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Avian Immunobiology
Avian Immunobiology W. P. JAFFE*
Department of Poultry Science, Ohio State University, Columbus, Ohio (Received for publication July 23, 1965)
I
N THE last few years the chicken has become increasingly popular as a subject for immunological studies and much information of a specific nature as well as of general biological interest has been obtained. BLOOD GROUPS
At least ten, and possibly as many as twelve different loci determining red cell antigens have been reported in the chicken. The majority of these are diallelic but the B system is a multiple allelic one, in which over 20 alleles are known (Briles, 1962; Gilmour, 1962; McDermid, 1964). Antigens determined by the B and C system are carried by the leucocytes as well, the others are not (Schierman and Nordskog, 1961). Special interest centres on their role in tissue-transplantation. Such antigens are known as histocompatibility antigens and in mice at least four loci are known. While the reaction between donor and host represents the cumulative effects of differences in histocompatibility antigens between them, one, the H2 locus, presents the strongest barrier. This locus, like B in chickens, also determines erythrocyte antigens and has a number of alleles (Gorer et al, 1948; Allen, 19SS; Snell, 1958). A further locus has been found on the Y chromosome and is the only active gene known on that chromosome in mice (Eichwald and Silmser, 1955). Since in mice and chickens major histocompatibility antigens are also red cell antigens, knowledge of the role of blood group compatibility in graft *On leave of absence from School of Veterinary Science, University of Bristol, England.
MECHANISM OF GRAFT REJECTION
Grafted animals produce antibodies against the donor of the grafted tissue but attempts to transfer immunity to grafts passively with serum from animals immunized by previous exposure to grafts has usually been unsuccessful (Brent and Medawar, 1962). On the contrary, antiserum frequently facilitates takes of tumor grafts, a phenomenon known as enhancement; enhancement of normal tissues has probably not been clearly demonstrated (Kaliss, 1958). Although such antibodies show evidence of lymphocyte toxicity and can probably cause the rejection of dispersed cellular homografts, this is a different matter from rejecting organized tissues. Transplantation immunity can, however, be transferred adoptively by regional lymph node cells, thoracic duct lymphocytes and blood leucocytes (Gowan et al., 1961).
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survival is of great practical interest. In rabbits the Hg blood group locus plays a positive role in takes of skin grafts (Cohen et al., 1964) but neither in man (Woodruff and Allan, 1953) nor in dogs (Thomas et al., 1964) do the major blood groups have an effect on histocompatibility. Although leucocytes are a powerful source of transplantation antigens, lack of specific sera has hampered the development of leucocyte serology. Thus no more than a possible relationship between graft survival and leucocyte compatibility has so far been shown (Goldsmith, 1965). Transplantation antigens are also present on platelets but absent from erythrocytes in man.
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Cellular elementes evidently play a major role in graft rejection (Murphy, 1926). Lymphocytes and immature plasma cells begin to appear in the graft bed after 5 to 6 days. Their part in the rejection mechanism is obscure, but it could occur through release of antibody in high local concentration. Complement also pays an important part in the destruction of foreign cells (Winn, 1962). NOMENCLATURE
Grafts on self: Autografts Grafts from same genotype as host: Syngeneic homografts Grafts from same species as host: Allogeneic homograts Grafts from species different from host: Xenograft. To bring blood group terminology into line with that used in transplantation, the terms allo-antigen and antibody have been proposed in place of iso-antigen and antibody, an allo-antigen being a constituent of an animal which evokes the formation of antibody (allo-antibody) in genetically distinct individuals of the same species. The situation governing rejection of foreign tissues is subject to the same rules as those of blood groups. Autografts and syngeneic grafts are accepted, provided the lines are sufficiently inbred. Crosses between inbred lines have antigens absent from one or other of the inbred parents; in consequence grafts from the parent lines are accepted by the hybrids, but grafts
TOLERANCE
The state of acquired immunological tolerance, leading to prolonged or permanent retention of foreign tissue is of great practical importance as well as being of interest for immunological theory. It was first discovered in the natural state in non-identical cattle twins the majority of which accept grafts of each others skin. Takes occurred in those pairs in which a common blood circulation had been established. (Anderson et al., 1951.) This state can be produced experimentally by injecting embryos or neonates with tissue from genetically foreign donors. Grafts of skin and other tissue are accepted from the original donor when the animal is immunologically mature (Billingham et al., 1953). In birds, artificial twins can be made by uniting the blood circulation of developing embryos via the chorio-allantoic membrane. As adults, birds from such parabiosed eggs are incapable of forming antibody to each others erythrocytes (Hazek, 1956). What is the nature of this incapacity? It could be: a) inability of graft antigens to reach the antibody forming host cells. b) failure of the antibody mechanism to act on graft cells. c) an alteration in the activity of the antibody forming tissue. When tolerant animals bearing a foreign graft are injected with lymphoid cells from a normal animal of the same strain as the tolerant one, the graft is rejected. Tolerance can thus be abrogated by adoptive
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The literature on transplantation has suffered unduly from a confused terminology. The word homograft, for instance, has so many meanings that it has become meaningless. The nomenclature now accepted by most workers in this field distinguishes between the various types of graft as follows (Gorer et al., 1961):
from the hybrid to either parent are rejected. Grafts from the same or different species are normally rejected, but to this rule there are important exceptions.
AVIAN IMMUNOBIOLOGY
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immunisation, indicating the third possibil- produced as the cell matures and presence ity to be the correct one. of antibody is then a stimulus to further Two points are to be noted: 1) unre- proliferation and to antibody formation sponsiveness is restricted to the antigen(s) (Burnet, 1959). with which the embryo initially comes into The idea of cell death necessarily precontact; response to others is normal. 2) supposes a selective theory; on any inTolerance is maintained only as long as the structive theory all antibody producing antigen is present. cells would be wiped out. Furthermore, tolBut tolerance can also be developed in erant cells do not exist on this theory, only adults, either after high doses of ionising tolerant individuals. At the present time selective theories radiation, or in normal adults exposed to most satisfactorily explain the majority of high concentrations of antigen. Immunity and tolerance are alternative observations. This does not prove them to be reactions to the same stimulus; the out- correct; indeed, many difficulties remain. come depends on the time of administraOne is the mechanism required for the tion and dosage of antigen. enormous number of clones needed to atSince an antigen is usually denned by its tack all possible antigens. That this may capacity to induce an immune response, be quite small is suggested by recent infortolerance to an antigen is a contradiction mation on the structure of the most comin terms. Clearly a redefinition to include mon type of antibody, 7S. This is composed of four parts, two heavy A chains tolerance is needed. Tolerance to foreign antigen may be re- and two light B chains. Assuming the comgarded as identical with the mechanism by bining site is shared by these two types of which an organism becomes tolerant of its chain and the configuration is gene conown body constituents and is presumably a trolled, then quite a small number of genes device for preventing "horror autotoxicus". could produce a great variety of combinaTheories of tolerance are an extension of tions (Edelman and Gaily, 1964). theories of antibody production in general made only against those by which they There is at present no indication that and nowadays centre on the concept of immunological maturity at the cellular level. antigen controls the shape of the combinOn this view the lymphoid system is com- ing site in the manner of a template for the posed of a mixture of immunologically im- antibody, as envisaged by some instructive mature and mature cells, the essential theories. On the contrary, isotope labelling difference between embryos and adults studies show little if any antigen actually being in the proportion of the two types. inside the antibody producing cells. The According to selective theories of antibody presence of antigen is apparently all that is formation, a complete range of cells, each needed for antibody production in cells of producing antibody of different specificity the appropriate genetic specificity to prois required. When these cells are engaged ceed (Nossal, 1964). by antibody, two effects, depending on A somewhat less hazardous method the stage of development of the cells, are might be expected to have been favoured envisaged. Immature cells, being highly by natural selection. This could be most susceptible to specific antibody, are elimi- simply achieved by the participation of nated by its presence. In its absence, two cell types, one to elaborate the mesclones of cells of identical specificity are sage, the other to manufacture antibody.
