Concepts and Mechanisms of Immune Activation, Graft Rejection, Immunosuppression, and Tolerance

  • W. Müller-Ruchholtz


A widely distributed understanding defines immunology as the science of self/nonself-discrimination. However, to discriminate an individual’s own tissues from genetically different ones and, more importantly, from structures which do not belong to its own species is by no means the speciality of the immune system. This capacity is vital for all invertebrates and vertebrates because of biotic threats to individuality, such as cellular or microbial parasitism. There is a wide variety of recognition systems, most of them poorly understood, such as lectins, adhesion molecular systems, and other systems of so-called innate immunity and specific immunity. In evolutionary terms, the latter developed relatively late, some 300–350 million years ago, among the deuterostomata; some people call it the ingenious immuno big bang of nature. Since then molecules are created which are composed of several variable regions, allowing a large variety of reaction specificities by genetic rearrangements of these regions. Rearrangement rather than prearrangement is the ingenious principle which became applied twofold, namely in T-lymphocyte cell surface receptors and in humoral antibodies, and which allows for a tremendous diversification of reaction specificities of these molecules.


Major Histocompatibility Complex Major Histocompatibility Complex Class Immune Activation Acute Rejection Graft Rejection 
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  1. 1.
    Akbar AN Salmon M (1997) Cellular environments and apoptosis: tissue microenvironments control activated T cell death. Immunol Today 18:72–76PubMedCrossRefGoogle Scholar
  2. 2.
    Azuma H, Paul LC, Tilney NL (1996) Insights into acute and chronic rejection. Transplant Proc 28:2081–2084PubMedGoogle Scholar
  3. 3.
    Benichou G, Tarn RC, Soares LRB, Fedoseyeva EV (1997) Indirect T-cell derecognition: perspectives for peptide-based therapy in transplantation. Immunol Today 18:67–71PubMedCrossRefGoogle Scholar
  4. 4.
    Bluestone JA (1996) Costimulation and its role in organ transplantation. Clin Transplant 10:104–109PubMedGoogle Scholar
  5. 5.
    Brazelton TR, Morris RE (1996) Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Curr Opin Immunol 8:710–720PubMedCrossRefGoogle Scholar
  6. 6.
    Brenner M, Porcelli S (1997) Antigen presentation: a balanced diet. Science 277:332PubMedCrossRefGoogle Scholar
  7. 7.
    Calhoun R, Mohanakumar T, Flye MW (1996) Tissue- and organ-specific immune responses: role in human disease and allograft immunity. Transplant Rev 10:34–45CrossRefGoogle Scholar
  8. 8.
    Calne R (1997) Progress toward tolerance and xenografting. Transplant Proc 29:16–18PubMedCrossRefGoogle Scholar
  9. 9.
    Chambers CA, Allison JP (1997) Co-stimulation in T cell responses. Curr Opin Immunol 9:396–404PubMedCrossRefGoogle Scholar
  10. 10.
    Chatenoud L (1997) Biological immunosuppressants: the way to clinical transplantation tolerance. Transplant Proc 29:51–55PubMedCrossRefGoogle Scholar
  11. 11.
    Däëron M (1997) ITIM-bearing negative coreceptors. Immunologist 5: 79–86Google Scholar
  12. 12.
    Dalloul AH, Chmouzis E, Ngo K, Fung-Leung WP-P (1996) Adoptively transferred CD4+ lymphocytes from CD8-/- mice are sufficient to mediate the rejection of MHC class II or class I disparate skin grafts. J Immunol 156:4114–4119PubMedGoogle Scholar
  13. 13.
    Davies JD, Cobbold SP, Waldmann H (1997) Strain variation in susceptibility to monoclonal antibody-induced transplantation tolerance. Transplantation 63:1570–1573PubMedCrossRefGoogle Scholar
  14. 14.
    Doherty PC, Zinkernagel RM (1975) A biological role for the major histocompatibility antigens. Lancet 1: 406–409Google Scholar
  15. 15.
    Field EH, Gao Q, Chen N, Rouse TM (1997) Balancing the immune system for tolerance. Transplantation 64:1–7PubMedCrossRefGoogle Scholar
  16. 16.
    Forbes RDC, Zheng SX-X, Gomersall M, Guttmann RD (1997) Irreversible chronic vascular rejection occurs only after development of advanced allograft vasculopathy. Transplantation 63:743–749PubMedCrossRefGoogle Scholar
  17. 17.
    Giangrande J, Yamada K, Arn S, Lorf T, Sachs DH, LoGuern C (1997) Selective increase in CD4-positive graft-infiltrating mononuclear cells among the infiltrates in class I disparate kidney grafts undergoing rejection. Transplantation 63:722–728PubMedCrossRefGoogle Scholar
