Abstract
In many species, the rejection of liver allografts is milder than that of other organs. This is especially so in the rat where, without immunosuppressive treatment, liver grafts between certain strain combinations are accepted permanently, whereas skin, heart and renal allografts undergo acute rejection. Reliable surgical methods, together with the availability of inbred strains and a rapidly developing knowledge of its MHC and immune system in general, have made the rat a prime species in which to study the immunological events which follow liver grafting. In non-rejector combinations, liver allografts possess remarkable properties of tolerance induction and antigen-specific immunosuppression, leading to a state of donor-specific unresponsiveness in which grafts of other organs are also accepted. Moreover, liver transplantation can terminate ongoing rejection reactions in other organs and convert an existing state of sensitization against donor antigens into one of unresponsiveness. This review describes recent progress in understanding the immunological mechanisms behind these phenomena. The topics discussed include the rat MHC (RT1) antigens and their distribution in the liver; the genetic control of rejection and non-rejection, including the role of MHC-linked immune response genes; and cellular and humoral mechanisms involved in tolerance and immunosuppression, such as clonal deletion of alloreactive lymphocytes and antibody-mediated enhancement.
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- Blankenhorn E. P., Symington F. W., Cramer D. V. Biochemical characterization of Ia antigens encoded by the RT1.B and RT1.D loci in the rat MHC. Immunogenetics. 1983;17(5):475–484. doi: 10.1007/BF00696871. [DOI] [PubMed] [Google Scholar]
- Butcher G. W., Corvalán J. R., Licence D. R., Howard J. C. Immune response genes controlling responsiveness to major transplantation antigens. Specific major histocompatibility complex-linked defect for antibody responses to class I alloantigens. J Exp Med. 1982 Jan 1;155(1):303–320. doi: 10.1084/jem.155.1.303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Butcher G. W., Howard J. C. Genetic control of transplant rejection. Transplantation. 1982 Oct;34(4):161–166. [PubMed] [Google Scholar]
- Calne R. Y., Davis D. R., Hadjiyannakis E., Sells R. A., White D., Herbertson B. M., Millard P. R., Joysey V. C., Davies D. A., Binns R. M. Immunosuppressive effects of soluble cell membrane fractions, donor blood and serum on renal allograft survival. Nature. 1970 Aug 29;227(5261):903–906. doi: 10.1038/227903a0. [DOI] [PubMed] [Google Scholar]
- Calne R. Y., Sells R. A., Pena J. R., Davis D. R., Millard P. R., Herbertson B. M., Binns R. M., Davies D. A. Induction of immunological tolerance by porcine liver allografts. Nature. 1969 Aug 2;223(5205):472–476. doi: 10.1038/223472a0. [DOI] [PubMed] [Google Scholar]
- Calne R. Y. The present status of liver transplantation. Transplant Proc. 1977 Mar;9(1):209–216. [PubMed] [Google Scholar]
- Calne R. Y., White H. J., Yoffa D. E., Binns R. M., Maginn R. R., Herbertson R. M., Millard P. R., Molina V. P., Davis D. R. Prolonged survival of liver transplants in the pig. Br Med J. 1967 Dec 16;4(5580):645–648. doi: 10.1136/bmj.4.5580.645. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davies D. A., Staines N. A. A cardinal role for I-region antigens (Ia) in immunological enhancement, and the clinical implications. Transplant Rev. 1976;30:18–39. doi: 10.1111/j.1600-065x.1976.tb00213.x. [DOI] [PubMed] [Google Scholar]
