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Transplantation immunobiology

Author
John Vella, MD, FACP, FRCP, FASN
Section Editor
Daniel C Brennan, MD, FACP
Deputy Editor
Albert Q Lam, MD

INTRODUCTION

The mammalian immune system is an extraordinarily complex system that has developed in response to evolutionary stressors provided by coexistence with micro-organisms over millions of years. The system can be divided into two components:

Natural immunity, which refers to the nonspecific immune response

Adaptive immunity, which refers to the response to a specific antigen

In organ transplantation, the principal target of the immune response to the graft are the major histocompatibility complex (MHC) molecules expressed on the surface of donor cells (allo-MHC); this feature is a form of adaptive immunity.

The immunobiology of solid transplantation will be reviewed here. The immunobiology of bone marrow or stem transplantation, which primarily involves graft-versus-host (GVH) and graft-versus-tumor effects, is presented separately. (See "Pathogenesis of graft-versus-host disease" and "Biology of the graft-versus-tumor effect following hematopoietic cell transplantation".)

                              

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Literature review current through: Nov 2016. | This topic last updated: Thu Aug 06 00:00:00 GMT+00:00 2015.
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References
Top
  1. Wyburn KR, Jose MD, Wu H, et al. The role of macrophages in allograft rejection. Transplantation 2005; 80:1641.
  2. Andrade CF, Waddell TK, Keshavjee S, Liu M. Innate immunity and organ transplantation: the potential role of toll-like receptors. Am J Transplant 2005; 5:969.
  3. Lakkis FG, Sayegh MH. Memory T cells: a hurdle to immunologic tolerance. J Am Soc Nephrol 2003; 14:2402.
  4. Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med 2002; 8:582.
  5. Fan X, Ang A, Pollock-Barziv SM, et al. Donor-specific B-cell tolerance after ABO-incompatible infant heart transplantation. Nat Med 2004; 10:1227.
  6. Sun Q, Cheng Z, Cheng D, et al. De novo development of circulating anti-endothelial cell antibodies rather than pre-existing antibodies is associated with post-transplant allograft rejection. Kidney Int 2011; 79:655.
  7. Breimer ME, Rydberg L, Jackson AM, et al. Multicenter evaluation of a novel endothelial cell crossmatch test in kidney transplantation. Transplantation 2009; 87:549.
  8. Sayegh MH, Turka LA. The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 1998; 338:1813.
  9. Warren EH, Greenberg PD, Riddell SR. Cytotoxic T-lymphocyte-defined human minor histocompatibility antigens with a restricted tissue distribution. Blood 1998; 91:2197.
  10. Scott DM, Ehrmann IE, Ellis PS, et al. Why do some females reject males? The molecular basis for male-specific graft rejection. J Mol Med (Berl) 1997; 75:103.
  11. Simpson E, Roopenian D. Minor histocompatibility antigens. Curr Opin Immunol 1997; 9:655.
  12. Chen TC, Waldmann H, Fairchild PJ. Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby. J Clin Invest 2004; 113:1754.
  13. Sherman LA, Chattopadhyay S. The molecular basis of allorecognition. Annu Rev Immunol 1993; 11:385.
  14. Matzinger P, Bevan MJ. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol 1977; 29:1.
  15. Kreisel D, Krupnick AS, Gelman AE, et al. Non-hematopoietic allograft cells directly activate CD8+ T cells and trigger acute rejection: an alternative mechanism of allorecognition. Nat Med 2002; 8:233.
  16. Vella J, Knoflach A, Waaga A, Sayegh M. T cell mediated immune responses in chronic allograft rejection: Role of indirect allorecognition and costimulatory pathways. Graft 1998; 1:S11.
  17. Azzi J, Sayegh MH. Clinical transplantation tolerance: a myth no more, but... Am J Kidney Dis 2009; 54:1005.
  18. Vella JP, Spadafora-Ferreira M, Murphy B, et al. Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction. Transplantation 1997; 64:795.
  19. Liu Z, Colovai AI, Tugulea S, et al. Indirect recognition of donor HLA-DR peptides in organ allograft rejection. J Clin Invest 1996; 98:1150.
  20. Vella JP, Vos L, Carpenter CB, Sayegh MH. Role of indirect allorecognition in experimental late acute rejection. Transplantation 1997; 64:1823.
  21. Vella JP, Magee C, Vos L, et al. Cellular and humoral mechanisms of vascularized allograft rejection induced by indirect recognition of donor MHC allopeptides. Transplantation 1999; 67:1523.
  22. Sayegh MH, Perico N, Imberti O, et al. Thymic recognition of class II major histocompatibility complex allopeptides induces donor-specific unresponsiveness to renal allografts. Transplantation 1993; 56:461.