  18. 18.
    Goldstein J, Mortowsky H, Tung J, Hon H, Brunswick M, Kozlowski S (1997) Naive allo-reactive CD8 T cells are activated by purified major histocompatibility complex class I and antigenic peptide. Eur J Immunol 27:871–878PubMedCrossRefGoogle Scholar
  19. 19.
    Goodnow CC (1996) Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires. Proc Natl Acad Sci U S A 93:2264–2271PubMedCrossRefGoogle Scholar
  20. 20.
    Granstein RD (1996) New strategy for allotransplantation. Lancet 348:838–839PubMedCrossRefGoogle Scholar
  21. 21.
    Grewal IS, Flavell RA (1996) A central role of CD40 ligand in the regulation of CD4+ T cell responses. Immunol Today 17:410–414PubMedCrossRefGoogle Scholar
  22. 22.
    Halloran PF (1996) Molecular mechanisms of new immunosuppressants. Clin Transplant 10:118–123PubMedGoogle Scholar
  23. 23.
    Halloran PF, Homik J, Goes N, Lui SL, Urmson J, Ramassar V, Cockfield SM (1997) The “injury response”: a concept linking nonspecific injury, acute rejection, and long-term transplant outcomes. Transplant Proc 29:79–81PubMedCrossRefGoogle Scholar
  24. 24.
    Häyry P (1995) Aspects of allograft rejection, I: molecular pathology of acute and chronic rejection. Transplant Rev 9:113–120CrossRefGoogle Scholar
  25. 25.
    Häyry P, Myllärniemi M, Ramirez LC, Aavik E, Loubtchenkov M, Koskinen P, Lemström K, Räisänen-Sokolowski A (1997) Immunobiology and pathology of chronic rejection. Transplant Proc 29:77–78PubMedCrossRefGoogle Scholar
  26. 26.
    Jankowsi RA, Ildstad ST (1996) Current progress in chimerism and donor-specific tolerance. Transplant Proc 28:2071–2074Google Scholar
  27. 27.
    Kasahara M, Flajnik MF, Ishibashi T, Natori T (1995) Evolution of the major histocompatibility complex: a current overview. Transplant Immunol 3:1–20CrossRefGoogle Scholar
  28. 28.
    Kemeny DM, Noble A, Holmes BJ, Diaz-Sanchez D (1994) Immune regulation: a new role for the CD8+ T cell. Immunol Today 15:107–110PubMedCrossRefGoogle Scholar
  29. 29.
    Kroemer G (1997) The proto-oncogene Bcl-2 and its role in regulating apoptosis. Nature Med 3:614–620PubMedCrossRefGoogle Scholar
  30. 30.
    Kruisbeek AM, Amsen D (1996) Mechanisms underlying T-cell tolerance. Curr Opin Immunol 8:233–244PubMedCrossRefGoogle Scholar
  31. 31.
    Lafferty KJ (1995) Role of second signals in the induction of T cells and graft rejection. Immunologist 3:256–258Google Scholar
  32. 32.
    Lau HT, Stoeckert CJ (1997) FasL — too much of a good thing? Nature Med 3:727–728PubMedCrossRefGoogle Scholar
  33. 33.
    Lu L, Qian S, Hershberger PA, Rudert WA, Lynch DM, Thomson AW (1997) Fas ligand (CD95L) and B7 expression on dendritic cells provide counter-regulatory signals for T cell survival and proliferation. J Immunol 158:5676–5684PubMedGoogle Scholar
  34. 34.
    Matechak EO, Killeen N, Hedrick SM, Fowlkes BJ (1996) MHC class II-specific T cells can develop in the CD8 lineage when CD4 is absent. Immunity 4:337–347PubMedCrossRefGoogle Scholar
  35. 35.
    Metcalf D (1997) Another way to generate T cells? Nature Med 3:18–19PubMedCrossRefGoogle Scholar
  36. 36.
    Müller-Ruchholtz W (1992) Specific down-regulation of allograft reactivity at the cellular level: graft cells and responder T cells. Immunol Lett 32:1–6PubMedCrossRefGoogle Scholar
  37. 37.
    Müller-Ruchholtz W (1998) Glances at the history of transplantation. Transplant Proc 30: (in press)Google Scholar
  38. 38.
    Murphy B, Sayegh M (1996) Why do we reject a graft? Mechanisms of recognition of transplantation antigens. Transplant Rev 10:150–159CrossRefGoogle Scholar
  39. 39.
    Nadeau KC, Azuma H, Tilney NL (1996) Cytokines in the pathophysiology of acute and chronic allograft rejection. Transplant Rev 10:99–107CrossRefGoogle Scholar
  40. 40.
    Naji A (1996) Induction of tolerance by intrathymic inoculation of alloantigen. Curr Opin Immunol 8:704–709PubMedCrossRefGoogle Scholar
  41. 41.
    O’Shea JJ (1997) Key molecules involved in receptor-mediated lymphocyte activation. Curr Protocols Immunol [Suppl 22]: A.1J, 1–14Google Scholar
  42. 42.
    Orosz CG, Bergese SD, Wakely E, Xia D, Gordillo GM, VanBuskirk AM (1997) Acute versus chronic graft rejection: related manifestations of allosensitization in graft recipients. Transplant Rev 11:38–50CrossRefGoogle Scholar
