• 1.川北醫(yī)學(xué)院附屬醫(yī)院普外科（四川南充 637000）;;
  • 2.重慶醫(yī)科大學(xué)附屬第二醫(yī)院肝膽外科（重慶 400010）;

目的  介紹共刺激分子與器官移植免疫耐受的研究進(jìn)展。方法  復(fù)習(xí)近年來國內(nèi)、外相關(guān)文獻(xiàn)并作綜述。結(jié)果  目前有多條共刺激通路與移植免疫的關(guān)系已闡明，主要有B7-CD28/CTLA4、CD40-CD154、4-1BB/4-1BBL、ICOS-B7h等。大量研究表明，單一阻斷某個(gè)共刺激通路難以達(dá)到持久、穩(wěn)定的免疫耐受，只有協(xié)同阻斷或是與其他免疫抑制方法聯(lián)合應(yīng)用時(shí)才表現(xiàn)出更好的效果。結(jié)論  隨著免疫學(xué)和分子生物學(xué)的發(fā)展，T淋巴細(xì)胞活化的共刺激通路將被進(jìn)一步闡明，相信將來還會有新的共刺激分子被發(fā)現(xiàn)，為誘導(dǎo)器官移植免疫耐受提供理論依據(jù)。

引用本文： 彭勇,龔建平. 共刺激分子與移植免疫耐受. 中國普外基礎(chǔ)與臨床雜志, 2010, 17(6): 552-556. doi: 復(fù)制

1. Brown RS, Belton AM, Martin JM, et al. Evolution of quality at the Organ Center of the Organ Procurement and Transplantation Network/United Network for Organ Sharing [J]. Prog Transplant, 2009; 19(3): 221-226.
2. Daniel V, Opelz G. Clinical relevance of immune monitoring in solid organ transplantation [J]. Int Rev Immunol, 2009； 28(3-4): 155-184.
3. Rath T, Oliveira-Frick V. Mutagenicity of immunosuppressive medications among renal transplant recipients [J]. Am J Nephrol, 2009； 30(6): 514-520.
4. Xie B, Chen J, Xia J, et al. Combined costimulation blockade inhibits accelerated rejection mediated by alloantigen-primed memory T cells in mice [J]. Immunol Invest, 2009； 38(7): 639-651.
5. Ritter T, Nosov M, Griffin MD. Gene therapy in transplantation: Toward clinical trials [J]. Curr Opin Mol Ther, 2009； 11(5): 504-512.
6. Li S, Kuang A, Huang R. Can proliferation signal inhibitor-induced Tregs really reflect transplantation tolerance in clinical solid organ transplantation? [J]. Int Rev Immunol, 2009； 28(5): 367-375.
7. de Jager SC, Canté-Barrett K, Bot I, et al. Impaired effector memory T-cell regulation facilitates graft versus host disease in CCR7-deficient bone marrow transplant chimeras [J]. Transplantation, 2009； 88(5): 631-639.
8. Du JF, Li SY, Yu B. Rapamycin-rather than FK506-might promote allograft tolerance induced by CD4+CD25+ regulatory T cells [J]. Surgery, 2009； 142(1): 67-73.
9. Martins PN. Impact of donor and recipient age on allograft tolerance [J]. Exp Clin Transplant, 2009； 7（2）: 67-77.
10. Kim SY, Kim DW, Choi JY, et al. Full donor chimerism using stem-cell transplantation for tolerance induction in the human leukocyte antigen-matched liver transplant setting [J]. Transplantation, 2009； 88(4): 601-603.
11. Zheng J, Liu Y, Qin G, et al. Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells [J]. J Immunol, 2009； 183(6): 3742-3750.
12. Graves SS, Stone D, Loretz C, et al. Establishment of long-term tolerance to SRBC in dogs by recombinant canine CTLA4-Ig [J]. Transplantation, 2009； 88(3): 317-322.
13. Schroeder RA, Marroquin CE, Kuo PC. Tolerance and the “Holy Grail” of transplantation [J]. J Surg Res, 2003; 111(1): 109-119.
