• 1.昆明醫(yī)學(xué)院第二附屬醫(yī)院肝膽胰一病區(qū)（昆明 650101）;;
  • 2.昆明市第一人民醫(yī)院暨昆明醫(yī)學(xué)院附屬甘美醫(yī)院肝移植中心（昆明 650011）;

目的  總結(jié)胰腺移植免疫耐受的研究進(jìn)展。方法  分析近年來有關(guān)胰腺移植免疫耐受研究進(jìn)展的文獻(xiàn)報道。 結(jié)果  外周性耐受及中樞性耐受是誘導(dǎo)免疫耐受的主要方法，其中通過供體特異性骨髓細(xì)胞輸注誘導(dǎo)嵌合體形成是目前的研究熱點(diǎn)。結(jié)論  供體特異性骨髓細(xì)胞輸注聯(lián)合一種或多種外周性耐受方法有望誘導(dǎo)胰腺移植免疫耐受，但需進(jìn)行深入研究。

引用本文： 魏曉平,李立. 胰腺移植免疫耐受研究進(jìn)展. 中國普外基礎(chǔ)與臨床雜志, 2008, 15(12): 883-886. doi: 復(fù)制

1. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004 [J]. Clin Transplant, 2005; 19(4)∶433.
2. Masaki H, Appel MC, Leahy L, et al. Anti-mouse CD154 antibody treatment facilitates generation of mixed xenogeneic rat hematopoietic chimerism, prevents wasting disease and prolongs xenograft survival in mice [J]. Xenotransplantation, 2006; 13(3)∶224.
3. Pan H, Lu HM, Hu WM, et al. Anti-CD25 mAb, anti-IL2 mAb, and IL2 block tolerance induction through anti-CD154 mAb and rapamycin in xenogeneic islet transplantation [J]. Transplant Proc, 2007; 39(10)∶3452.
4. 李 濤， 羅 軍， 溫 浩. 細(xì)胞凋亡在大鼠胰腺移植急性排斥反應(yīng)中的作用 [J]. 中國普外基礎(chǔ)與臨床雜志, 2007; 14（1）∶59.
5. Wang Z, Davies JD. CD8 blockade promotes antigen responsiveness to nontolerizing antigen in tolerant mice by inhibiting apoptosis of CD4+ T cells [J]. J Immunol, 2007; 178(10)∶6148.
6. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity [J]. Nat Rev Immunol, 2007; 7(8)∶622.
7. Wu X, Guo R, Wang Y, et al. The role of ICAM-1 in endotoxin-induced acute renal failure [J]. Am J Physiol Renal Physiol, 2007; 293(4)∶F1262.
8. Filby A, Seddon B, Kleczkowska J, et al. Fyn regulates the duration of TCR engagement needed for commitment to effector function [J]. J Immunol, 2007; 179(7)∶4635.
9. Foell J, Hewes B, Mittler RS. T cell costimulatory and inhibitory receptors as therapeutic targets for inducing anti-tumor immunity [J]. Curr Cancer Drug Targets, 2007; 7(1)∶55.
10. Scharpf J, Strome M, Siemionow M. Immunomodulation with anti-alphabeta T-cell receptor monoclonal antibodies in combination with cyclosporine A improves regeneration in nerve allografts [J]. Microsurgery, 2006; 26(8)∶599.
11. Lee JH, Ha J, Kim SH, et al. IL-2 pathway blocking in combination with anti-CD154 synergistically establishes mixed macrochimerism with limited dose of bone marrow cells and prolongs skin graft survival in mice [J]. J Korean Med Sci, 2006; 21(6)∶1005.
12. Chavez H, Beaudreuil S, Abbed K, et al. Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28-CD80/86 blockade [J]. Transpl Immunol, 2007; 17(4)∶243.
13. Li ZL, Xue WJ, Tian PX, et al. Prolongation of islet allograft survival by coexpression of CTLA4Ig and CD40LIg in mice [J]. Transplant Proc, 2007; 39(10)∶3436.
14. 鄭樹森， 于吉人， 王偉林主編. 胰腺移植 [M]. 第1版. 北京： 人民衛(wèi)生出版社， 2002∶59~61.
15. Yamazaki M, Pearson T, Brehm MA, et al. Different mechanisms control peripheral and central tolerance in hematopoietic chimeric mice [J]. Am J Transplant, 2007; 7(7)∶1710.
16. Starzl TE, Demetris AJ, Trucco M, et al. Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation [J]. Transplantation, 1993; 55(6)∶1272.