- Dorsch S., Roser B. The adoptive transfer of first-set allograft responses by recirculating small lymphocytes in the rat. Aust J Exp Biol Med Sci. 1974 Feb;52(1):33–44. doi: 10.1038/icb.1974.3. [DOI] [PubMed] [Google Scholar]
- Engemann R., Ulrichs K., Thiede A., Müller-Ruchholtz W., Hamelmann H. Value of a physiological liver transplant model in rats. Induction of specific graft tolerance in a fully allogeneic strain combination. Transplantation. 1982 May;33(5):566–568. [PubMed] [Google Scholar]
- Gallico G. G., Butcher G. W., Howard J. C. The role of subregions of the rat major histocompatibility complex in the rejection and passive enhancement of renal allografts. J Exp Med. 1979 Jan 1;149(1):244–253. doi: 10.1084/jem.149.1.244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Garnier H., Clot J. P., Bertrand M., Camplez P., Kunlin A., Gorin J. P., Le Goaziou F., Lévy R., Cordier G. Greffe de foie chez le porc: approche chirurgicale. C R Acad Sci Hebd Seances Acad Sci D. 1965 May 24;260(21):5621–5623. [PubMed] [Google Scholar]
- Garnier H., Clot J. P., Chomette G. Orthotopic transplantation of the porcine liver. Surg Gynecol Obstet. 1970 Jan;130(1):105–111. [PubMed] [Google Scholar]
- Gugenheim J., Houssin D., Tamisier D., Franco D., Martin E., Lang P., Bismuth H. Spontaneous long-term survival of liver allografts in inbred rats: influence of the hepatectomy of the recipient's own liver. Transplantation. 1981 Nov;32(5):445–450. [PubMed] [Google Scholar]
- Günther E., Stark O., Koch C. Genetic definition of I region-determined antigens of the rat major histocompatibility complex. Eur J Immunol. 1978 Mar;8(3):206–212. doi: 10.1002/eji.1830080313. [DOI] [PubMed] [Google Scholar]
- Hall B. M., Dorsch S. E. Cells mediating allograft rejection. Immunol Rev. 1984;77:31–59. doi: 10.1111/j.1600-065x.1984.tb00717.x. [DOI] [PubMed] [Google Scholar]
- Hall B. M., Dorsch S., Roser B. The cellular basis of allograft rejection in vivo. II. The nature of memory cells mediating second set heart graft rejection. J Exp Med. 1978 Oct 1;148(4):890–902. doi: 10.1084/jem.148.4.890. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hart D. N., Fabre J. W. Demonstration and characterization of Ia-positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. J Exp Med. 1981 Aug 1;154(2):347–361. doi: 10.1084/jem.154.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hart D. N., Fabre J. W. Quantitative studies on the tissue distribution of Ia and SD antigens in the DA and Lewis rat strains. Transplantation. 1979 Feb;27(2):110–119. doi: 10.1097/00007890-197902000-00009. [DOI] [PubMed] [Google Scholar]
- Hess F., Willemen A., Jerusalem C. Auxiliary liver transplantation in the rat, influence of the condition of the recipient's liver on the fate of the graft. Eur Surg Res. 1977;9(4):270–279. doi: 10.1159/000127946. [DOI] [PubMed] [Google Scholar]
- Homan W. P., Fabre J. W., Millard P. R., Morris P. J. Effect of cyclosporin A upon second-set rejection of rat renal allografts. Transplantation. 1980 Nov;30(5):354–357. doi: 10.1097/00007890-198011000-00009. [DOI] [PubMed] [Google Scholar]
- Houssin D., Charpentier B., Gugenheim J., Baudot P., Tamisier D., Lang P., Gigou M., Bismuth H. Spontaneous long-term acceptance of RT-1-incompatible liver allografts in inbred rats. Analysis of the immune status. Transplantation. 1983 Dec;36(6):615–620. doi: 10.1097/00007890-198336060-00004. [DOI] [PubMed] [Google Scholar]
