- Email: [email protected]
Veterinary immunology: opportunities and challenges
4
Research Update
responses by up- or down-regulating the expression of TCR, inhibiting T-cell proliferation, inducing growth arrest and, finally, contributing to CD95-mediated cell death through multiple mechanisms. The different levels at which ceramide acts are summarized in Figure 1. We are still far from a conclusive picture of exactly how ceramide or its metabolites mediate their pleiotropic effects in T cells. However, we hope that further research in this field will provide encouraging new insights into T-cell biology and ultimately, lead also to the development of new clinical and therapeutic approaches towards immunological diseases. Acknowledgements
This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 415). We apologize to any authors whose work we were unable to cite owing to space constraints. References 1 Van Brocklyn, J.R. et al. (1998) Sphingosine-1phosphate: a lipid second messenger regulating cell growth and survival. J. Liposome Res. 8, 135–145 2 Hannun, Y.A. et al. (2001) Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochemistry 40, 4893–4903 3 Tonnetti, L. et al. (2000) A role for neutral sphingomyelinase-mediated ceramide production in T-cell-receptor-induced apoptosis and mitogenactivated protein-kinase-mediated signal transduction. J. Exp. Med. 189, 1581–1589
TRENDS in Immunology Vol.23 No.1 January 2002
4 Flores, I. et al. (2000) Changes in the balance between mitogenic and antimitogenic lipid second messengers during proliferation, cell arrest and apoptosis in T lymphocytes. FASEB J. 14, 1873–1875 5 Flores, I. et al. (1998) Dual role of ceramide in the control of apoptosis following IL-2 withdrawal. J. Immunol. 160, 3528–3533 6 Menné, C. et al. (2000) Ceramide-induced TCR up-regulation. J. Immunol. 165, 3065–3072 7 Menné, C. et al. (2001) T-cell receptor downregulation by ceramide-induced caspase activation and cleavage of the ζ chain. Scand. J. Immunol. 53, 176–183 8 Kirkham, P.A. et al. (2000) Ligation of the WC1 receptor induces γδ T-cell growth arrest through fumonisin-B1-sensitive increases in cellular ceramide. J. Immunol. 165, 3564–3570 9 Sciorati, C. et al. (1999) Generation of nitric oxide by the inducible nitric oxide synthase protects γδ T cells from Mycobacteriumtuberculosis-induced apoptosis. J. Immunol. 163, 1570–1576 10 Sciorati, C. et al. (1997) Autocrine nitric oxide modulates CD95-induced apoptosis in γδ T lymphocytes. J. Biol. Chem. 272, 23211–23215 11 Boucher, L-M. et al. (1995) CD28 signals through acidic sphingomyelinase. J. Exp. Med. 181, 2059–2068 12 Chan, G. and Ochi, A. (1995) Sphingomyelin–ceramide turnover in CD28 costimulatory signaling. Eur. J. Immunol. 25, 1999–2004 13 Kaga, S. et al. (1998) Activation of p21-CDC42/Rac-activated kinases by CD28 signaling: p21-activated kinase (PAK) and MEK kinase 1 (MEKK1) may mediate the interplay between CD3 and CD28 signals. J. Immunol. 160, 4182–4189 14 O’Byrne, D. and Sansom, D. (2000) Lack of costimulation by both sphingomyelinase and C2 ceramide in resting human T cells. Immunology 100, 225–230
15 Viola, A. (2001) The amplification of TCR signaling by dynamic membrane microdomains. Trends Immunol. 22, 322–327 16 Kirschnek, S. et al. (2000) CD95-mediated apoptosis in vivo involves acid sphingomyelinase. J. Biol. Chem. 275, 27316–27323 17 Lin, T. et al. (2000) Role of acidic sphingomyelinase in Fas/CD95-mediated cell death. J. Biol. Chem. 275, 8657–8663 18 Grassmé, H. et al. (2001) CD95 signaling via ceramide-rich membrane rafts. J. Biol. Chem. 276, 20589–20596 19 Cremesti, A. et al. (2001) Ceramide enables Fas to cap and kill. J. Biol. Chem. 276, 23954–23961 20 Hueber, A-O. (2000) CD95: more than just a death factor? Nat. Cell Biol. 2, E23–E25 21 Holler, N. et al. (2000) Fas triggers an alternative, caspase-8-independent cell-death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 22 Strelow, A. et al. (2000) Overexpression of acid ceramidase protects from tumor-necrosisfactor-induced cell death. J. Exp. Med. 192, 601–612 23 Heinrich, M. et al. (1999) Cathepsin D targeted by acid-sphingomyelinase-derived ceramide. EMBO J. 18, 5252–5263 24 Kroesen, B-J. et al. (2001) Induction of apoptosis through B-cell receptor cross-linking occurs via de-novo-generated C16-ceramide and involves mitochondria. J. Biol. Chem. 276, 13606–13614
Dieter Adam* Michael Heinrich Dieter Kabelitz Stefan Schütze Institut für Immunologie, Christian-AlbrechtsUniversität Kiel, Michaelisstr. 5, 24105 Kiel, Germany. *e-mail: [email protected]
Meeting Report
Veterinary immunology: opportunities and challenges Joan K. Lunney, Caroline Fossum, Gunnar V. Alm, Falko Steinbach and Eva Wattrang The 6th International Veterinary Immunology Symposium (6IVIS) was held in Uppsala, Sweden from 15–20 July 2001.