14. Rivas MN, Weatherly K, Hazzan M, et al. Reviving function in CD4+ T cells adapted to persistent systemic antigen [J]. J Immunol, 2009； 183(7): 4284-4291.
15. Shilling RA, Clay BS, Tesciuba AG, et al. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo [J]. Cell Immunol, 2009； 259(2): 177-184.
16. Riley JL, June CH. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation [J]. Blood, 2005； 105(1): 13-21.
17. Halloran PF. T-cell activation pathways: a transplantation perspective [J]. Transplant Proc, 1999； 31(1-2): 769-771.
18. Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily-CTLA4 [J]. Nature, 1987； 328(6127): 267-270.
19. Greenfield EA, Nguyen KA, Kuchroo VK. CD28/B7 costimulation: a review [J]. Crit Rev Immunol, 1998； 18(5): 389-418.
20. Tector M, Khatri BO, Kozinski K, et al. Biochemical analysis of CTLA-4 immunoreactive material from human blood [J]. BMC Immunol, 2009； 10: 51.
21. Kroczek R, Hamelmann E. T-cell costimulatory molecules: optimal targets for the treatment of allergic airway disease with monoclonal antibodies [J]. J Allergy Clin Immunol, 2005； 116(4): 906-909.
22. Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies [J]. J Exp Med, 2009； 206(8): 1717-1725.
23. Jochum C, Beste M, Stone D, et al. Development and in vitro characterization of canine CD40-Ig [J]. Vet Immunol Immunopathol, 2008； 123(3-4): 260-265.
24. Wang GM, Ma JB, Jin YZ, et al. Long-term survival of cardiac allografts induced by cyclophosphamide combined with CTLA4Ig-gene transfer mediated by adenoviral vector [J]. Transplant Proc, 2006； 38(9): 3043-3045.
25. Lu S, Yu Y, Gao Y, et al. Immunological inhibition of transplanted liver allografts by adeno-associated virus vector encoding CTLA4Ig in rats[J]. Hepatobiliary Pancreat Dis Int, 2008； 7(3): 258-263.
26. Xu H, Yan J, Huang Y, et al. Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization[J]. Blood, 2008； 111(6): 3266-3275.
27. Shoker A, George D, Yang H, et al. Heightened CD40 ligand gene expression in peripheral CD4+ T cells from patients with kidney allograft rejection [J]. Transplantation, 2000; 70(3): 497-505.
28. Kover KL, Geng Z, Hess DM, et al. Anti-CD154 (CD40L) prevents recurrence of diabetes in islet isografts in the DR-BB rat [J]. Diabetes, 2000； 49(10): 1666-1670.
29. Graca L, Honey K, Adams E, et al. Cutting edge: anti-CD154 therapeutic antibodies induce infectious transplantation tolerance [J]. J Immunol， 2000； 165(9): 4783-4786.
30. Shimizu K, Schnbeck U, Mach F, et al. Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis [J]. J Immunol, 2000； 165(6): 3506-3518.
31. Bauquet AT, Jin H, Paterson AM, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells [J]. Nat Immunol, 2009； 10(2): 167-175.
32. Chen Y, Liu H, Liu Z, et al. Blockade of inducible costimulator pathway to prevent acute rejection in rat liver transplantation [J]. Am J Surg, 2009； 198(2): 244-249.
33. Pan XC, Guo L, Deng YB, et al. Further study of anti-ICOS immunotherapy for rat cardiac allograft rejection [J]. Surg Today, 2008; 38(9): 815-825.
34. Kwon BS, Kestler DP, Eshhar Z, et al. Expression characteristics of two potential T cell mediator genes [J]. Cell Immunol, 1989； 121(2): 414-422.
35. Goodwin RG, Din WS, Davis-Smith T, et al. Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor[J]. Eur J Immunol, 1993； 23(10): 2631-2641.
36. Xu K, Li C, Pan X, et al. Study of relieving graft-versus-host disease by blocking CD137-CD137 ligand costimulatory pathway in vitro [J]. Int J Hematol, 2007； 86(1): 84-90.