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Evidence from recent work on chickens provides experimental support for such a system and its operation has also been inferred in mammals, although a dissociation of immunological function is harder to demonstrate. CONSEQUENCES OF TOLERANCE
AUTOIMMUNITY All specialised organs probably contain tissue specific antigens, but under normal conditions no immune reaction is directed against them, presumably because they are protected by tolerance. The nature of the ban on autoimmunity centres on the mechanism by which tolerance is normally achieved. Autoimmunity is produced when the mechanism responsible for tolerance breaks down. In autoimmune diseases in man and certain strains of mice, there is a genetic liability for clones of cells less subject to inhibition by antigen to arise. These "forbidden clones" then react against the antigenic determinants of the host. Experimental autoimmunity can be produced by means of physiologically unnatu-
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Inhibition of antibody response is expected to extend to other substances which share antigenic determinants with those to which the animal has become tolerant. This could explain why some substances are good and others bad antigens, and some individuals good and others bad antibody producers. It also provides an explanation of "faulty perspective". Landsteiner first used this term to describe the finding that rabbits immunised against one rodent species gave a greater reaction against this species than against other species of rodent, whereas they showed little variation in their reaction to different species of birds after immunisation with one of them (Landsteiner, 1945). Because variation in protein structure of different species depends on their evolutionary relationship, rodents have many characteristics in common. Antibody is made only against those by which they differ; thus, only a small proportion of antibody produced against, say, mouse, will react with rat. Bird proteins differ more from mammals and a larger proportion of rabbit antibody molecules react equally with antigen of different bird species (Cinader, 1963). Individuals of the same species vary in antigenic determinants, such as blood groups, and serum and milk proteins. Since these are excluded from immunogenicity by tolerance, the antibody response of individuals is expected to vary. The ABO blood group story in man may be used to illustrate this. Blood group chimeras have been observed in O group indi-
viduals which have received cells from their A group twin. Such individuals do not have anti-A in their serum. Evidently the presence of A group cells induced tolerance and prevented the synthesis of the appropriate antibody. This raises the question of how such antibodies are normally produced. Pneumococci are known to contain capsular polysaccharides which react with blood group antigens, hence the production of A and B antibodies could be the result of bacterial infection. Similarly, chickens possess hemagglutinins for human group B red cells. These are not present in germ free chicks, but infection with E. coli, which contain antigen reacting with the B substance, causes the appearance of antibody (Springer et al., 19S8). That tolerance induced to a pathogen can affect resistance to it is shown in the case of Rous sarcoma, which shares antigens with chicken cell membranes. Chickens are highly susceptible but turkeys are resistant, but when turkeys are made tolerant to chickens, they also become susceptible to Rous sarcoma (Harris, 1956).
AVIAN IMMUNOBIOLOGY
GRAFT V. HOST REACTIONS When transplants containing immunocytes are made to hosts unable to reject them, but containing histocompatibility antigens absent from the donor, graft v. host reactions may develop (Simonsen, 1957). The necessary host unresponsiveness may arise in one of four ways: 1) Hosts are tolerant of donor antigens. 2) Hosts are embryos or neonates. Here the graft may or may not induce tolerance; if tolerance is not developed the reaction may proceed until the host is destroyed. 3) Hosts are genetically unable to react to donor cells, as in parent strain donors on Fj hosts of the same sex. 4) Irradiation of adults to destroy their immunological defences. The outcome of the graft v. host reaction varies with the age of the host, the strain combinations involved and the type
and amount of inoculum employed. A general pattern is proliferation of the lymphoid cells, leading to splenomegally and other changes, followed by lymphoid atrophy, loss of weight (ranting) and death, probably as a result of invasion by pathogens. Donor cells destroy host lymphoid tissue in areas in which they settle and divide; this is the reverse of what occurs in the homograft reaction. Host immunological unresponsiveness is then the result of the destruction of its lymphoid tissue by donor cells. Supporting evidence for this explanation comes from the appearance of similar syndromes produced by other methods known to lead to lymphoid deficiency. These are thymectomy of baby mice and lethal irradiation followed by restoration with syngeneic inocula scarce in lymphoid cells, i. e. fetal liver or bone marror (Barnes et al., 1962). CELL TYPES RESPONSIBLE Lymphoid cells have so far been treated as a single group, but two types of cell of interest in this connection may be distinguished morphologically. These are the lymphocytes, classified into large, medium and small, and the plasma cells, which secrete antibody. The large lymphocyte, capable of mitotic division was thought to be the candidate for the immunocyte in the homograft and graft v. host reactions, but recently the small lymphocyte, previously regarded as an end cell, has been shown to be responsible for the graft v. host reaction in rats (Gowans et al., 1961). In chickens, on the other hand, the ability to cause graft v. host reactions, as measured by the initiation of foci on the chorioallantoic membrane, is related to the number of medium and large lymphocytes (Szenberg and Warner 1962). Added interest is provided by the recent discovery that small lymphocytes are able
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ral manipulations. Administration of body tissues in Freunds adjuvant is an effective method. The antigen is probably altered in some way so as to be regarded as foreign. Alteration of body constitutents may play a major role in certain autoimmune conditions. It may follow from tissue damage, as in cardiac surgery, where antibody to heart muscle is frequently seen. What part, if any, autoantibody plays in tissue damage is uncertain; it is more likely the result than the cause of autoimmunity. Nowadays autoantibody is realized to be of widespread occurence in diseased as well as healthy subjects (Glynn, 1963). There is agreement that the production of autoimmune disease is the consequence of the activity of immunocytes antigenically different from the host. Examples of tolerated cells engaging in immunological activity against the antigenic components of the host are the basis of graft v. host reactions.
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to transform to cells morphologically like plasma cells. The role played by donor and host cells in the graft v. host reaction, particularly in its early, proliferative phase, is a matter for speculation. In some mouse strains total replacement by donor cells is seen, whereas in others cellular proliferation is mainly of host origin. In chick embryos, up to 70% of the dividing cells in the spleen are of donor origin at the height of the proliferative phase (Seto and Albright, 1965).
Once started, the graft v. host reaction is very difficult to stop, but the serverity of its effect may be reduced in a number of ways. Injection with adult syngeneic cells is effective but must be done very shortly after the allogeneic cells are given. If preimmunised cells are used, protection even after several days is possible. This is the situation in mice (Russel, 1962). In chickens only preimmunised cells are effective and those must be given within half an hour of the allogeneic cells in B incompatible donor-host combinations (Jaffe, 1965). CRITERIA
For a quantitative assessment of the reaction the following criteria are used: 1) Mortality. This is not very sensitive but direct and useful for strong combinations. 2) Weight gain. Failure of runts to grow or loss of weight of adults compared to untreated controls. 3) Spleen assay. Splenomegaly is a good quantitative method but involves killing the host. 4) Phagocytosis. Rate of carbon clearance is accelerated during the proliferative phase. 5) Discriminant spleen assay. This is
THYMECTOMY AND BURSECTOMY
A wasting disease similar to that seen in graft v. host reactions occurs in mice thymectomised at birth. In such animals the lymph nodes and the lymphoid follicles of the spleen are underdeveloped and there is a shortage of circulating lymphocytes. Their immunological activity to a variety of antigens is restricted; rejection of homografts and the ability to cause graft v. host reactions is reduced, and a fatal wasting disease occurs at three to four weeks of age (Miller, 1962). In adults, thymectomy has no permanent effect; secondary lymphoid organs are presumably able to carry on with their own complement of cells. But if the adults are irradiated and then thymectomised, immunological reactions are reduced and runting sets in. In both adults and newborn, immunological activity is restored and runting prevented by grafts of adult thymus or spleen cells, suggesting that the defect is primarily due to a lack of cells. However, in such restored animals, the lymphoid cells are predominantly of host origin. Thus the protective effect of the implanted thymus does not act solely by means of donating cells. Evidence that the contribution may be a hormonal one comes from experiments on thymus grafts enclosed in cell-retaining millipore chambers, which permit development of immunologic
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THERAPY
a method of estimating the activity of immunocytes in chimeric spleens. A mixed population of A and B spleen cells is injected onto infant A X C and B X C hosts. Cells of on genotype produce a graft v. host reaction in each, the others are rejected (Simonsen and Jensen, 1959). 6) CAM assay. Donor leucocytes produce foci on the chorio-allantoic membrane of embryos bearing antigen not present in the donor (Boyer, 1960).