Veterinary immunology is dedicated to the improvement of animal health. Thus, immunity to infections was a focal point of the 6th International Veterinary Immunology Symposium (6IVIS), at which 450 delegates from 46 countries gathered to discuss the immunobiology of livestock, companion animal species and wildlife, including marine animals. This year, it was a particularly important topic, given the worldwide attention focused on the efforts http://immunology.trends.com
to control foot-and-mouth disease (FMD), avian influenza and bovine spongiform encephalopathy (BSE) in farm animals [1]. Infectious diseases jeopardize animal welfare and the agricultural economy in both developed and developing countries (see the World Organization for Animal Health website at http://www.oie.int). The situation is exacerbated by the fact that diseases such as brucellosis, classical swine fever (CSF), paratuberculosis, distemper and rabies move readily between domesticated species and wildlife. Moreover, many diseases pose a potential threat to human health.
Although the number of scientists and groups working on veterinary immunology is relatively small, there is an immense number of species and topics to be covered. Thus, communication and collaboration between researchers is a necessity. The Veterinary Immunology Committee of the International Union of Immunological Societies (VIC-IUIS) (http://www.cvm.missouri.edu/aavi/ VIC-IUIS.html) facilitates international and interdisciplinary research contacts by sponsoring workshops, an electronic bulletin board and symposia, such as the IVIS [2,3].
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)02126-3
Research Update
Immune-system diversity
Most species share immune-system mechanisms; therefore, approaches developed in humans and rodents can be adapted for disease prevention and control in veterinary species. However, there is still enormous diversity and close attention must be paid to species-specific differences. …many diseases pose a potential threat to ‘… human health.’
Unique cell populations and control mechanisms have been reported for various species. Swine have substantial numbers of double-positive CD4+CD8+ memory T cells, and numbers of these cells in the peripheral blood increase with age (A. Saalmüller, Tübingen, Germany). Ruminants and swine have major peripheral γδ T-cell populations that respond to numerous infections and might be important as early immune stimulators (M. Parkhouse, Oeiras, Portugal). The immune system of fish deviates from that of mammals to such an extent that the information gained from classical immunology is of very little help. The evolutionary scheme and nomenclature system devised for mammals cannot be applied simply to fish (L. Pilstrom, Uppsala, Sweden). For example, there are three or more Ig light-chain isotypes with clustered loci repeated in the genome of fish. IgM has diversified its structure over 500 million years of evolution, existing as a monomer, pentamer and tetramer and, even, in a truncated form (G. Warr, Charleston, USA). In chickens and ducks, a unique inversion of the segment containing the α- and µ-chain genes must occur during class switch to IgA. In camelids, IgG2 and IgG3 are homodimers of heavy chains (S. Muyldermans, Brussels, Belgium). Further details concerning the Igs in different animal species are available at the VIC-IUISsupported website of the Comparative Immunoglobulin Workshop (http://www.medicine.uiowa.edu/CIgW) (J. Butler, Iowa City, USA). At present, analyses of immune cells and proteins are limited by the lack of species-specific reagents. Cross-species reactivity of monoclonal antibodies (mAbs), and cytokines and/or chemokines and their receptors cannot be predicted. Major improvements are expected to http://immunology.trends.com
TRENDS in Immunology Vol.23 No.1 January 2002
5
Key outcomes of the meeting • Roles of unique cell subsets determined – for example, memory CD4+CD8+ T cells in pigs and immunostimulatory peripheral γδ T cells in ruminants and pigs. • Veterinary immunologists use DNA vaccines, edible vaccines and mucosal vaccination, including the successful vaccination of newborns. • Substantial role of microorganisms and nutrition in the development of the neonatal porcine mucosal immune system clarified. • Genomic regions controlling disease resistance and general immune responses established for pigs, cattle and chickens. • Enormous variety across species revealed in the genomic structure of Ig genes. • Investment into the investigation of basic species immunology is required to improve substantially disease prevention and aid vaccine developments in veterinary species.