17. 李紀(jì)鵬， 黃 怡， 王為忠， 等. TGF-β1基因修飾的未成熟樹突狀細(xì)胞對小腸移植大鼠外周血及移植腸浸潤T細(xì)胞的影響 [J]. 中國普外基礎(chǔ)與臨床雜志, 2008; 15(2)∶96.
18. Ito H, Takeuchi Y, Shaffer J, et al. Anti-CD40L monoclonal antibodies can replace anti-CD4 monoclonal antibodies for the nonmyeloablative induction of mixed xenogeneic chimerism [J]. Transplantation, 2006; 82(2)∶251.
19. Takeuchi Y, Ito H, Kurtz J, et al. Earlier low-dose TBI or DST overcomes CD8+ T-cell-mediated alloresistance to allogeneic marrow in recipients of anti-CD40L [J]. Am J Transplant, 2004; 4(1)∶31.
20. Kurtz J, Shaffer J, Lie A, et al. Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells [J]. Blood, 2004; 103(11)∶4336.
21. Ito T, Stepkowski SM, Kahan BD. Soluble antigen and cyclosporine-induced specific unresponsiveness in rats. Frequency of alloantigen-specific T cytotoxic cells in normal, sensitized, and unresponsive rats [J]. Transplantation, 1990; 49(2)∶422.
22. Ito T, Uchikoshi F, Tori M, et al. Immunological characteristics of pancreas transplantation: review and our experimental experience [J]. Pancreas, 2003; 27(1)∶31.
23. 冷希圣, 黃萃庭. 供體脾細(xì)胞在大鼠胰十二指腸移植中抗免疫排斥作用的初步觀察 [J]. 中華實(shí)驗外科雜志, 1989; 6(3)∶106.
24. 周 峰, 萬赤丹, 熊炯炘, 等. 供體特異性輸血對大鼠胰十二指腸移植的保護(hù)作用 [J]. 中華實(shí)驗外科雜志, 2004; 21(12)∶1477.
25. 韓曙光, 徐澤寬, 張 軒, 等. 可誘導(dǎo)性共刺激分子單抗聯(lián)合細(xì)胞毒T淋巴細(xì)胞4Ig在大鼠胰腺移植中的作用 [J]. 中華實(shí)驗外科雜志, 2007; 24(4)∶ 420.
26. 孟令祥, 胡偉明, 張肇達(dá), 等. Ad-CTLA-4Ig基因?qū)雽σ仁改c移植大鼠免疫耐受的實(shí)驗研究 [J]. 四川大學(xué)學(xué)報(醫(yī)學(xué)版), 2007; 38(3)∶ 374.
27. Bitter-Suermann H. Survival of unmodified spleen allografts in rats [J]. Nature, 1974; 247(441)∶465.
28. Schulak JA, Engelstad KM. Immunologic consequences of combined pancreas-spleen transplantation in the rat [J]. J Surg Res, 1989; 47(1)∶52.
29. Sakuma Y, Sato Y, Inoue S, et al. Lympho-myeloid chimerism achieved by spleen graft of green fluorescent protein transgenic rat in a combined pancreas transplantation model (TI03-029) [J]. Transpl Immunol, 2004; 12(2)∶115.
30. Zhong T, Liu Y, Jiang J, et al. Long-term limb allograft survival using a short course of anti-CD45RB monoclonal antibody, LF 15-0195, and rapamycin in a mouse model [J]. Transplantation, 2007; 84(12)∶1636.
31. Masaki Y, Suzuki K, Yan H, et al. Quantitative aspects of microchimerism after rat small bowel and pancreaticoduodenal transplantation [J]. Transplant Proc, 2000; 32(7)∶2483.
32. Hayashi H, Toki J, Zhexiong L, et al. Long-term (>1 year) analyses of chimerism and tolerance in mixed allogeneic chimeric mice using normal mouse combinations [J]. Stem Cells, 2000; 18(4)∶273.
33. Jin T, Toki J, Inaba M, Sugiura K, et al. A novel strategy for organ allografts using sublethal (7 Gy) irradiation followed by injection of donor bone marrow cells via portal vein [J]. Transplantation, 2001; 71(12)∶1725.
34. Drevillon C, Elian N, Zinzindohoue F, et al. Prolonged improvement of total pancreatic allograft function by previous intrathymic bone marrow cell injection in rats [J]. Eur Surg Res, 2003; 35(1)∶1.
35. Burke GW, Ciancio G, Garcia-Morales R, et al. Evidence for microchimerism in peripheral blood, bone marrow, and skin following donor bone marrow/kidney-pancreas transplantation at 3 years [J]. Transplant Proc, 1998; 30(4)∶1555.
36. Corry RJ, Chakrabarti PK, Shapiro R, et al. Simultaneous administration of adjuvant donor bone marrow in pancreas transplant recipients [J]. Ann Surg, 1999; 230(3)∶372.