- Houssin D., Charpentier B., Lang P., Tamisier D., Gugenheim J., Gigou M., Bismuth H. In vivo and in vitro correlates of the specific transplantation tolerance induced by spontaneously tolerated liver allografts in inbred strains of rats. Transplant Proc. 1981 Mar;13(1 Pt 1):619–622. [PubMed] [Google Scholar]
- Houssin D., Gigou M., Franco D., Bismuth H., Charpentier B., Lang P., Martin E. Specific transplantation tolerance induced by spontaneously tolerated liver allograft in inbred strains of rats. Transplantation. 1980 May;29(5):418–419. doi: 10.1097/00007890-198005000-00015. [DOI] [PubMed] [Google Scholar]
- Houssin D., Gigou M., Franco D., Szekely A. M., Bismuth H. Spontaneous long-term survival of liver allograft in inbred rats. Transplant Proc. 1979 Mar;11(1):567–570. [PubMed] [Google Scholar]
- Howard J. C., Butcher G. W. The mechanism of graft rejection and the concept of antigenic strength. Scand J Immunol. 1981 Dec;14(6):687–691. doi: 10.1111/j.1365-3083.1981.tb00611.x. [DOI] [PubMed] [Google Scholar]
- Hutchinson I. V., Zola H. Antigen-reactive cell opsonization in passive enhancement of rat renal allografts. Transplant Proc. 1977 Mar;9(1):961–963. [PubMed] [Google Scholar]
- Häyry P., von Willebrand E., Parthenais E., Nemlander A., Soots A., Lautenschlager I., Alfoldy P., Renkonen R. The inflammatory mechanisms of allograft rejection. Immunol Rev. 1984;77:85–142. doi: 10.1111/j.1600-065x.1984.tb00719.x. [DOI] [PubMed] [Google Scholar]
- Kamada N., Brons G., Davies H. S. Fully allogeneic liver grafting in rats induces a state of systemic nonreactivity to donor transplantation antigens. Transplantation. 1980 May;29(5):429–431. doi: 10.1097/00007890-198005000-00021. [DOI] [PubMed] [Google Scholar]
- Kamada N., Davies H. S., Roser B. Reversal of transplantation immunity by liver grafting. Nature. 1981 Aug 27;292(5826):840–842. doi: 10.1038/292840a0. [DOI] [PubMed] [Google Scholar]
- Kamada N., Davies H. S., Wight D., Culank L., Roser B. Liver transplantation in the rat. Biochemical and histological evidence of complete tolerance induction in non-rejector strains. Transplantation. 1983 Apr;35(4):304–311. [PubMed] [Google Scholar]
- Kamada N. Transfer of specific immunosuppression of graft rejection using lymph from tolerant liver-grafted rats. Immunology. 1985 Jun;55(2):241–247. [PMC free article] [PubMed] [Google Scholar]
- Kamada N., Wight D. G. Antigen-specific immunosuppression induced by liver transplantation in the rat. Transplantation. 1984 Sep;38(3):217–221. doi: 10.1097/00007890-198409000-00004. [DOI] [PubMed] [Google Scholar]
- Kress M., Cosman D., Khoury G., Jay G. Secretion of a transplantation-related antigen. Cell. 1983 Aug;34(1):189–196. doi: 10.1016/0092-8674(83)90149-6. [DOI] [PubMed] [Google Scholar]
- Lampert I. A., Suitters A. J., Chisholm P. M. Expression of Ia antigen on epidermal keratinocytes in graft-versus-host disease. Nature. 1981 Sep 10;293(5828):149–150. doi: 10.1038/293149a0. [DOI] [PubMed] [Google Scholar]
- Lautenschlager I., Häyry P. Expression of the major histocompatibility complex antigens on different liver cellular components in rat and man. Scand J Immunol. 1981 Oct;14(4):421–426. doi: 10.1111/j.1365-3083.1981.tb00582.x. [DOI] [PubMed] [Google Scholar]
- Lautenschlager I., Nyman N., Vänänen H., Lehto V. P., Virtanen I., Häyry P. Antigenic and immunogenic components in rat liver. Scand J Immunol. 1983 Jan;17(1):61–68. doi: 10.1111/j.1365-3083.1983.tb00766.x. [DOI] [PubMed] [Google Scholar]