AVIAN IMMUNOBIOLOGY
mal in bursectomised birds, the 7S component being principally involved (Long and Pierce, 1963). Higher antibody titres have been reported in birds with bigger bursas, (Sadler and Glick, 1962) and the better disease resistance of White Leghorns may be correlated with their larger bursa (Jaap, 1958). Since in bursectomised birds, even a small amount of residual bursa is usually able to permit antibody response, the interpretation of these findings is not a simple one. A specific effect of bursectomy on disease resistance is the higher mortality from challenge with live Salmonella typhimurium, reported by Chang et al. (1959). No difference in resistance to coccidiosis has been reported. Delayed type hypersensitive reactions appear not to be influenced by bursectomy, at least as far as the experiments employing surgical removal are concerned. Skin graft survival times are also normal (Jankovic et al., 1963). It may be concluded that lymphocytes are responsible for mediating these reactions and that circulating antibody plays no part. Birds evidently have two populations of immunologically competent cells, one associated with the thymus and responsible for cell mediated reactions, the other concerned with the production of circulating antibody and originating in the bursa. There may be yet a third population which controls the ability to cause graft v. host reactions, since neither bursectomy, thymectomy nor a combination of the two has yet been shown to modify this reaction. In corroboration of this, two types of tissue are seen in avian spleen; an early developing white pulp which is reduced in thymectomised birds and considered thymus dependent as well as later developing lymphoid follicles which resemble those seen in the bursa. These are absent in bur-
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capacity. In the chicken, thymectomy affects the ability to reject skin grafts, the formation of circulating antibody is not impaired and ranting does not occur (Warner and Szenberg, 1962). In comparison with the mouse, lymphoid development of the thymus occurs earlier in development, so that "peripheralisation" of lymphoid cells to the secondary lymphoid organs may already have proceeded further before hatching (Aspinall et al., 1962). In birds there are two primary lymphoid organs, the thymus and the Bursa of Fabricius. In this structure, which arises as a dorsal diverticulum from the cloaca, lymphoid elements begin to develop on the 14th day of incubation. Its role in antibody production was first reported less than ten years ago, until then its function had been completely unknown (Glick et al., 1956). Bursectomised birds have a reduced ability to react to a variety of antigens; the earlier in life the bursa is removed, the more pronounced the effect. Injection of testosterone into young embryos prevents the development of lymphoid tissue in the bursa; in a small proportion of birds the thymus may also be inhibited (Szenberg and Warner, 1962). Partial restoration of bursal activity may be accomplished by inplanting pieces of bursal tissue enclosed in millipore chambers (St. Pierre and Ackerman, 1965). Saline extracts of acetone dried bursa are also effective (Glick, 1960). These findings suggest the existence of a humoral agent, responsible for immunological activity. Bursectomised birds show a striking reduction in plasma cells, but the number of blood lymphocytes and lymphoid follicles is only slightly reduced (Long and Pierce, 1963). This is the converse of the situation seen in thymectomised birds (Warner and Szenberg, 1962). Levels of serum glubulins are below nor-
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EVOLUTIONARY ASPECTS
Adaptive immunity is a process developing late both in ontogeny and in phylogeny. In evolution, its appearance is linked to the development of a thymus and lymphoid cells, first seen in species above the lamprey. It is not present in invertebrates, which deal with their pathogens by phagocytic and enzymatic mechanisms. Since they share many environments with vertebrates, where both are exposed to a similar array of pathogens, the latter presumably have no greater need for protection. Immune responses are thus not entirely protective. What purpose, then, does this system serve? Higher animals are characterised by increased specialization, possess highly complicated organs and specialized cells. Antigenic changes are known to occur in
tumour formation due to somatic mutation or virus transformation and the function of this system may be to detect and eliminate such cell lines as they arise (Good and Papermaster, 1964). GENETIC POLYMORPHISM
Diseases, particularly those reaching epidemic proportions, are selective forces of extreme potency and it is possible that individuals maybe more susceptible to pathogens with which they share antigens. Thus the antigenic relationship between smallpox virus and A blood group substance may explain the rarity of the A gene in the world's great smallpox epidemic areas (Pettenkofer et al., 1962). A similar situation appears to exist for plague and B blood group substance. The maintenance of blood group and other polymorphism in chicken might be similarly determined. REFERENCES Allen, S. L., 1955. H — 2'. A tenth allele at the histocompatibility —2 locus in the mouse as determined by tumor transplantation. Cancer Research, 15: 315-319. Anderson, D., R. E. Billingham, G. H. Lampkin and P. B. Medawar, 1951. The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle. Heredity, 5: 379397. Aspinall, R. L., R. K. Meyer, M. A. Graetzer and H. R. Wolfe, 1962. Effect of thymectomy and bursectomy on the survival of skin homografts in chickens. J. Immunol. 90: 872-877. Barnes, D. W. H., J. F. Loutit and H. S. Micklem, 1962. "Secondary disease" in lethally irradiated mice restored with syngeneic or allogeneic foetal liver cells. In Mechanisms of Immunological Tolerance, Czechoslovak Academy of Science, Prague. Billingham, R. E., L. Brent and P. B. Medawar, 1953. "Actively acquired tolerance" of foreign cells. Nature, 172 : 603-606. Boyer, C , 1960. Chorioallantoic membrane lesions produced by inoculation of adult fowl leucocytes. Nature, 185: 327-328.
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sectomised birds and are regarded as bursa dependent. Presence of the bursa is necessary for the development of visceral lymphomatosis, bursectomised birds don't get the disease and in affected birds this tissue is greatly increased. This resembles the immunological picture of patients suffering from the Bruton type of sex-linked agammaglobulinaemia. They fail to produce yglobulins, and lack plasma cells, but are able to reject skin grafts and express delayed hypersensitivity a situation exactly parallel to that in bursectomised chickens (Cooper et al., 1965). In mamals the lymphoid organs associated with the gut epithelium may serve the function of the bursa; the appendix and intestinal tonsil of the rabbit have been assigned this homologous role. Thus may be visualised the basis of the two-cell system of antibody production previously suggested, in which the thymus cells provide the recognition mechanism and the bursa cells produce antibody.