  43. 43.
    Paul LC (1995) Aspects of allograft rejection, III. Transplant Rev 9:127–137CrossRefGoogle Scholar
  44. 44.
    Pennisi E (1996) Teetering on the brink of danger. Science 271:1665–1667PubMedCrossRefGoogle Scholar
  45. 45.
    Perez VL, VanParijs L, Biuckians A, Zheng XX, Strom TB, Abbas AK (1997) Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 6:411–417PubMedCrossRefGoogle Scholar
  46. 46.
    Piccotti JR, Chan SY, VanBuskirk AM, Eichwald EJ, Bishop DK (1997) Are Th2 helper T lymphocytes beneficial, deleterious, or irrelevant in promoting allograft survial? Transplantation 63:619–624PubMedCrossRefGoogle Scholar
  47. 47.
    Pion S, Fontaine P, Desaulniers M, Jutras J, Filep JG, Perreault C (1997) On the mechanisms of immunodominance in cytotoxic T lymphocyte responses to minor histocompatibility antigens. Eur J Immunol 27:421–430PubMedCrossRefGoogle Scholar
  48. 48.
    Pirenne J, Benedetti E, Dunn DL (1996) Graft versus host response: clinical and biological relevance after transplantation of solid organs. Transplant Rev 10:46–68CrossRefGoogle Scholar
  49. 49.
    Quill H (1996) Anergy as a mechanism of peripheral T cell tolerance. J Immunol 156:1325–1327PubMedGoogle Scholar
  50. 50.
    Rodriguez-Iturbe B (1996) Cellular adhesion molecules in transplantation. Tranplant Proc 28:3285–3289Google Scholar
  51. 51.
    Ross R (1996) Genetically modified mice as models of transplant atherosclerosis. Nature Med 2:527–528PubMedCrossRefGoogle Scholar
  52. 52.
    Rothenberg EV (1996) How T cells count. Science 273:78–79PubMedCrossRefGoogle Scholar
  53. 53.
    Schwartz RH (1996) Models of T cell anergy: is there a common molecular mechanism? J Exp Med 184:1–8PubMedCrossRefGoogle Scholar
  54. 54.
    Scully R, Cobbold SP, Mellor AL, Wissing M, Arnold B, Waldmann H (1997) A role for Th2 cytokines in the suppression of CD8+ T cell-mediated graft rejection. Eur J Immunol 27:1663–1670PubMedCrossRefGoogle Scholar
  55. 55.
    Soares LRB, Rivas A, Tsavaler L, Engleman EG (1997) Ligation of the V7 molecule on T cells blocks anergy induction through a CD28-independent mechanism. J Immunol 159:1115–1124PubMedGoogle Scholar
  56. 56.
    Steiger J, Nickerson PW, Steurer W, Moscovitch-Lopatin M, Strom TB (1995) IL-2 knockout recipient mice reject islet cell allografts. J Immunol 155:489–498PubMedGoogle Scholar
  57. 57.
    Steinman L (1996) A few autoreactive cells in an autoimmune infiltrate control a vast population of nonspecific cells: a tale of smart bombs and the infantry. Proc Natl Acad Sci U S A 93:2253–2256PubMedCrossRefGoogle Scholar
  58. 58.
    Streilein JW (1996) Peripheral tolerance induction: lessons from immune privileged sites and tissues. Transplant Proc 28:2066–2070PubMedGoogle Scholar
  59. 59.
    Sundstrom JB, Ansari AA (1995) Comparative study of the role of professional versus semiprofessional or nonprofessional antigen presenting cells in the rejection of vascularized organ allografts. Transplant Immunol 3:273–289CrossRefGoogle Scholar
  60. 60.
    Sykes M (1996) Chimerism and central tolerance. Curr Opin Immunol 8:694–703PubMedCrossRefGoogle Scholar
  61. 61.
    Sykes M, Szot GL, Swenson KA, Pearson DA (1997) Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning. Nature Med 3:783–787PubMedCrossRefGoogle Scholar
  62. 62.
    Ward ES, Qadri A (1997) Biophysical and structural studies of TCRs and ligands: implications for T cell signaling. Curr Opin Immunol 9:97–106PubMedCrossRefGoogle Scholar
  63. 63.
    Watts C (1997) Inside the gearbox of the dendritic cell. Nature 388:724–725PubMedCrossRefGoogle Scholar
  64. 64.
    Wen T, Kono K, Shahinian A, Kiessling R, Mak TW, Klein G (1997) CD28 is not required for rejection of unmanipulated syngeneic and autologous tumors. Eur J Immunol 27:1988–1993PubMedCrossRefGoogle Scholar
  65. 65.
    Yang E, Korsmeyer SJ (1996) Molecular thanatopsis: a discourse on the BCL2 family and cell death. Blood 88:386–401PubMedGoogle Scholar
  66. 66.
    Zavazava N, Krönke M (1996) Soluble HLA class I molecules induce apoptosis in alloreactive cytotoxic T lymphocytes. Nature Med 2:1005–1010PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1998

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  • W. Müller-Ruchholtz

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