37. Kuhr CS, Nelson K, Gaur L, et al. Induced microchimerism by spleen reperfusion affords no immunological advantage in pancreas transplantation [J]. Transplant Proc, 2003; 35(2)∶878.
  1. 1. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of June 2004 [J]. Clin Transplant, 2005; 19(4)∶433.
  2. 2. Masaki H, Appel MC, Leahy L, et al. Anti-mouse CD154 antibody treatment facilitates generation of mixed xenogeneic rat hematopoietic chimerism, prevents wasting disease and prolongs xenograft survival in mice [J]. Xenotransplantation, 2006; 13(3)∶224.
  3. 3. Pan H, Lu HM, Hu WM, et al. Anti-CD25 mAb, anti-IL2 mAb, and IL2 block tolerance induction through anti-CD154 mAb and rapamycin in xenogeneic islet transplantation [J]. Transplant Proc, 2007; 39(10)∶3452.
  4. 4. 李 濤， 羅 軍， 溫 浩. 細(xì)胞凋亡在大鼠胰腺移植急性排斥反應(yīng)中的作用 [J]. 中國普外基礎(chǔ)與臨床雜志, 2007; 14（1）∶59.
  5. 5. Wang Z, Davies JD. CD8 blockade promotes antigen responsiveness to nontolerizing antigen in tolerant mice by inhibiting apoptosis of CD4+ T cells [J]. J Immunol, 2007; 178(10)∶6148.
  6. 6. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity [J]. Nat Rev Immunol, 2007; 7(8)∶622.
  7. 7. Wu X, Guo R, Wang Y, et al. The role of ICAM-1 in endotoxin-induced acute renal failure [J]. Am J Physiol Renal Physiol, 2007; 293(4)∶F1262.
  8. 8. Filby A, Seddon B, Kleczkowska J, et al. Fyn regulates the duration of TCR engagement needed for commitment to effector function [J]. J Immunol, 2007; 179(7)∶4635.
  9. 9. Foell J, Hewes B, Mittler RS. T cell costimulatory and inhibitory receptors as therapeutic targets for inducing anti-tumor immunity [J]. Curr Cancer Drug Targets, 2007; 7(1)∶55.
  10. 10. Scharpf J, Strome M, Siemionow M. Immunomodulation with anti-alphabeta T-cell receptor monoclonal antibodies in combination with cyclosporine A improves regeneration in nerve allografts [J]. Microsurgery, 2006; 26(8)∶599.
  11. 11. Lee JH, Ha J, Kim SH, et al. IL-2 pathway blocking in combination with anti-CD154 synergistically establishes mixed macrochimerism with limited dose of bone marrow cells and prolongs skin graft survival in mice [J]. J Korean Med Sci, 2006; 21(6)∶1005.
  12. 12. Chavez H, Beaudreuil S, Abbed K, et al. Absence of CD4CD25 regulatory T cell expansion in renal transplanted patients treated in vivo with Belatacept mediated CD28-CD80/86 blockade [J]. Transpl Immunol, 2007; 17(4)∶243.
  13. 13. Li ZL, Xue WJ, Tian PX, et al. Prolongation of islet allograft survival by coexpression of CTLA4Ig and CD40LIg in mice [J]. Transplant Proc, 2007; 39(10)∶3436.
  14. 14. 鄭樹森， 于吉人， 王偉林主編. 胰腺移植 [M]. 第1版. 北京： 人民衛(wèi)生出版社， 2002∶59~61.
  15. 15. Yamazaki M, Pearson T, Brehm MA, et al. Different mechanisms control peripheral and central tolerance in hematopoietic chimeric mice [J]. Am J Transplant, 2007; 7(7)∶1710.
  16. 16. Starzl TE, Demetris AJ, Trucco M, et al. Chimerism and donor-specific nonreactivity 27 to 29 years after kidney allotransplantation [J]. Transplantation, 1993; 55(6)∶1272.
  17. 17. 李紀(jì)鵬， 黃 怡， 王為忠， 等. TGF-β1基因修飾的未成熟樹突狀細(xì)胞對小腸移植大鼠外周血及移植腸浸潤T細(xì)胞的影響 [J]. 中國普外基礎(chǔ)與臨床雜志, 2008; 15(2)∶96.
  18. 18. Ito H, Takeuchi Y, Shaffer J, et al. Anti-CD40L monoclonal antibodies can replace anti-CD4 monoclonal antibodies for the nonmyeloablative induction of mixed xenogeneic chimerism [J]. Transplantation, 2006; 82(2)∶251.