37. Huang BJ, Yin H, Huang YF, et al. Gene therapy using adenoviral vector encoding 4-1BBIg gene significantly prolonged murine cardiac allograft survival [J]. Transpl Immunol, 2006； 16(2): 88-94.
  1. 1. Brown RS, Belton AM, Martin JM, et al. Evolution of quality at the Organ Center of the Organ Procurement and Transplantation Network/United Network for Organ Sharing [J]. Prog Transplant, 2009; 19(3): 221-226.
  2. 2. Daniel V, Opelz G. Clinical relevance of immune monitoring in solid organ transplantation [J]. Int Rev Immunol, 2009； 28(3-4): 155-184.
  3. 3. Rath T, Oliveira-Frick V. Mutagenicity of immunosuppressive medications among renal transplant recipients [J]. Am J Nephrol, 2009； 30(6): 514-520.
  4. 4. Xie B, Chen J, Xia J, et al. Combined costimulation blockade inhibits accelerated rejection mediated by alloantigen-primed memory T cells in mice [J]. Immunol Invest, 2009； 38(7): 639-651.
  5. 5. Ritter T, Nosov M, Griffin MD. Gene therapy in transplantation: Toward clinical trials [J]. Curr Opin Mol Ther, 2009； 11(5): 504-512.
  6. 6. Li S, Kuang A, Huang R. Can proliferation signal inhibitor-induced Tregs really reflect transplantation tolerance in clinical solid organ transplantation? [J]. Int Rev Immunol, 2009； 28(5): 367-375.
  7. 7. de Jager SC, Canté-Barrett K, Bot I, et al. Impaired effector memory T-cell regulation facilitates graft versus host disease in CCR7-deficient bone marrow transplant chimeras [J]. Transplantation, 2009； 88(5): 631-639.
  8. 8. Du JF, Li SY, Yu B. Rapamycin-rather than FK506-might promote allograft tolerance induced by CD4+CD25+ regulatory T cells [J]. Surgery, 2009； 142(1): 67-73.
  9. 9. Martins PN. Impact of donor and recipient age on allograft tolerance [J]. Exp Clin Transplant, 2009； 7（2）: 67-77.
  10. 10. Kim SY, Kim DW, Choi JY, et al. Full donor chimerism using stem-cell transplantation for tolerance induction in the human leukocyte antigen-matched liver transplant setting [J]. Transplantation, 2009； 88(4): 601-603.
  11. 11. Zheng J, Liu Y, Qin G, et al. Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells [J]. J Immunol, 2009； 183(6): 3742-3750.
  12. 12. Graves SS, Stone D, Loretz C, et al. Establishment of long-term tolerance to SRBC in dogs by recombinant canine CTLA4-Ig [J]. Transplantation, 2009； 88(3): 317-322.
  13. 13. Schroeder RA, Marroquin CE, Kuo PC. Tolerance and the “Holy Grail” of transplantation [J]. J Surg Res, 2003; 111(1): 109-119.
  14. 14. Rivas MN, Weatherly K, Hazzan M, et al. Reviving function in CD4+ T cells adapted to persistent systemic antigen [J]. J Immunol, 2009； 183(7): 4284-4291.
  15. 15. Shilling RA, Clay BS, Tesciuba AG, et al. CD28 and ICOS play complementary non-overlapping roles in the development of Th2 immunity in vivo [J]. Cell Immunol, 2009； 259(2): 177-184.
  16. 16. Riley JL, June CH. The CD28 family: a T-cell rheostat for therapeutic control of T-cell activation [J]. Blood, 2005； 105(1): 13-21.
  17. 17. Halloran PF. T-cell activation pathways: a transplantation perspective [J]. Transplant Proc, 1999； 31(1-2): 769-771.
  18. 18. Brunet JF, Denizot F, Luciani MF, et al. A new member of the immunoglobulin superfamily-CTLA4 [J]. Nature, 1987； 328(6127): 267-270.