come from the Animal Homologs section of the 8th International Workshop on Human Leukocyte Differentiation Antigens (http://www.HLDA8.org), in which all mAbs will be assessed for cross-reactivity (A. Saalmüller, Tübingen, Germany; B. Aasted, Copenhagen, Denmark). Vaccinology
Animals for consumption in developed countries are now raised in relatively biosecure facilities to decrease their dependence on antibiotics and vaccines. However, the emergence of new infectious diseases – for example, porcine reproductive and respiratory syndrome virus and BSE – or the re-emergence of highly virulent existing organisms (e.g. FMD) has put even these animals at risk. Specific diagnostic and preventative measures are required for disease control. Distinguishing vaccinated from infected animals is essential for effective disease-control programs in both captive and wild species (B.M. Buddle, Upper Hutt, New Zealand). The field of veterinary vaccinology is expanding rapidly. For example, the identification of cytotoxic-T-lymphocyte epitopes that confer protection against equine infectious anemia virus might lead to the development of effective vaccines for horses with this lentiviral infection and also, be informative for the vaccination of other outbred species (T. McGuire, Pullman, USA). Investigations of the function of the immune system in the respiratory tract will facilitate the development of nasal vaccines (A. Stanley, Penicuik, UK). Edible vaccines using corn and clover that express viral and bacterial antigens are already proving their efficacy (I. Tizard, College Station, USA;
P. Shewen, Guelph, Canada). Novel vaccine technologies, using microbial genome data and new adjuvants (e.g. CpG oligodeoxynucleotides), are transforming approaches to vaccination, as are methods that steer the immune response in an appropriate direction (Y. Van der Stede, Ghent, Belgium; R. Pontarello, Saskatoon, Canada). DNA vaccination has been evaluated in several species, with some vaccines undergoing clinical trials already. In contrast to laboratory animals, the vaccination of relatively long-lived species, such as dogs, cattle or horses, offers a unique possibility for monitoring the efficacy and possible side-effects of novel vaccine strategies (H. Hogen-Esch, West Lafayette, USA). ‘Unique cell populations and control mechanisms have been reported for various species.’
Research into neonatal immunology has been particularly fruitful. Studies in gnotobiotic pigs revealed that the appearance of CD4+ or CD8+ T cells and CD2− B cells is dependent on contact of the immune system with microorganisms (J. Sinkora and H. Tlaskalova, Prague, Czech Republic). Moreover, compelling data was presented on how nutritional components can modify the development of the mucosal immune system. The immunization of neonates is a challenge for vaccine technology. It has been shown that it is possible to induce a T-helper-1type response even in the presence of maternal antibodies (B. Morein, Uppsala, Sweden). Genetic resistance
Today, the use of every available modern molecular tool is being incorporated into
6
Research Update
veterinary research; reagents and knowledge are expanding exponentially. The use of microarray technology, together with previously established genomic libraries and the immune expressed-sequence-tag (EST) databases that are under development in many species, will further enhance these efforts. Already, veterinary immunologists use genomics to determine the factors influencing genetic resistance to infectious diseases. Using planned crosses of divergent breeds or lines that differ widely in immune function and disease resistance, significant progress has been made in defining genetic resistance to specific diseases – such as …the use of every available modern ‘… molecular tool is being incorporated into …’ veterinary research…
salmonellosis in chickens and trypanosomiasis in cattle (S. Lamont, Ames, USA; J. Naessens, Nairobi, Kenya) – and identifying chromosomal regions that influence immune functions in pigs and chickens (I. Edfors-Lilja, Växjö, Sweden; M-H. Pinard van der Laan, Jouy-en-Josas, France).