  19. 19. Takeuchi Y, Ito H, Kurtz J, et al. Earlier low-dose TBI or DST overcomes CD8+ T-cell-mediated alloresistance to allogeneic marrow in recipients of anti-CD40L [J]. Am J Transplant, 2004; 4(1)∶31.
  20. 20. Kurtz J, Shaffer J, Lie A, et al. Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells [J]. Blood, 2004; 103(11)∶4336.
  21. 21. Ito T, Stepkowski SM, Kahan BD. Soluble antigen and cyclosporine-induced specific unresponsiveness in rats. Frequency of alloantigen-specific T cytotoxic cells in normal, sensitized, and unresponsive rats [J]. Transplantation, 1990; 49(2)∶422.
  22. 22. Ito T, Uchikoshi F, Tori M, et al. Immunological characteristics of pancreas transplantation: review and our experimental experience [J]. Pancreas, 2003; 27(1)∶31.
  23. 23. 冷希圣, 黃萃庭. 供體脾細(xì)胞在大鼠胰十二指腸移植中抗免疫排斥作用的初步觀察 [J]. 中華實(shí)驗外科雜志, 1989; 6(3)∶106.
  24. 24. 周 峰, 萬赤丹, 熊炯炘, 等. 供體特異性輸血對大鼠胰十二指腸移植的保護(hù)作用 [J]. 中華實(shí)驗外科雜志, 2004; 21(12)∶1477.
  25. 25. 韓曙光, 徐澤寬, 張 軒, 等. 可誘導(dǎo)性共刺激分子單抗聯(lián)合細(xì)胞毒T淋巴細(xì)胞4Ig在大鼠胰腺移植中的作用 [J]. 中華實(shí)驗外科雜志, 2007; 24(4)∶ 420.
  26. 26. 孟令祥, 胡偉明, 張肇達(dá), 等. Ad-CTLA-4Ig基因?qū)雽σ仁改c移植大鼠免疫耐受的實(shí)驗研究 [J]. 四川大學(xué)學(xué)報(醫(yī)學(xué)版), 2007; 38(3)∶ 374.
  27. 27. Bitter-Suermann H. Survival of unmodified spleen allografts in rats [J]. Nature, 1974; 247(441)∶465.
  28. 28. Schulak JA, Engelstad KM. Immunologic consequences of combined pancreas-spleen transplantation in the rat [J]. J Surg Res, 1989; 47(1)∶52.
  29. 29. Sakuma Y, Sato Y, Inoue S, et al. Lympho-myeloid chimerism achieved by spleen graft of green fluorescent protein transgenic rat in a combined pancreas transplantation model (TI03-029) [J]. Transpl Immunol, 2004; 12(2)∶115.
  30. 30. Zhong T, Liu Y, Jiang J, et al. Long-term limb allograft survival using a short course of anti-CD45RB monoclonal antibody, LF 15-0195, and rapamycin in a mouse model [J]. Transplantation, 2007; 84(12)∶1636.
  31. 31. Masaki Y, Suzuki K, Yan H, et al. Quantitative aspects of microchimerism after rat small bowel and pancreaticoduodenal transplantation [J]. Transplant Proc, 2000; 32(7)∶2483.
  32. 32. Hayashi H, Toki J, Zhexiong L, et al. Long-term (>1 year) analyses of chimerism and tolerance in mixed allogeneic chimeric mice using normal mouse combinations [J]. Stem Cells, 2000; 18(4)∶273.
  33. 33. Jin T, Toki J, Inaba M, Sugiura K, et al. A novel strategy for organ allografts using sublethal (7 Gy) irradiation followed by injection of donor bone marrow cells via portal vein [J]. Transplantation, 2001; 71(12)∶1725.
  34. 34. Drevillon C, Elian N, Zinzindohoue F, et al. Prolonged improvement of total pancreatic allograft function by previous intrathymic bone marrow cell injection in rats [J]. Eur Surg Res, 2003; 35(1)∶1.
  35. 35. Burke GW, Ciancio G, Garcia-Morales R, et al. Evidence for microchimerism in peripheral blood, bone marrow, and skin following donor bone marrow/kidney-pancreas transplantation at 3 years [J]. Transplant Proc, 1998; 30(4)∶1555.
  36. 36. Corry RJ, Chakrabarti PK, Shapiro R, et al. Simultaneous administration of adjuvant donor bone marrow in pancreas transplant recipients [J]. Ann Surg, 1999; 230(3)∶372.
  37. 37. Kuhr CS, Nelson K, Gaur L, et al. Induced microchimerism by spleen reperfusion affords no immunological advantage in pancreas transplantation [J]. Transplant Proc, 2003; 35(2)∶878.