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Brent, L., and P. B. Medawar, 1962. Quantitative Studies on the genetic and antigenic basis of studies on tissue transplantation immunity, V. tumour transplantation. Proc. Roy. Soc. B 135: Proc. Roy. Soc. B 155: 392-416. 499-505. Briles, W. E., 1962. Additional blood group sysGowans, J. L., B. M. Gesner and D. D. Mctems in the chicken. Ann. New York Acad. Sci. Gregor, 1961. The immunological activity of 97: 173-183. lymphocytes. In Biological Activity of the LeuBurnet, F. M., 1959. The Clonal Selection Theory cocyte. Ciba Foundation Study Group No. 10. of Acquired Immunity. Cambridge University Churchill, London. Press, London. Harris, R. J. C , 1956. Acquired tolerance of turChang, T. S., M. S. Rheins and A. R. Winter, keys to Rous sarcoma agent. Proc. Roy. Soc. 1959. The significance of the bursa of Fabricius B. 146: 59-66. of chickens in antibody production. 3. ResistHasek, M., 1956. Tolerance phenomena in birds. ance to Salmonella typhimurium infection. Proc. Roy. Soc. B. 146: 67-77. Poultry Sci. 38: 174-176. Jaap, R. G., 1958. Large bursae Fabricii in legCinader, B., 1963. Dependence of antibody rehorn-type baby chicks. Poultry Sci. 37: 1462sponses on structure and polymorphism of au1464. tologous macromolecules. British Med. Bull. 19: Jaffe, W. P., 1965. Protection against splenome219-224. galy in chicks. Transplantation. In press. Cohen, C , R. G. De Palma, J. E. Colberg, R. G. Jankovic, B. D., M. Isvaneski, M. Milosevic and Tissot and C. A. Hubay, 1964. The relationL. Popeskovic, 1963. Delayed hypersensitive reship between blood groups and histocompatiactions in bursectomised chickens. Nature, 198: bility in the rabbit. Ann. New York Acad. Sci. 298-299. 120: 356-361. Kaliss, N., 1958. Immunological enhancement of Cooper, M. D., R. D. A. Peterson and R. A. tumor homografts in mice. Cancer Research, 18: Good, 1965. Delineation of the thymic and bur992-1003. sal lymphoid system in the chicken. Nature, Landsteiner, K., 1945. The Specificity of Serologi205: 143-146. cal Reactions. Harvard University Press, CamEdelman, G. M., and J. A. Gaily, 1964. A model bridge, Massachusetts. for the S7 antibody molecule. Proc. Nat. Acad. Long, P. L., and A. E. Pierce, 1963. Role of celluSci. 51: 846-853. lar factors in the mediation of immunity to Eichwald, E. J., and C. R. Silmer, 1955. Communiavian coccidiosis. Nature, 200: 426-427. cation. Transplant. Bull. 2: 148-149. McDermid, E. M., 1964. Immunogenetics of the Gilmour, D. G., 1963. Current status of blood chicken. Vox Sang. 9 : 249-267. groups in chickens. Ann. New York Acad. Sci. Miller, J. F. A. P., 1962. Effect of neonatal thy97: 166-172. mectomy on the immunological responsiveness Glick, B., 1960. Extracts from the bursa of Fabricof the mouse. Proc. Roy. Soc. B 156: 415ius—a lympho-epithelial gland of the chicken— 428. stimulate the production of antibodies in burNossal, G. J. V., 1964. How cells make antibodies. sectomised birds. Poultry Sci. 39: 1097-1101. Scientific American, D e c : 106-115. Glick, B., T. S. Chang and R. G. Jaap, 1956. The Pettenkofer, H. J., B. Stoss, W. Helmbold and F. bursa of Fabricius and antibody production. Vogel, 1962. Alleged causes of the present-day Poultry Sci. 3S: 224-225. world distribution of human ABO blood Glynn, L. E., 1963. Auto-immunity. In Modern groups. Nature, 193 : 445-446. Trends in Immunology. Butterworth, London. Russell, P. S., 1962. The modification of runt disGoldsmith, K. L. G., 1965. Donor selection and ease in mice by various means. In Ciba Foundacompatibility typing. British Med. Bull. 21: tion Symposium on Transplantation. Churchill, 162-165. London. Good, R. A., and B. W. Papermaster, 1964. OnSadler, C. R., and B. Glick, 1962. The relationship togeny and phylogeny of adaptive immunity. of the size of the bursa of Fabricius to antibody Advances in Immunol. 4 : 1-113. production. Poultry Sci. 4 1 : 508-510. Gorer, P. A., J. F. Loutit and H. S. Micklem, Schierman, L. W., and A. W. Nordskog, 1961. Re1961. Proposed revisions of "transplantese." Nalationship of blood type to histocompatibility ture, 189: 1024-1025. in chickens. Science, 134: 1008-1009. Gorer, P. A., S. Lyman and G. D. Snell, 1948. Seto, F., and J. F. Albright, 1965. An analysis of
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with a hormonally arrested development of lymphoid follicles. Nature, 194: 146-147. Szenberg, A., and N. L. Warner, 1962. Large lymphocytes in the Simonsen phenomenon. Nature, 191: 920. Thomas, E. D., S. Kasakura, J. A. Cavins, S. N. Swisher and J. W. Ferrebee, 1964. Significance of blood groups in homotransplantation of marrow in the dog. Ann. New York Acad. Sci. 120:362-366 Warner, N. L., and A. Szenberg, 1962. Effect of neonatal thymectomy on the immune response in the chicken. Nature, 196: 784-785. Winn, H. L., 1962. The participation of complement in isoimmune reactions. Ann. New York Acad. Sci. 101: 23-45. Woodruff, M. F. A., and T. M. Allan, 1953. Blood groups and the homograft problem. Brit. J. Plastic Surg. 5 : 238-242.
Estimates by Sex of Genetic Parameters for Body Weight and Skeletal Dimensions in a Random Bred Strain of Meat Type Fowl1 E.
Canada Department
S.
MERRITT
of Agriculture, Research Branch, Ottawa, Ontario, Canada (Received for publication July 25, 1965)
"D ELATIVELY few of the many report- based on a population of meat-type chick•*• *- ed estimates of genetic parameters ens maintained as a random bred control for traits in the fowl have been based on strain. The history and development of this control or unselected populations. In addi- strain have been previously reported by tion to characterizing the population itself, Merritt and Gowe (1962). estimates based on such populations can be Only traits, namely body weights and very useful in quantitative inheritance skeletal dimensions, obtained on both sexes studies. to broiler age are reported in this study. King (1961) has pointed out that estiJaap et al. (1962) and King et al. mates on unselected populations based on (1963) have reported heritability estimates the commonly used variance component for early body weight in random bred conanalyses, are free of the bias that could re- trol strains. sult from selection of parents. Establishing Heritabilities and genetic correlations changes, if any, in genetic parameters of for certain body weights and measurements selected lines drawn from the control popu- have been reported for a random bred conlation has been mentioned by King as trol strain of turkeys by McCartney being an important use for such estimates. (1961). The estimates reported in this study are Estimates of genetic parameters on se1 lected populations have been more numerContribution No. 210, Animal Research Inous; 176 heritability estimates for 6 to stitute, Research Branch, Ottawa, Ontario.