TRENDS in Immunology Vol.23 No.1 January 2002
Concluding remarks
Consolidation within the pharmaceutical industry and regulations on drug usage in animals for consumption have resulted in reduced investment in new drugs and vaccines just at the time when innovation is necessary and advances in animal health and disease prevention are readily accessible. Increased investment in veterinary immunology is required to facilitate advances in animal health, and the diagnosis and prevention of disease, primarily, for the benefit of animals but also, humans, in terms of safer foods and improved biomedical models. Acknowledgements
The Veterinary Immunology Committee is supported by the International Union of Immunological Societies (IUIS) (http://www.iuisonline.org). Full details of the conference can be found at http://www.service.slu.se/conference/ ivis2001. We thank Cynthia Baldwin for her thoughtful editorial comments. References 1 Miller, L.J. (2001) Foot and mouth. Nat. Immunol. 2, 565 2 Oberoi, M. and Naessens, J. (1999) Proceedings of the 5th International Veterinary Immunology
Symposium. Vet. Immunol. Immunopathol. 72, 1–248 3 Fossum, C. and Wattrang, E. Proceedings of the 6th International Veterinary Immunology Symposium. Vet. Immunol. Immunopathol. (in press)
Joan K. Lunney* Immunology and Disease Resistance Laboratory, Building 1040, Room 105, Beltsville, MD 20705, USA. *e-mail: [email protected] Caroline Fossum Gunnar V. Alm Section of Immunology, Dept of Veterinary Microbiology, Swedish University for Agricultural Sciences Biomedical Center, PO Box 588, SE-751-23 Uppsala, Sweden. Falko Steinbach Institute for Zoo and Wildlife Research (IZW), Alfred-Kowalke-Str. 17, 10315 Berlin, Germany. Eva Wattrang Unit of Comparative Physiology and Medicine, Dept of Large Animal Clinical Sciences, Swedish University of Agricultural Sciences, PO Box 7018, SE-750-07 Uppsala, Sweden.
Langerhans cells: still a fundamental paradigm for studying the immunobiology of dendritic cells Giampiero Girolomoni, Christophe Caux, Colette Dezutter-Dambuyant, Serge Lebecque and Paola Ricciardi-Castagnoli The 7th International Workshop on Langerhans Cells was held in Stresa, Italy from 7–9 September 2001.
Dendritic cells (DCs) are the professional antigen-presenting cells (APCs) responsible for the initiation of immune responses. Langerhans cells (LCs) are a type of DC that populate squamous epithelia typically, including the skin and conjunctiva, and oral, respiratory and genital mucosae. LCs differ from other DCs in terms of the presence of unique intracellular organelles, known as Birbeck granules (BGs), which are involved in endocytosis (Fig. 1). In addition, they differ in terms of the factors that drive their differentiation and the presence of distinct markers. In common with other DCs, LCs http://immunology.trends.com
residing in steady-state tissues are in an ‘immature’ state; their primary function is to monitor the environment for candidate danger signals (primarily, from infectious agents) and capture, process and transduce them. When a certain threshold is reached, LCs become ‘mature’ cells, acquiring the ability to migrate from the epidermis to regional lymph nodes and stimulate T cells potently. LCs were among the first types of DC to be studied and are, therefore, some of the most thoroughly investigated; they are still providing important clues for understanding the role of DCs in the immune system. Origin of Langerhans cells
LCs originate from bone-marrow-derived progenitors and acquire their peculiar
characteristics upon localization in the target tissues; peripheral blood contains very low or undetectable numbers of DCs containing BGs. Transforming growth factor β (TGF-β) is recognized now as an essential factor for the development of both mouse and human LCs; mice genetically null for this cytokine are devoid of LCs, and TGF-β drives the differentiation of human monocyte and CD34+ precursors into LCs. Of note, both TGF-β and the ligation of E-cadherin – an adhesion molecule that retains LCs in the epidermis by establishing homotypic interactions with keratinocytes – inhibit the maturation of LCs. J. Banchereau (Dallas, TX, USA) reported on the ability of interleukin-15 (IL-15) to elicit, together with granulocyte–macrophage
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)02125-1
Research Update