  23. Sayegh MH, Perico N, Gallon L, et al. Mechanisms of acquired thymic unresponsiveness to renal allografts. Thymic recognition of immunodominant allo-MHC peptides induces peripheral T cell anergy. Transplantation 1994; 58:125.
  24. Habicht A, Sayegh MH. T cell costimulatory pathways in allograft rejection and tolerance: What's new. Curr Opin Org Transpl 2007; 12:17.
  25. Durrbach A, Francois H, Jacquet A, et al. Co-signals in organ transplantation. Curr Opin Organ Transplant 2010; 15:474.
  26. Stamper CC, Zhang Y, Tobin JF, et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits human immune responses. Nature 2001; 410:608.
  27. Schwartz JC, Zhang X, Fedorov AA, et al. Structural basis for co-stimulation by the human CTLA-4/B7-2 complex. Nature 2001; 410:604.
  28. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 2004; 4:336.
  29. Clarkson MR, Sayegh MH. T-cell costimulatory pathways in allograft rejection and tolerance. Transplantation 2005; 80:555.
  30. Larsen CP, Knechtle SJ, Adams A, et al. A new look at blockade of T-cell costimulation: a therapeutic strategy for long-term maintenance immunosuppression. Am J Transplant 2006; 6:876.
  31. Zang X, Allison JP. To be or not to be B7. J Clin Invest 2006; 116:2590.
  32. Radvanyi LG, Shi Y, Vaziri H, et al. CD28 costimulation inhibits TCR-induced apoptosis during a primary T cell response. J Immunol 1996; 156:1788.
  33. Walunas TL, Lenschow DJ, Bakker CY, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994; 1:405.
  34. Hodi FS. Cytotoxic T-lymphocyte-associated antigen-4. Clin Cancer Res 2007; 13:5238.
  35. Tivol EA, Borriello F, Schweitzer AN, et al. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995; 3:541.
  36. Perez VL, Van Parijs L, Biuckians A, et al. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 1997; 6:411.
  37. Schaub M, Stadlbauer TH, Chandraker A, et al. Comparative strategies to induce long-term graft acceptance in fully allogeneic renal versus cardiac allograft models by CD28-B7 T cell costimulatory blockade: role of thymus and spleen. J Am Soc Nephrol 1998; 9:891.
  38. Azuma H, Chandraker A, Nadeau K, et al. Blockade of T-cell costimulation prevents development of experimental chronic renal allograft rejection. Proc Natl Acad Sci U S A 1996; 93:12439.
  39. Chandraker A, Russell ME, Glysing-Jensen T, et al. T-cell costimulatory blockade in experimental chronic cardiac allograft rejection: effects of cyclosporine and donor antigen. Transplantation 1997; 63:1053.
  40. Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005; 5:443.
  41. Vincenti F. Costimulation blockade--what will the future bring? Nephrol Dial Transplant 2007; 22:1293.
  42. Denton MD, Reul RM, Dharnidharka VR, et al. Central role for CD40/CD40 ligand (CD154) interactions in transplant rejection. Pediatr Transplant 1998; 2:6.
  43. DiSanto JP, Bonnefoy JY, Gauchat JF, et al. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature 1993; 361:541.
  44. Reul RM, Fang JC, Denton MD, et al. CD40 and CD40 ligand (CD154) are coexpressed on microvessels in vivo in human cardiac allograft rejection. Transplantation 1997; 64:1765.
  45. Sun H, Subbotin V, Chen C, et al. Prevention of chronic rejection in mouse aortic allografts by combined treatment with CTLA4-Ig and anti-CD40 ligand monoclonal antibody. Transplantation 1997; 64:1838.
  46. Yamada A, Salama AD, Sayegh MH. The role of novel T cell costimulatory pathways in autoimmunity and transplantation. J Am Soc Nephrol 2002; 13:559.
  47. Sandner SE, Clarkson MR, Salama AD, et al. Mechanisms of tolerance induced by donor-specific transfusion and ICOS-B7h blockade in a model of CD4+ T-cell-mediated allograft rejection. Am J Transplant 2005; 5:31.
  48. Fuggle SV, Koo DD. Cell adhesion molecules in clinical renal transplantation. Transplantation 1998; 65:763.
  49. Brady HR. Leukocyte adhesion molecules: potential targets for therapeutic intervention in kidney diseases. Curr Opin Nephrol Hypertens 1993; 2:171.
  50. Walcheck B, Moore KL, McEver RP, Kishimoto TK. Neutrophil-neutrophil interactions under hydrodynamic shear stress involve L-selectin and PSGL-1. A mechanism that amplifies initial leukocyte accumulation of P-selectin in vitro. J Clin Invest 1996; 98:1081.
  51. Luster AD. Chemokines--chemotactic cytokines that mediate inflammation. N Engl J Med 1998; 338:436.
  52. Ali S, Malik G, Burns A, et al. Renal transplantation: examination of the regulation of chemokine binding during acute rejection. Transplantation 2005; 79:672.
  53. Hancock WW, Gao W, Faia KL, Csizmadia V. Chemokines and their receptors in allograft rejection. Curr Opin Immunol 2000; 12:511.
  54. Colvin BL, Thomson AW. Chemokines, their receptors, and transplant outcome. Transplantation 2002; 74:149.