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host and donor contributions to splenic enlargement in chick embryos inoculated with adult spleen cells. Developmental Biology, 11: 1-24. Simonsen, M., and E. Jensen, 1959. The graft versus host assay in transplantation chimaeras. In Biological Problems of Grafting. Blackwell, Oxford. Simonsen, M., 1957. The impact on the developing embryo and newborn animal of adult homologous cells. Acta path, microbiol. scand. 40: 480-500. Snell, G. D., 1953. The genetics of transplantation. J. Nat. Cancer Inst. 14: 691-700. St. Pierre, R. L., and G. A. Ackerman, 1965. Bursa of Fabricius in chickens: possible humoral factor. Science, 147: 1307-1308. Szenberg, A., and N. L. Warner, 1962. Dissociation of immunological responsiveness in fowls
JAFFE
Department of Poultry Science, Ohio State University, Columbus, Ohio (Received for publication July 23, 1965)
I
N THE last few years the chicken has become increasingly popular as a subject for immunological studies and much information of a specific nature as well as of general biological interest has been obtained. BLOOD GROUPS
At least ten, and possibly as many as twelve different loci determining red cell antigens have been reported in the chicken. The majority of these are diallelic but the B system is a multiple allelic one, in which over 20 alleles are known (Briles, 1962; Gilmour, 1962; McDermid, 1964). Antigens determined by the B and C system are carried by the leucocytes as well, the others are not (Schierman and Nordskog, 1961). Special interest centres on their role in tissue-transplantation. Such antigens are known as histocompatibility antigens and in mice at least four loci are known. While the reaction between donor and host represents the cumulative effects of differences in histocompatibility antigens between them, one, the H2 locus, presents the strongest barrier. This locus, like B in chickens, also determines erythrocyte antigens and has a number of alleles (Gorer et al, 1948; Allen, 19SS; Snell, 1958). A further locus has been found on the Y chromosome and is the only active gene known on that chromosome in mice (Eichwald and Silmser, 1955). Since in mice and chickens major histocompatibility antigens are also red cell antigens, knowledge of the role of blood group compatibility in graft *On leave of absence from School of Veterinary Science, University of Bristol, England.
MECHANISM OF GRAFT REJECTION
Grafted animals produce antibodies against the donor of the grafted tissue but attempts to transfer immunity to grafts passively with serum from animals immunized by previous exposure to grafts has usually been unsuccessful (Brent and Medawar, 1962). On the contrary, antiserum frequently facilitates takes of tumor grafts, a phenomenon known as enhancement; enhancement of normal tissues has probably not been clearly demonstrated (Kaliss, 1958). Although such antibodies show evidence of lymphocyte toxicity and can probably cause the rejection of dispersed cellular homografts, this is a different matter from rejecting organized tissues. Transplantation immunity can, however, be transferred adoptively by regional lymph node cells, thoracic duct lymphocytes and blood leucocytes (Gowan et al., 1961).
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survival is of great practical interest. In rabbits the Hg blood group locus plays a positive role in takes of skin grafts (Cohen et al., 1964) but neither in man (Woodruff and Allan, 1953) nor in dogs (Thomas et al., 1964) do the major blood groups have an effect on histocompatibility. Although leucocytes are a powerful source of transplantation antigens, lack of specific sera has hampered the development of leucocyte serology. Thus no more than a possible relationship between graft survival and leucocyte compatibility has so far been shown (Goldsmith, 1965). Transplantation antigens are also present on platelets but absent from erythrocytes in man.
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Cellular elementes evidently play a major role in graft rejection (Murphy, 1926). Lymphocytes and immature plasma cells begin to appear in the graft bed after 5 to 6 days. Their part in the rejection mechanism is obscure, but it could occur through release of antibody in high local concentration. Complement also pays an important part in the destruction of foreign cells (Winn, 1962). NOMENCLATURE
Grafts on self: Autografts Grafts from same genotype as host: Syngeneic homografts Grafts from same species as host: Allogeneic homograts Grafts from species different from host: Xenograft. To bring blood group terminology into line with that used in transplantation, the terms allo-antigen and antibody have been proposed in place of iso-antigen and antibody, an allo-antigen being a constituent of an animal which evokes the formation of antibody (allo-antibody) in genetically distinct individuals of the same species. The situation governing rejection of foreign tissues is subject to the same rules as those of blood groups. Autografts and syngeneic grafts are accepted, provided the lines are sufficiently inbred. Crosses between inbred lines have antigens absent from one or other of the inbred parents; in consequence grafts from the parent lines are accepted by the hybrids, but grafts
TOLERANCE
The state of acquired immunological tolerance, leading to prolonged or permanent retention of foreign tissue is of great practical importance as well as being of interest for immunological theory. It was first discovered in the natural state in non-identical cattle twins the majority of which accept grafts of each others skin. Takes occurred in those pairs in which a common blood circulation had been established. (Anderson et al., 1951.) This state can be produced experimentally by injecting embryos or neonates with tissue from genetically foreign donors. Grafts of skin and other tissue are accepted from the original donor when the animal is immunologically mature (Billingham et al., 1953). In birds, artificial twins can be made by uniting the blood circulation of developing embryos via the chorio-allantoic membrane. As adults, birds from such parabiosed eggs are incapable of forming antibody to each others erythrocytes (Hazek, 1956). What is the nature of this incapacity? It could be: a) inability of graft antigens to reach the antibody forming host cells. b) failure of the antibody mechanism to act on graft cells. c) an alteration in the activity of the antibody forming tissue. When tolerant animals bearing a foreign graft are injected with lymphoid cells from a normal animal of the same strain as the tolerant one, the graft is rejected. Tolerance can thus be abrogated by adoptive
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The literature on transplantation has suffered unduly from a confused terminology. The word homograft, for instance, has so many meanings that it has become meaningless. The nomenclature now accepted by most workers in this field distinguishes between the various types of graft as follows (Gorer et al., 1961):
from the hybrid to either parent are rejected. Grafts from the same or different species are normally rejected, but to this rule there are important exceptions.
AVIAN IMMUNOBIOLOGY
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immunisation, indicating the third possibil- produced as the cell matures and presence ity to be the correct one. of antibody is then a stimulus to further Two points are to be noted: 1) unre- proliferation and to antibody formation sponsiveness is restricted to the antigen(s) (Burnet, 1959). with which the embryo initially comes into The idea of cell death necessarily precontact; response to others is normal. 2) supposes a selective theory; on any inTolerance is maintained only as long as the structive theory all antibody producing antigen is present. cells would be wiped out. Furthermore, tolBut tolerance can also be developed in erant cells do not exist on this theory, only adults, either after high doses of ionising tolerant individuals. At the present time selective theories radiation, or in normal adults exposed to most satisfactorily explain the majority of high concentrations of antigen. Immunity and tolerance are alternative observations. This does not prove them to be reactions to the same stimulus; the out- correct; indeed, many difficulties remain. come depends on the time of administraOne is the mechanism required for the tion and dosage of antigen. enormous number of clones needed to atSince an antigen is usually denned by its tack all possible antigens. That this may capacity to induce an immune response, be quite small is suggested by recent infortolerance to an antigen is a contradiction mation on the structure of the most comin terms. Clearly a redefinition to include mon type of antibody, 7S. This is composed of four parts, two heavy A chains tolerance is needed. Tolerance to foreign antigen may be re- and two light B chains. Assuming the comgarded as identical with the mechanism by bining site is shared by these two types of which an organism becomes tolerant of its chain and the configuration is gene conown body constituents and is presumably a trolled, then quite a small number of genes device for preventing "horror autotoxicus". could produce a great variety of combinaTheories of tolerance are an extension of tions (Edelman and Gaily, 1964). theories of antibody production in general made only against those by which they There is at present no indication that and nowadays centre on the concept of immunological maturity at the cellular level. antigen controls the shape of the combinOn this view the lymphoid system is com- ing site in the manner of a template for the posed of a mixture of immunologically im- antibody, as envisaged by some instructive mature and mature cells, the essential theories. On the contrary, isotope labelling difference between embryos and adults studies show little if any antigen actually being in the proportion of the two types. inside the antibody producing cells. The According to selective theories of antibody presence of antigen is apparently all that is formation, a complete range of cells, each needed for antibody production in cells of producing antibody of different specificity the appropriate genetic specificity to prois required. When these cells are engaged ceed (Nossal, 1964). by antibody, two effects, depending on A somewhat less hazardous method the stage of development of the cells, are might be expected to have been favoured envisaged. Immature cells, being highly by natural selection. This could be most susceptible to specific antibody, are elimi- simply achieved by the participation of nated by its presence. In its absence, two cell types, one to elaborate the mesclones of cells of identical specificity are sage, the other to manufacture antibody.
