia in chickens as measured by in vitro colony formation. J Cell Physiol 1973;83:187±92. Bryant D, Smith R, Sharma S, Dodge WH. Some circulating factors which in¯uence granulocyte-monocyte production in the chick with myeloblastic leukemia. Cancer Res 1980;40:4031±6. Dodge WH, Love SH, Bryant DL, Mitchell RH. Properties of colony-stimulating and inhibiting activities of chicken serum. Exp Hematol 1980;8:395±403. Bryant DL, Dodge WH. Studies on the circulating, colony-stimulatory activities in normal chicks and in chicks with myeloblastic leukemia. Exp Hematol 1981;9:457±67. Bryant DL, Whitaker JM, Gruber KA, Dodge WH. Characterization of an inhibitor of granulocyte/monocyte colony formation in leukemic chicken plasma. Exp Hematol 1981;9:479±88. Bryant DL, Smith RE, Dodge WH. Levels of colonystimulating inhibiting activities in chicks with myeloblastic leukemia are related to disease progression. Exp Hematol 1982;10:249±55. Byrnes S, Eaton R, Kogut M. In vitro interleukin-1 and tumor necrosis factor-alpha production by macrophages from chickens infected with either Eimeria maxima or Eimeria tenella. Int J Parasitol 1993;23:639± 45. Zhang S, Lillehoj HS, Ru€ MD. Chicken tumor necrosis-like factor. I. In vitro production by macrophages stimulated with Eimeria tenella or bacterial ploysaccharide. Poultry Sci 1995;74:1304±10. Zhang S, Lillehoj HS, Ru€ MD. In vivo role of tumor necrosis-like factor in Eimeria tenella infection. Avian Dis 1995;39:859±66. Yang Z, Petitte JN. Use of avian cytokines in mammalian embryonic stem cell culture. Poultry Sci 1994;73:965±74. Samarut J, Nigon V. In vitro development of chicken erythropoietin-sensitive cells. Exp Cell Res 1976;100:245±8. Vainio O, Imhof BA. The immunology and developmental biology of the chicken. Immunol Today 1995;16:365±70. Beug H, Metz T, Mullner EW, Hayman MJ. Selfrenewal and di€erentiation in primary avian hemato-

C. Siatskas, R. Boyd / Developmental and Comparative Immunology 24 (2000) 37±59

[192]

[193] [194] [195]

poietic cells: an alternative to mammalian in vitro models. In: Wol€ L, Perkins AS, editors. Molecular aspects of myeloid stem cell development. Berlin: Springer, 1996. p. 29±39. Nicolas-Bolnet C, Johnson PA, Kemper AE, Ricks C, Petitte JN. Synergistic action of two sources of avian growth factors on proliferative di€erentiation of chick embryonic hematopoietic cells. Poultry Sci 1995;74:1102±16. Johnson PA, Liu H, O'Connell T, Phelps P, Bland M, Tyczkowski J, et al. Applications in in ovo technology. Poultry Sci 1997;76:165±78. Klasing K. Avian leukocytic cytokines. Poultry Sci 1994;73:1035±43. Petrenko O, Ischenko I, Enrietto PJ. Isolation of a cDNA encoding a novel chicken chemokine homolo-

[196] [197]

[198] [199] [200]

59

gous to mammalian macrophage in¯ammatory protein1b. Gene 1995;160:305±6. Barger BO, Pace JL, Inman FP, Ragland WL. Puri®cation and partial characterization of an avian thymic hormone. Thymus 1991;17:181±97. Audhya T, Kroon D, Heavner G, Viamontes G, Goldstein G. Tripeptide structure of bursin, a selective B cell di€erentiating hormone of the bursa of Fabricius. Science 1986;231:997±9. Armani DL, Mauzy-Melitz D, Mosesson MW. E€ect of hepatocyte stimulating factor and glycocorticoids on plasma ®bronectin levels. J Biochem 1986;238:365±71. Marsh JA. The humoral activity of the avian thymic microenvironment. Poultry Sci 1993;72:1294±300. Choi KD, Lillehoj HS, Song KD, Han JY. Molecular and functional characterisation of chicken IL-15. Dev Comp Immunol 1999;23:165±77.