responses by up- or down-regulating the expression of TCR, inhibiting T-cell proliferation, inducing growth arrest and, finally, contributing to CD95-mediated cell death through multiple mechanisms. The different levels at which ceramide acts are summarized in Figure 1. We are still far from a conclusive picture of exactly how ceramide or its metabolites mediate their pleiotropic effects in T cells. However, we hope that further research in this field will provide encouraging new insights into T-cell biology and ultimately, lead also to the development of new clinical and therapeutic approaches towards immunological diseases. Acknowledgements
This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 415). We apologize to any authors whose work we were unable to cite owing to space constraints. References 1 Van Brocklyn, J.R. et al. (1998) Sphingosine-1phosphate: a lipid second messenger regulating cell growth and survival. J. Liposome Res. 8, 135–145 2 Hannun, Y.A. et al. (2001) Enzymes of sphingolipid metabolism: from modular to integrative signaling. Biochemistry 40, 4893–4903 3 Tonnetti, L. et al. (2000) A role for neutral sphingomyelinase-mediated ceramide production in T-cell-receptor-induced apoptosis and mitogenactivated protein-kinase-mediated signal transduction. J. Exp. Med. 189, 1581–1589
TRENDS in Immunology Vol.23 No.1 January 2002
4 Flores, I. et al. (2000) Changes in the balance between mitogenic and antimitogenic lipid second messengers during proliferation, cell arrest and apoptosis in T lymphocytes. FASEB J. 14, 1873–1875 5 Flores, I. et al. (1998) Dual role of ceramide in the control of apoptosis following IL-2 withdrawal. J. Immunol. 160, 3528–3533 6 Menné, C. et al. (2000) Ceramide-induced TCR up-regulation. J. Immunol. 165, 3065–3072 7 Menné, C. et al. (2001) T-cell receptor downregulation by ceramide-induced caspase activation and cleavage of the ζ chain. Scand. J. Immunol. 53, 176–183 8 Kirkham, P.A. et al. (2000) Ligation of the WC1 receptor induces γδ T-cell growth arrest through fumonisin-B1-sensitive increases in cellular ceramide. J. Immunol. 165, 3564–3570 9 Sciorati, C. et al. (1999) Generation of nitric oxide by the inducible nitric oxide synthase protects γδ T cells from Mycobacteriumtuberculosis-induced apoptosis. J. Immunol. 163, 1570–1576 10 Sciorati, C. et al. (1997) Autocrine nitric oxide modulates CD95-induced apoptosis in γδ T lymphocytes. J. Biol. Chem. 272, 23211–23215 11 Boucher, L-M. et al. (1995) CD28 signals through acidic sphingomyelinase. J. Exp. Med. 181, 2059–2068 12 Chan, G. and Ochi, A. (1995) Sphingomyelin–ceramide turnover in CD28 costimulatory signaling. Eur. J. Immunol. 25, 1999–2004 13 Kaga, S. et al. (1998) Activation of p21-CDC42/Rac-activated kinases by CD28 signaling: p21-activated kinase (PAK) and MEK kinase 1 (MEKK1) may mediate the interplay between CD3 and CD28 signals. J. Immunol. 160, 4182–4189 14 O’Byrne, D. and Sansom, D. (2000) Lack of costimulation by both sphingomyelinase and C2 ceramide in resting human T cells. Immunology 100, 225–230
15 Viola, A. (2001) The amplification of TCR signaling by dynamic membrane microdomains. Trends Immunol. 22, 322–327 16 Kirschnek, S. et al. (2000) CD95-mediated apoptosis in vivo involves acid sphingomyelinase. J. Biol. Chem. 275, 27316–27323 17 Lin, T. et al. (2000) Role of acidic sphingomyelinase in Fas/CD95-mediated cell death. J. Biol. Chem. 275, 8657–8663 18 Grassmé, H. et al. (2001) CD95 signaling via ceramide-rich membrane rafts. J. Biol. Chem. 276, 20589–20596 19 Cremesti, A. et al. (2001) Ceramide enables Fas to cap and kill. J. Biol. Chem. 276, 23954–23961 20 Hueber, A-O. (2000) CD95: more than just a death factor? Nat. Cell Biol. 2, E23–E25 21 Holler, N. et al. (2000) Fas triggers an alternative, caspase-8-independent cell-death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 22 Strelow, A. et al. (2000) Overexpression of acid ceramidase protects from tumor-necrosisfactor-induced cell death. J. Exp. Med. 192, 601–612 23 Heinrich, M. et al. (1999) Cathepsin D targeted by acid-sphingomyelinase-derived ceramide. EMBO J. 18, 5252–5263 24 Kroesen, B-J. et al. (2001) Induction of apoptosis through B-cell receptor cross-linking occurs via de-novo-generated C16-ceramide and involves mitochondria. J. Biol. Chem. 276, 13606–13614
Dieter Adam* Michael Heinrich Dieter Kabelitz Stefan Schütze Institut für Immunologie, Christian-AlbrechtsUniversität Kiel, Michaelisstr. 5, 24105 Kiel, Germany. *e-mail: [email protected]
Meeting Report
Veterinary immunology: opportunities and challenges Joan K. Lunney, Caroline Fossum, Gunnar V. Alm, Falko Steinbach and Eva Wattrang The 6th International Veterinary Immunology Symposium (6IVIS) was held in Uppsala, Sweden from 15–20 July 2001.