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Evidence from recent work on chickens provides experimental support for such a system and its operation has also been inferred in mammals, although a dissociation of immunological function is harder to demonstrate. CONSEQUENCES OF TOLERANCE
AUTOIMMUNITY All specialised organs probably contain tissue specific antigens, but under normal conditions no immune reaction is directed against them, presumably because they are protected by tolerance. The nature of the ban on autoimmunity centres on the mechanism by which tolerance is normally achieved. Autoimmunity is produced when the mechanism responsible for tolerance breaks down. In autoimmune diseases in man and certain strains of mice, there is a genetic liability for clones of cells less subject to inhibition by antigen to arise. These "forbidden clones" then react against the antigenic determinants of the host. Experimental autoimmunity can be produced by means of physiologically unnatu-
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Inhibition of antibody response is expected to extend to other substances which share antigenic determinants with those to which the animal has become tolerant. This could explain why some substances are good and others bad antigens, and some individuals good and others bad antibody producers. It also provides an explanation of "faulty perspective". Landsteiner first used this term to describe the finding that rabbits immunised against one rodent species gave a greater reaction against this species than against other species of rodent, whereas they showed little variation in their reaction to different species of birds after immunisation with one of them (Landsteiner, 1945). Because variation in protein structure of different species depends on their evolutionary relationship, rodents have many characteristics in common. Antibody is made only against those by which they differ; thus, only a small proportion of antibody produced against, say, mouse, will react with rat. Bird proteins differ more from mammals and a larger proportion of rabbit antibody molecules react equally with antigen of different bird species (Cinader, 1963). Individuals of the same species vary in antigenic determinants, such as blood groups, and serum and milk proteins. Since these are excluded from immunogenicity by tolerance, the antibody response of individuals is expected to vary. The ABO blood group story in man may be used to illustrate this. Blood group chimeras have been observed in O group indi-
viduals which have received cells from their A group twin. Such individuals do not have anti-A in their serum. Evidently the presence of A group cells induced tolerance and prevented the synthesis of the appropriate antibody. This raises the question of how such antibodies are normally produced. Pneumococci are known to contain capsular polysaccharides which react with blood group antigens, hence the production of A and B antibodies could be the result of bacterial infection. Similarly, chickens possess hemagglutinins for human group B red cells. These are not present in germ free chicks, but infection with E. coli, which contain antigen reacting with the B substance, causes the appearance of antibody (Springer et al., 19S8). That tolerance induced to a pathogen can affect resistance to it is shown in the case of Rous sarcoma, which shares antigens with chicken cell membranes. Chickens are highly susceptible but turkeys are resistant, but when turkeys are made tolerant to chickens, they also become susceptible to Rous sarcoma (Harris, 1956).
AVIAN IMMUNOBIOLOGY
GRAFT V. HOST REACTIONS When transplants containing immunocytes are made to hosts unable to reject them, but containing histocompatibility antigens absent from the donor, graft v. host reactions may develop (Simonsen, 1957). The necessary host unresponsiveness may arise in one of four ways: 1) Hosts are tolerant of donor antigens. 2) Hosts are embryos or neonates. Here the graft may or may not induce tolerance; if tolerance is not developed the reaction may proceed until the host is destroyed. 3) Hosts are genetically unable to react to donor cells, as in parent strain donors on Fj hosts of the same sex. 4) Irradiation of adults to destroy their immunological defences. The outcome of the graft v. host reaction varies with the age of the host, the strain combinations involved and the type
and amount of inoculum employed. A general pattern is proliferation of the lymphoid cells, leading to splenomegally and other changes, followed by lymphoid atrophy, loss of weight (ranting) and death, probably as a result of invasion by pathogens. Donor cells destroy host lymphoid tissue in areas in which they settle and divide; this is the reverse of what occurs in the homograft reaction. Host immunological unresponsiveness is then the result of the destruction of its lymphoid tissue by donor cells. Supporting evidence for this explanation comes from the appearance of similar syndromes produced by other methods known to lead to lymphoid deficiency. These are thymectomy of baby mice and lethal irradiation followed by restoration with syngeneic inocula scarce in lymphoid cells, i. e. fetal liver or bone marror (Barnes et al., 1962). CELL TYPES RESPONSIBLE Lymphoid cells have so far been treated as a single group, but two types of cell of interest in this connection may be distinguished morphologically. These are the lymphocytes, classified into large, medium and small, and the plasma cells, which secrete antibody. The large lymphocyte, capable of mitotic division was thought to be the candidate for the immunocyte in the homograft and graft v. host reactions, but recently the small lymphocyte, previously regarded as an end cell, has been shown to be responsible for the graft v. host reaction in rats (Gowans et al., 1961). In chickens, on the other hand, the ability to cause graft v. host reactions, as measured by the initiation of foci on the chorioallantoic membrane, is related to the number of medium and large lymphocytes (Szenberg and Warner 1962). Added interest is provided by the recent discovery that small lymphocytes are able
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ral manipulations. Administration of body tissues in Freunds adjuvant is an effective method. The antigen is probably altered in some way so as to be regarded as foreign. Alteration of body constitutents may play a major role in certain autoimmune conditions. It may follow from tissue damage, as in cardiac surgery, where antibody to heart muscle is frequently seen. What part, if any, autoantibody plays in tissue damage is uncertain; it is more likely the result than the cause of autoimmunity. Nowadays autoantibody is realized to be of widespread occurence in diseased as well as healthy subjects (Glynn, 1963). There is agreement that the production of autoimmune disease is the consequence of the activity of immunocytes antigenically different from the host. Examples of tolerated cells engaging in immunological activity against the antigenic components of the host are the basis of graft v. host reactions.
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to transform to cells morphologically like plasma cells. The role played by donor and host cells in the graft v. host reaction, particularly in its early, proliferative phase, is a matter for speculation. In some mouse strains total replacement by donor cells is seen, whereas in others cellular proliferation is mainly of host origin. In chick embryos, up to 70% of the dividing cells in the spleen are of donor origin at the height of the proliferative phase (Seto and Albright, 1965).
Once started, the graft v. host reaction is very difficult to stop, but the serverity of its effect may be reduced in a number of ways. Injection with adult syngeneic cells is effective but must be done very shortly after the allogeneic cells are given. If preimmunised cells are used, protection even after several days is possible. This is the situation in mice (Russel, 1962). In chickens only preimmunised cells are effective and those must be given within half an hour of the allogeneic cells in B incompatible donor-host combinations (Jaffe, 1965). CRITERIA
For a quantitative assessment of the reaction the following criteria are used: 1) Mortality. This is not very sensitive but direct and useful for strong combinations. 2) Weight gain. Failure of runts to grow or loss of weight of adults compared to untreated controls. 3) Spleen assay. Splenomegaly is a good quantitative method but involves killing the host. 4) Phagocytosis. Rate of carbon clearance is accelerated during the proliferative phase. 5) Discriminant spleen assay. This is
THYMECTOMY AND BURSECTOMY
A wasting disease similar to that seen in graft v. host reactions occurs in mice thymectomised at birth. In such animals the lymph nodes and the lymphoid follicles of the spleen are underdeveloped and there is a shortage of circulating lymphocytes. Their immunological activity to a variety of antigens is restricted; rejection of homografts and the ability to cause graft v. host reactions is reduced, and a fatal wasting disease occurs at three to four weeks of age (Miller, 1962). In adults, thymectomy has no permanent effect; secondary lymphoid organs are presumably able to carry on with their own complement of cells. But if the adults are irradiated and then thymectomised, immunological reactions are reduced and runting sets in. In both adults and newborn, immunological activity is restored and runting prevented by grafts of adult thymus or spleen cells, suggesting that the defect is primarily due to a lack of cells. However, in such restored animals, the lymphoid cells are predominantly of host origin. Thus the protective effect of the implanted thymus does not act solely by means of donating cells. Evidence that the contribution may be a hormonal one comes from experiments on thymus grafts enclosed in cell-retaining millipore chambers, which permit development of immunologic
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THERAPY
a method of estimating the activity of immunocytes in chimeric spleens. A mixed population of A and B spleen cells is injected onto infant A X C and B X C hosts. Cells of on genotype produce a graft v. host reaction in each, the others are rejected (Simonsen and Jensen, 1959). 6) CAM assay. Donor leucocytes produce foci on the chorio-allantoic membrane of embryos bearing antigen not present in the donor (Boyer, 1960).