  55. Fairchild RL. Raising the direction signposts that guide T cell trafficking into allografts. Transplantation 2005; 79:646.
  56. Gao W, Faia KL, Csizmadia V, et al. Beneficial effects of targeting CCR5 in allograft recipients. Transplantation 2001; 72:1199.
  57. Fischereder M, Luckow B, Hocher B, et al. CC chemokine receptor 5 and renal-transplant survival. Lancet 2001; 357:1758.
  58. Abdi R, Tran TB, Sahagun-Ruiz A, et al. Chemokine receptor polymorphism and risk of acute rejection in human renal transplantation. J Am Soc Nephrol 2002; 13:754.
  59. Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989; 170:2081.
  60. Goriely S, Goldman M. The interleukin-12 family: new players in transplantation immunity? Am J Transplant 2007; 7:278.
  61. Joffre O, Santolaria T, Calise D, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med 2008; 14:88.
  62. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature 2008; 453:1051.
  63. Miossec P, Korn T, Kuchroo VK. Interleukin-17 and type 17 helper T cells. N Engl J Med 2009; 361:888.
  64. Crome SQ, Wang AY, Levings MK. Translational mini-review series on Th17 cells: function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2010; 159:109.
  65. Hancock WW, Sayegh MH, Kwok CA, et al. Oral, but not intravenous, alloantigen prevents accelerated allograft rejection by selective intragraft Th2 cell activation. Transplantation 1993; 55:1112.
  66. Sayegh MH, Akalin E, Hancock WW, et al. CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med 1995; 181:1869.
  67. Chadha R, Heidt S, Jones ND, Wood KJ. Th17: contributors to allograft rejection and a barrier to the induction of transplantation tolerance? Transplantation 2011; 91:939.
  68. Shihab FS, Andoh TF, Tanner AM, et al. Role of transforming growth factor-beta 1 in experimental chronic cyclosporine nephropathy. Kidney Int 1996; 49:1141.
  69. Tsaur I, Gasser M, Aviles B, et al. Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients. Kidney Int 2011; 79:1005.
  70. Wesselborg S, Fruman DA, Sagoo JK, et al. Identification of a physical interaction between calcineurin and nuclear factor of activated T cells (NFATp). J Biol Chem 1996; 271:1274.
  71. Bierer BE, Holländer G, Fruman D, Burakoff SJ. Cyclosporin A and FK506: molecular mechanisms of immunosuppression and probes for transplantation biology. Curr Opin Immunol 1993; 5:763.
  72. Brown EJ, Albers MW, Shin TB, et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994; 369:756.
  73. Zuckerman SH, Evans GF, Guthrie L. Transcriptional and post-transcriptional mechanisms involved in the differential expression of LPS-induced IL-1 and TNF mRNA. Immunology 1991; 73:460.
  74. Auphan N, DiDonato JA, Rosette C, et al. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995; 270:286.
  75. Ransohoff RM. Cellular responses to interferons and other cytokines: the JAK-STAT paradigm. N Engl J Med 1998; 338:616.
  76. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994; 264:1415.
  77. Velazquez L, Fellous M, Stark GR, Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell 1992; 70:313.
  78. Tullius SG, Tilney NL. Both alloantigen-dependent and -independent factors influence chronic allograft rejection. Transplantation 1995; 59:313.
  79. Le Moine A, Goldman M, Abramowicz D. Multiple pathways to allograft rejection. Transplantation 2002; 73:1373.
  80. Adams AB, Williams MA, Jones TR, et al. Heterologous immunity provides a potent barrier to transplantation tolerance. J Clin Invest 2003; 111:1887.
  81. Jabs WJ, Maurmann S, Wagner HJ, et al. Time course and frequency of Epstein-Barr virus reactivation after kidney transplantation: linkage to renal allograft rejection. J Infect Dis 2004; 190:1600.
  82. Halloran PF, Homik J, Goes N, et al. The "injury response": a concept linking nonspecific injury, acute rejection, and long-term transplant outcomes. Transplant Proc 1997; 29:79.
  83. Forbes RD, Zheng SX, Gomersall M, et al. Evidence that recipient CD8+ T cell depletion does not alter development of chronic vascular rejection in a rat heart allograft model. Transplantation 1994; 57:1238.
  84. Nadeau KC, Azuma H, Tilney NL. Sequential cytokine dynamics in chronic rejection of rat renal allografts: roles for cytokines RANTES and MCP-1. Proc Natl Acad Sci U S A 1995; 92:8729.
  85. Segerer S, Cui Y, Eitner F, et al. Expression of chemokines and chemokine receptors during human renal transplant rejection. Am J Kidney Dis 2001; 37:518.
  86. Watschinger B, Sayegh MH. Endothelin in organ transplantation. Am J Kidney Dis 1996; 27:151.
  87. Suthanthiran M. Molecular analyses of human renal allografts: differential intragraft gene expression during rejection. Kidney Int Suppl 1997; 58:S15.