Veterinary immunology is dedicated to the improvement of animal health. Thus, immunity to infections was a focal point of the 6th International Veterinary Immunology Symposium (6IVIS), at which 450 delegates from 46 countries gathered to discuss the immunobiology of livestock, companion animal species and wildlife, including marine animals. This year, it was a particularly important topic, given the worldwide attention focused on the efforts http://immunology.trends.com
to control foot-and-mouth disease (FMD), avian influenza and bovine spongiform encephalopathy (BSE) in farm animals [1]. Infectious diseases jeopardize animal welfare and the agricultural economy in both developed and developing countries (see the World Organization for Animal Health website at http://www.oie.int). The situation is exacerbated by the fact that diseases such as brucellosis, classical swine fever (CSF), paratuberculosis, distemper and rabies move readily between domesticated species and wildlife. Moreover, many diseases pose a potential threat to human health.
Although the number of scientists and groups working on veterinary immunology is relatively small, there is an immense number of species and topics to be covered. Thus, communication and collaboration between researchers is a necessity. The Veterinary Immunology Committee of the International Union of Immunological Societies (VIC-IUIS) (http://www.cvm.missouri.edu/aavi/ VIC-IUIS.html) facilitates international and interdisciplinary research contacts by sponsoring workshops, an electronic bulletin board and symposia, such as the IVIS [2,3].
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S1471-4906(01)02126-3
Research Update
Immune-system diversity
Most species share immune-system mechanisms; therefore, approaches developed in humans and rodents can be adapted for disease prevention and control in veterinary species. However, there is still enormous diversity and close attention must be paid to species-specific differences. …many diseases pose a potential threat to ‘… human health.’
Unique cell populations and control mechanisms have been reported for various species. Swine have substantial numbers of double-positive CD4+CD8+ memory T cells, and numbers of these cells in the peripheral blood increase with age (A. Saalmüller, Tübingen, Germany). Ruminants and swine have major peripheral γδ T-cell populations that respond to numerous infections and might be important as early immune stimulators (M. Parkhouse, Oeiras, Portugal). The immune system of fish deviates from that of mammals to such an extent that the information gained from classical immunology is of very little help. The evolutionary scheme and nomenclature system devised for mammals cannot be applied simply to fish (L. Pilstrom, Uppsala, Sweden). For example, there are three or more Ig light-chain isotypes with clustered loci repeated in the genome of fish. IgM has diversified its structure over 500 million years of evolution, existing as a monomer, pentamer and tetramer and, even, in a truncated form (G. Warr, Charleston, USA). In chickens and ducks, a unique inversion of the segment containing the α- and µ-chain genes must occur during class switch to IgA. In camelids, IgG2 and IgG3 are homodimers of heavy chains (S. Muyldermans, Brussels, Belgium). Further details concerning the Igs in different animal species are available at the VIC-IUISsupported website of the Comparative Immunoglobulin Workshop (http://www.medicine.uiowa.edu/CIgW) (J. Butler, Iowa City, USA). At present, analyses of immune cells and proteins are limited by the lack of species-specific reagents. Cross-species reactivity of monoclonal antibodies (mAbs), and cytokines and/or chemokines and their receptors cannot be predicted. Major improvements are expected to http://immunology.trends.com
TRENDS in Immunology Vol.23 No.1 January 2002
5
Key outcomes of the meeting • Roles of unique cell subsets determined – for example, memory CD4+CD8+ T cells in pigs and immunostimulatory peripheral γδ T cells in ruminants and pigs. • Veterinary immunologists use DNA vaccines, edible vaccines and mucosal vaccination, including the successful vaccination of newborns. • Substantial role of microorganisms and nutrition in the development of the neonatal porcine mucosal immune system clarified. • Genomic regions controlling disease resistance and general immune responses established for pigs, cattle and chickens. • Enormous variety across species revealed in the genomic structure of Ig genes. • Investment into the investigation of basic species immunology is required to improve substantially disease prevention and aid vaccine developments in veterinary species.