AVIAN IMMUNOBIOLOGY
mal in bursectomised birds, the 7S component being principally involved (Long and Pierce, 1963). Higher antibody titres have been reported in birds with bigger bursas, (Sadler and Glick, 1962) and the better disease resistance of White Leghorns may be correlated with their larger bursa (Jaap, 1958). Since in bursectomised birds, even a small amount of residual bursa is usually able to permit antibody response, the interpretation of these findings is not a simple one. A specific effect of bursectomy on disease resistance is the higher mortality from challenge with live Salmonella typhimurium, reported by Chang et al. (1959). No difference in resistance to coccidiosis has been reported. Delayed type hypersensitive reactions appear not to be influenced by bursectomy, at least as far as the experiments employing surgical removal are concerned. Skin graft survival times are also normal (Jankovic et al., 1963). It may be concluded that lymphocytes are responsible for mediating these reactions and that circulating antibody plays no part. Birds evidently have two populations of immunologically competent cells, one associated with the thymus and responsible for cell mediated reactions, the other concerned with the production of circulating antibody and originating in the bursa. There may be yet a third population which controls the ability to cause graft v. host reactions, since neither bursectomy, thymectomy nor a combination of the two has yet been shown to modify this reaction. In corroboration of this, two types of tissue are seen in avian spleen; an early developing white pulp which is reduced in thymectomised birds and considered thymus dependent as well as later developing lymphoid follicles which resemble those seen in the bursa. These are absent in bur-
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capacity. In the chicken, thymectomy affects the ability to reject skin grafts, the formation of circulating antibody is not impaired and ranting does not occur (Warner and Szenberg, 1962). In comparison with the mouse, lymphoid development of the thymus occurs earlier in development, so that "peripheralisation" of lymphoid cells to the secondary lymphoid organs may already have proceeded further before hatching (Aspinall et al., 1962). In birds there are two primary lymphoid organs, the thymus and the Bursa of Fabricius. In this structure, which arises as a dorsal diverticulum from the cloaca, lymphoid elements begin to develop on the 14th day of incubation. Its role in antibody production was first reported less than ten years ago, until then its function had been completely unknown (Glick et al., 1956). Bursectomised birds have a reduced ability to react to a variety of antigens; the earlier in life the bursa is removed, the more pronounced the effect. Injection of testosterone into young embryos prevents the development of lymphoid tissue in the bursa; in a small proportion of birds the thymus may also be inhibited (Szenberg and Warner, 1962). Partial restoration of bursal activity may be accomplished by inplanting pieces of bursal tissue enclosed in millipore chambers (St. Pierre and Ackerman, 1965). Saline extracts of acetone dried bursa are also effective (Glick, 1960). These findings suggest the existence of a humoral agent, responsible for immunological activity. Bursectomised birds show a striking reduction in plasma cells, but the number of blood lymphocytes and lymphoid follicles is only slightly reduced (Long and Pierce, 1963). This is the converse of the situation seen in thymectomised birds (Warner and Szenberg, 1962). Levels of serum glubulins are below nor-
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EVOLUTIONARY ASPECTS
Adaptive immunity is a process developing late both in ontogeny and in phylogeny. In evolution, its appearance is linked to the development of a thymus and lymphoid cells, first seen in species above the lamprey. It is not present in invertebrates, which deal with their pathogens by phagocytic and enzymatic mechanisms. Since they share many environments with vertebrates, where both are exposed to a similar array of pathogens, the latter presumably have no greater need for protection. Immune responses are thus not entirely protective. What purpose, then, does this system serve? Higher animals are characterised by increased specialization, possess highly complicated organs and specialized cells. Antigenic changes are known to occur in
tumour formation due to somatic mutation or virus transformation and the function of this system may be to detect and eliminate such cell lines as they arise (Good and Papermaster, 1964). GENETIC POLYMORPHISM
Diseases, particularly those reaching epidemic proportions, are selective forces of extreme potency and it is possible that individuals maybe more susceptible to pathogens with which they share antigens. Thus the antigenic relationship between smallpox virus and A blood group substance may explain the rarity of the A gene in the world's great smallpox epidemic areas (Pettenkofer et al., 1962). A similar situation appears to exist for plague and B blood group substance. The maintenance of blood group and other polymorphism in chicken might be similarly determined. REFERENCES Allen, S. L., 1955. H — 2'. A tenth allele at the histocompatibility —2 locus in the mouse as determined by tumor transplantation. Cancer Research, 15: 315-319. Anderson, D., R. E. Billingham, G. H. Lampkin and P. B. Medawar, 1951. The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle. Heredity, 5: 379397. Aspinall, R. L., R. K. Meyer, M. A. Graetzer and H. R. Wolfe, 1962. Effect of thymectomy and bursectomy on the survival of skin homografts in chickens. J. Immunol. 90: 872-877. Barnes, D. W. H., J. F. Loutit and H. S. Micklem, 1962. "Secondary disease" in lethally irradiated mice restored with syngeneic or allogeneic foetal liver cells. In Mechanisms of Immunological Tolerance, Czechoslovak Academy of Science, Prague. Billingham, R. E., L. Brent and P. B. Medawar, 1953. "Actively acquired tolerance" of foreign cells. Nature, 172 : 603-606. Boyer, C , 1960. Chorioallantoic membrane lesions produced by inoculation of adult fowl leucocytes. Nature, 185: 327-328.
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sectomised birds and are regarded as bursa dependent. Presence of the bursa is necessary for the development of visceral lymphomatosis, bursectomised birds don't get the disease and in affected birds this tissue is greatly increased. This resembles the immunological picture of patients suffering from the Bruton type of sex-linked agammaglobulinaemia. They fail to produce yglobulins, and lack plasma cells, but are able to reject skin grafts and express delayed hypersensitivity a situation exactly parallel to that in bursectomised chickens (Cooper et al., 1965). In mamals the lymphoid organs associated with the gut epithelium may serve the function of the bursa; the appendix and intestinal tonsil of the rabbit have been assigned this homologous role. Thus may be visualised the basis of the two-cell system of antibody production previously suggested, in which the thymus cells provide the recognition mechanism and the bursa cells produce antibody.