  19. 19. Greenfield EA, Nguyen KA, Kuchroo VK. CD28/B7 costimulation: a review [J]. Crit Rev Immunol, 1998； 18(5): 389-418.
  20. 20. Tector M, Khatri BO, Kozinski K, et al. Biochemical analysis of CTLA-4 immunoreactive material from human blood [J]. BMC Immunol, 2009； 10: 51.
  21. 21. Kroczek R, Hamelmann E. T-cell costimulatory molecules: optimal targets for the treatment of allergic airway disease with monoclonal antibodies [J]. J Allergy Clin Immunol, 2005； 116(4): 906-909.
  22. 22. Peggs KS, Quezada SA, Chambers CA, et al. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies [J]. J Exp Med, 2009； 206(8): 1717-1725.
  23. 23. Jochum C, Beste M, Stone D, et al. Development and in vitro characterization of canine CD40-Ig [J]. Vet Immunol Immunopathol, 2008； 123(3-4): 260-265.
  24. 24. Wang GM, Ma JB, Jin YZ, et al. Long-term survival of cardiac allografts induced by cyclophosphamide combined with CTLA4Ig-gene transfer mediated by adenoviral vector [J]. Transplant Proc, 2006； 38(9): 3043-3045.
  25. 25. Lu S, Yu Y, Gao Y, et al. Immunological inhibition of transplanted liver allografts by adeno-associated virus vector encoding CTLA4Ig in rats[J]. Hepatobiliary Pancreat Dis Int, 2008； 7(3): 258-263.
  26. 26. Xu H, Yan J, Huang Y, et al. Costimulatory blockade of CD154-CD40 in combination with T-cell lymphodepletion results in prevention of allogeneic sensitization[J]. Blood, 2008； 111(6): 3266-3275.
  27. 27. Shoker A, George D, Yang H, et al. Heightened CD40 ligand gene expression in peripheral CD4+ T cells from patients with kidney allograft rejection [J]. Transplantation, 2000; 70(3): 497-505.
  28. 28. Kover KL, Geng Z, Hess DM, et al. Anti-CD154 (CD40L) prevents recurrence of diabetes in islet isografts in the DR-BB rat [J]. Diabetes, 2000； 49(10): 1666-1670.
  29. 29. Graca L, Honey K, Adams E, et al. Cutting edge: anti-CD154 therapeutic antibodies induce infectious transplantation tolerance [J]. J Immunol， 2000； 165(9): 4783-4786.
  30. 30. Shimizu K, Schnbeck U, Mach F, et al. Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis [J]. J Immunol, 2000； 165(6): 3506-3518.
  31. 31. Bauquet AT, Jin H, Paterson AM, et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells [J]. Nat Immunol, 2009； 10(2): 167-175.
  32. 32. Chen Y, Liu H, Liu Z, et al. Blockade of inducible costimulator pathway to prevent acute rejection in rat liver transplantation [J]. Am J Surg, 2009； 198(2): 244-249.
  33. 33. Pan XC, Guo L, Deng YB, et al. Further study of anti-ICOS immunotherapy for rat cardiac allograft rejection [J]. Surg Today, 2008; 38(9): 815-825.
  34. 34. Kwon BS, Kestler DP, Eshhar Z, et al. Expression characteristics of two potential T cell mediator genes [J]. Cell Immunol, 1989； 121(2): 414-422.
  35. 35. Goodwin RG, Din WS, Davis-Smith T, et al. Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor[J]. Eur J Immunol, 1993； 23(10): 2631-2641.
  36. 36. Xu K, Li C, Pan X, et al. Study of relieving graft-versus-host disease by blocking CD137-CD137 ligand costimulatory pathway in vitro [J]. Int J Hematol, 2007； 86(1): 84-90.
  37. 37. Huang BJ, Yin H, Huang YF, et al. Gene therapy using adenoviral vector encoding 4-1BBIg gene significantly prolonged murine cardiac allograft survival [J]. Transpl Immunol, 2006； 16(2): 88-94.