come from the Animal Homologs section of the 8th International Workshop on Human Leukocyte Differentiation Antigens (http://www.HLDA8.org), in which all mAbs will be assessed for cross-reactivity (A. Saalmüller, Tübingen, Germany; B. Aasted, Copenhagen, Denmark). Vaccinology
Animals for consumption in developed countries are now raised in relatively biosecure facilities to decrease their dependence on antibiotics and vaccines. However, the emergence of new infectious diseases – for example, porcine reproductive and respiratory syndrome virus and BSE – or the re-emergence of highly virulent existing organisms (e.g. FMD) has put even these animals at risk. Specific diagnostic and preventative measures are required for disease control. Distinguishing vaccinated from infected animals is essential for effective disease-control programs in both captive and wild species (B.M. Buddle, Upper Hutt, New Zealand). The field of veterinary vaccinology is expanding rapidly. For example, the identification of cytotoxic-T-lymphocyte epitopes that confer protection against equine infectious anemia virus might lead to the development of effective vaccines for horses with this lentiviral infection and also, be informative for the vaccination of other outbred species (T. McGuire, Pullman, USA). Investigations of the function of the immune system in the respiratory tract will facilitate the development of nasal vaccines (A. Stanley, Penicuik, UK). Edible vaccines using corn and clover that express viral and bacterial antigens are already proving their efficacy (I. Tizard, College Station, USA;
P. Shewen, Guelph, Canada). Novel vaccine technologies, using microbial genome data and new adjuvants (e.g. CpG oligodeoxynucleotides), are transforming approaches to vaccination, as are methods that steer the immune response in an appropriate direction (Y. Van der Stede, Ghent, Belgium; R. Pontarello, Saskatoon, Canada). DNA vaccination has been evaluated in several species, with some vaccines undergoing clinical trials already. In contrast to laboratory animals, the vaccination of relatively long-lived species, such as dogs, cattle or horses, offers a unique possibility for monitoring the efficacy and possible side-effects of novel vaccine strategies (H. Hogen-Esch, West Lafayette, USA). ‘Unique cell populations and control mechanisms have been reported for various species.’
Research into neonatal immunology has been particularly fruitful. Studies in gnotobiotic pigs revealed that the appearance of CD4+ or CD8+ T cells and CD2− B cells is dependent on contact of the immune system with microorganisms (J. Sinkora and H. Tlaskalova, Prague, Czech Republic). Moreover, compelling data was presented on how nutritional components can modify the development of the mucosal immune system. The immunization of neonates is a challenge for vaccine technology. It has been shown that it is possible to induce a T-helper-1type response even in the presence of maternal antibodies (B. Morein, Uppsala, Sweden). Genetic resistance
Today, the use of every available modern molecular tool is being incorporated into
6
Research Update
veterinary research; reagents and knowledge are expanding exponentially. The use of microarray technology, together with previously established genomic libraries and the immune expressed-sequence-tag (EST) databases that are under development in many species, will further enhance these efforts. Already, veterinary immunologists use genomics to determine the factors influencing genetic resistance to infectious diseases. Using planned crosses of divergent breeds or lines that differ widely in immune function and disease resistance, significant progress has been made in defining genetic resistance to specific diseases – such as …the use of every available modern ‘… molecular tool is being incorporated into …’ veterinary research…
salmonellosis in chickens and trypanosomiasis in cattle (S. Lamont, Ames, USA; J. Naessens, Nairobi, Kenya) – and identifying chromosomal regions that influence immune functions in pigs and chickens (I. Edfors-Lilja, Växjö, Sweden; M-H. Pinard van der Laan, Jouy-en-Josas, France).