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Brent, L., and P. B. Medawar, 1962. Quantitative Studies on the genetic and antigenic basis of studies on tissue transplantation immunity, V. tumour transplantation. Proc. Roy. Soc. B 135: Proc. Roy. Soc. B 155: 392-416. 499-505. Briles, W. E., 1962. Additional blood group sysGowans, J. L., B. M. Gesner and D. D. Mctems in the chicken. Ann. New York Acad. Sci. Gregor, 1961. The immunological activity of 97: 173-183. lymphocytes. In Biological Activity of the LeuBurnet, F. M., 1959. The Clonal Selection Theory cocyte. Ciba Foundation Study Group No. 10. of Acquired Immunity. Cambridge University Churchill, London. Press, London. Harris, R. J. C , 1956. Acquired tolerance of turChang, T. S., M. S. Rheins and A. R. Winter, keys to Rous sarcoma agent. Proc. Roy. Soc. 1959. The significance of the bursa of Fabricius B. 146: 59-66. of chickens in antibody production. 3. ResistHasek, M., 1956. Tolerance phenomena in birds. ance to Salmonella typhimurium infection. Proc. Roy. Soc. B. 146: 67-77. Poultry Sci. 38: 174-176. Jaap, R. G., 1958. Large bursae Fabricii in legCinader, B., 1963. Dependence of antibody rehorn-type baby chicks. Poultry Sci. 37: 1462sponses on structure and polymorphism of au1464. tologous macromolecules. British Med. Bull. 19: Jaffe, W. P., 1965. Protection against splenome219-224. galy in chicks. Transplantation. In press. Cohen, C , R. G. De Palma, J. E. Colberg, R. G. Jankovic, B. D., M. Isvaneski, M. Milosevic and Tissot and C. A. Hubay, 1964. The relationL. Popeskovic, 1963. Delayed hypersensitive reship between blood groups and histocompatiactions in bursectomised chickens. Nature, 198: bility in the rabbit. Ann. New York Acad. Sci. 298-299. 120: 356-361. Kaliss, N., 1958. Immunological enhancement of Cooper, M. D., R. D. A. Peterson and R. A. tumor homografts in mice. Cancer Research, 18: Good, 1965. Delineation of the thymic and bur992-1003. sal lymphoid system in the chicken. Nature, Landsteiner, K., 1945. The Specificity of Serologi205: 143-146. cal Reactions. Harvard University Press, CamEdelman, G. M., and J. A. Gaily, 1964. A model bridge, Massachusetts. for the S7 antibody molecule. Proc. Nat. Acad. Long, P. L., and A. E. Pierce, 1963. Role of celluSci. 51: 846-853. lar factors in the mediation of immunity to Eichwald, E. J., and C. R. Silmer, 1955. Communiavian coccidiosis. Nature, 200: 426-427. cation. Transplant. Bull. 2: 148-149. McDermid, E. M., 1964. Immunogenetics of the Gilmour, D. G., 1963. Current status of blood chicken. Vox Sang. 9 : 249-267. groups in chickens. Ann. New York Acad. Sci. Miller, J. F. A. P., 1962. Effect of neonatal thy97: 166-172. mectomy on the immunological responsiveness Glick, B., 1960. Extracts from the bursa of Fabricof the mouse. Proc. Roy. Soc. B 156: 415ius—a lympho-epithelial gland of the chicken— 428. stimulate the production of antibodies in burNossal, G. J. V., 1964. How cells make antibodies. sectomised birds. Poultry Sci. 39: 1097-1101. Scientific American, D e c : 106-115. Glick, B., T. S. Chang and R. G. Jaap, 1956. The Pettenkofer, H. J., B. Stoss, W. Helmbold and F. bursa of Fabricius and antibody production. Vogel, 1962. Alleged causes of the present-day Poultry Sci. 3S: 224-225. world distribution of human ABO blood Glynn, L. E., 1963. Auto-immunity. In Modern groups. Nature, 193 : 445-446. Trends in Immunology. Butterworth, London. Russell, P. S., 1962. The modification of runt disGoldsmith, K. L. G., 1965. Donor selection and ease in mice by various means. In Ciba Foundacompatibility typing. British Med. Bull. 21: tion Symposium on Transplantation. Churchill, 162-165. London. Good, R. A., and B. W. Papermaster, 1964. OnSadler, C. R., and B. Glick, 1962. The relationship togeny and phylogeny of adaptive immunity. of the size of the bursa of Fabricius to antibody Advances in Immunol. 4 : 1-113. production. Poultry Sci. 4 1 : 508-510. Gorer, P. A., J. F. Loutit and H. S. Micklem, Schierman, L. W., and A. W. Nordskog, 1961. Re1961. Proposed revisions of "transplantese." Nalationship of blood type to histocompatibility ture, 189: 1024-1025. in chickens. Science, 134: 1008-1009. Gorer, P. A., S. Lyman and G. D. Snell, 1948. Seto, F., and J. F. Albright, 1965. An analysis of
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with a hormonally arrested development of lymphoid follicles. Nature, 194: 146-147. Szenberg, A., and N. L. Warner, 1962. Large lymphocytes in the Simonsen phenomenon. Nature, 191: 920. Thomas, E. D., S. Kasakura, J. A. Cavins, S. N. Swisher and J. W. Ferrebee, 1964. Significance of blood groups in homotransplantation of marrow in the dog. Ann. New York Acad. Sci. 120:362-366 Warner, N. L., and A. Szenberg, 1962. Effect of neonatal thymectomy on the immune response in the chicken. Nature, 196: 784-785. Winn, H. L., 1962. The participation of complement in isoimmune reactions. Ann. New York Acad. Sci. 101: 23-45. Woodruff, M. F. A., and T. M. Allan, 1953. Blood groups and the homograft problem. Brit. J. Plastic Surg. 5 : 238-242.
Estimates by Sex of Genetic Parameters for Body Weight and Skeletal Dimensions in a Random Bred Strain of Meat Type Fowl1 E.
Canada Department
S.
MERRITT
of Agriculture, Research Branch, Ottawa, Ontario, Canada (Received for publication July 25, 1965)
"D ELATIVELY few of the many report- based on a population of meat-type chick•*• *- ed estimates of genetic parameters ens maintained as a random bred control for traits in the fowl have been based on strain. The history and development of this control or unselected populations. In addi- strain have been previously reported by tion to characterizing the population itself, Merritt and Gowe (1962). estimates based on such populations can be Only traits, namely body weights and very useful in quantitative inheritance skeletal dimensions, obtained on both sexes studies. to broiler age are reported in this study. King (1961) has pointed out that estiJaap et al. (1962) and King et al. mates on unselected populations based on (1963) have reported heritability estimates the commonly used variance component for early body weight in random bred conanalyses, are free of the bias that could re- trol strains. sult from selection of parents. Establishing Heritabilities and genetic correlations changes, if any, in genetic parameters of for certain body weights and measurements selected lines drawn from the control popu- have been reported for a random bred conlation has been mentioned by King as trol strain of turkeys by McCartney being an important use for such estimates. (1961). The estimates reported in this study are Estimates of genetic parameters on se1 lected populations have been more numerContribution No. 210, Animal Research Inous; 176 heritability estimates for 6 to stitute, Research Branch, Ottawa, Ontario.
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host and donor contributions to splenic enlargement in chick embryos inoculated with adult spleen cells. Developmental Biology, 11: 1-24. Simonsen, M., and E. Jensen, 1959. The graft versus host assay in transplantation chimaeras. In Biological Problems of Grafting. Blackwell, Oxford. Simonsen, M., 1957. The impact on the developing embryo and newborn animal of adult homologous cells. Acta path, microbiol. scand. 40: 480-500. Snell, G. D., 1953. The genetics of transplantation. J. Nat. Cancer Inst. 14: 691-700. St. Pierre, R. L., and G. A. Ackerman, 1965. Bursa of Fabricius in chickens: possible humoral factor. Science, 147: 1307-1308. Szenberg, A., and N. L. Warner, 1962. Dissociation of immunological responsiveness in fowls
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