- Lee S., Charters A. C., 3rd, Orloff M. J. Simplified technic for orthotopic liver transplantation in the rat. Am J Surg. 1975 Jul;130(1):38–40. doi: 10.1016/0002-9610(75)90453-5. [DOI] [PubMed] [Google Scholar]
- Lee S., Charters A. C., Chandler J. G., Orloff M. J. A technique for orthotopic liver transplantation in the rat. Transplantation. 1973 Dec;16(6):664–669. doi: 10.1097/00007890-197312000-00019. [DOI] [PubMed] [Google Scholar]
- Limmer J., Herbertson B. M., Calne R. Y. Orthotopic rat liver transplantation using different combinations of four inbred strains. Eur Surg Res. 1980;12(5):343–348. doi: 10.1159/000128140. [DOI] [PubMed] [Google Scholar]
- Lobel S. A., Cramer D. V. Demonstration of a new genetic locus in the major histocompatibility system of the rat. Immunogenetics. 1981;13(6):465–473. doi: 10.1007/BF00343714. [DOI] [PubMed] [Google Scholar]
- Loveland B. E., McKenzie I. F. Which T cells cause graft rejection? Transplantation. 1982 Mar;33(3):217–221. doi: 10.1097/00007890-198203000-00001. [DOI] [PubMed] [Google Scholar]
- Mason D. W., Dallman M. J., Arthur R. P., Morris P. J. Mechanisms of allograft rejection: the roles of cytotoxic T-cells and delayed-type hypersensitivity. Immunol Rev. 1984;77:167–184. doi: 10.1111/j.1600-065x.1984.tb00721.x. [DOI] [PubMed] [Google Scholar]
- Mason D. W., Dallman M., Barclay A. N. Graft-versus-host disease induces expression of Ia antigen in rat epidermal cells and gut epithelium. Nature. 1981 Sep 10;293(5828):150–151. doi: 10.1038/293150a0. [DOI] [PubMed] [Google Scholar]
- Müller G. A simple technique for heterotopic auxiliary liver transplantation in the rat. Transplantation. 1983 Aug;36(2):221–222. doi: 10.1097/00007890-198308000-00028. [DOI] [PubMed] [Google Scholar]
- Pober J. S., Gimbrone M. A., Jr, Cotran R. S., Reiss C. S., Burakoff S. J., Fiers W., Ault K. A. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983 Apr 1;157(4):1339–1353. doi: 10.1084/jem.157.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Starzl T. E., Koep L. J., Halgrimson C. G., Hood J., Schröter G. P., Porter K. A., Weil R., 3rd Liver transplantation--1978. Transplant Proc. 1979 Mar;11(1):240–246. [PMC free article] [PubMed] [Google Scholar]
- Steeg P. S., Johnson H. M., Oppenheim J. J. Regulation of murine macrophage Ia antigen expression by an immune interferon-like lymphokine: inhibitory effect of endotoxin. J Immunol. 1982 Dec;129(6):2402–2406. [PubMed] [Google Scholar]
- Steinman R. M., Nussenzweig M. C. Dendritic cells: features and functions. Immunol Rev. 1980;53:127–147. doi: 10.1111/j.1600-065x.1980.tb01042.x. [DOI] [PubMed] [Google Scholar]
- Suitters A. J., Lampert I. A. Class II antigen induction in the liver of rats with graft-versus-host disease. Transplantation. 1984 Aug;38(2):194–196. [PubMed] [Google Scholar]
- Tamisier D., Houssin D., Gugenheim J., Brunaud M. D., Martin E., Bismuth H. Spontaneous long-term survival of liver allografts in inbred rats: comparison between semi-allogenic and fully allogeneic strain combinations. Eur Surg Res. 1983;15(3):145–150. doi: 10.1159/000128346. [DOI] [PubMed] [Google Scholar]
- Zimmermann F. A., Butcher G. W., Davies H. S., Brons G., Kamada N., Türel O. Techniques for orthotopic liver transplantation in the rat and some studies of the immunologic responses to fully allogeneic liver grafts. Transplant Proc. 1979 Mar;11(1):571–577. [PubMed] [Google Scholar]