TRENDS in Immunology Vol.23 No.1 January 2002
Concluding remarks
Consolidation within the pharmaceutical industry and regulations on drug usage in animals for consumption have resulted in reduced investment in new drugs and vaccines just at the time when innovation is necessary and advances in animal health and disease prevention are readily accessible. Increased investment in veterinary immunology is required to facilitate advances in animal health, and the diagnosis and prevention of disease, primarily, for the benefit of animals but also, humans, in terms of safer foods and improved biomedical models. Acknowledgements
The Veterinary Immunology Committee is supported by the International Union of Immunological Societies (IUIS) (http://www.iuisonline.org). Full details of the conference can be found at http://www.service.slu.se/conference/ ivis2001. We thank Cynthia Baldwin for her thoughtful editorial comments. References 1 Miller, L.J. (2001) Foot and mouth. Nat. Immunol. 2, 565 2 Oberoi, M. and Naessens, J. (1999) Proceedings of the 5th International Veterinary Immunology
Symposium. Vet. Immunol. Immunopathol. 72, 1–248 3 Fossum, C. and Wattrang, E. Proceedings of the 6th International Veterinary Immunology Symposium. Vet. Immunol. Immunopathol. (in press)
Joan K. Lunney* Immunology and Disease Resistance Laboratory, Building 1040, Room 105, Beltsville, MD 20705, USA. *e-mail: [email protected] Caroline Fossum Gunnar V. Alm Section of Immunology, Dept of Veterinary Microbiology, Swedish University for Agricultural Sciences Biomedical Center, PO Box 588, SE-751-23 Uppsala, Sweden. Falko Steinbach Institute for Zoo and Wildlife Research (IZW), Alfred-Kowalke-Str. 17, 10315 Berlin, Germany. Eva Wattrang Unit of Comparative Physiology and Medicine, Dept of Large Animal Clinical Sciences, Swedish University of Agricultural Sciences, PO Box 7018, SE-750-07 Uppsala, Sweden.
Langerhans cells: still a fundamental paradigm for studying the immunobiology of dendritic cells Giampiero Girolomoni, Christophe Caux, Colette Dezutter-Dambuyant, Serge Lebecque and Paola Ricciardi-Castagnoli The 7th International Workshop on Langerhans Cells was held in Stresa, Italy from 7–9 September 2001.
Dendritic cells (DCs) are the professional antigen-presenting cells (APCs) responsible for the initiation of immune responses. Langerhans cells (LCs) are a type of DC that populate squamous epithelia typically, including the skin and conjunctiva, and oral, respiratory and genital mucosae. LCs differ from other DCs in terms of the presence of unique intracellular organelles, known as Birbeck granules (BGs), which are involved in endocytosis (Fig. 1). In addition, they differ in terms of the factors that drive their differentiation and the presence of distinct markers. In common with other DCs, LCs http://immunology.trends.com
residing in steady-state tissues are in an ‘immature’ state; their primary function is to monitor the environment for candidate danger signals (primarily, from infectious agents) and capture, process and transduce them. When a certain threshold is reached, LCs become ‘mature’ cells, acquiring the ability to migrate from the epidermis to regional lymph nodes and stimulate T cells potently. LCs were among the first types of DC to be studied and are, therefore, some of the most thoroughly investigated; they are still providing important clues for understanding the role of DCs in the immune system. Origin of Langerhans cells
LCs originate from bone-marrow-derived progenitors and acquire their peculiar
characteristics upon localization in the target tissues; peripheral blood contains very low or undetectable numbers of DCs containing BGs. Transforming growth factor β (TGF-β) is recognized now as an essential factor for the development of both mouse and human LCs; mice genetically null for this cytokine are devoid of LCs, and TGF-β drives the differentiation of human monocyte and CD34+ precursors into LCs. Of note, both TGF-β and the ligation of E-cadherin – an adhesion molecule that retains LCs in the epidermis by establishing homotypic interactions with keratinocytes – inhibit the maturation of LCs. J. Banchereau (Dallas, TX, USA) reported on the ability of interleukin-15 (IL-15) to elicit, together with granulocyte–macrophage
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