Nasr Isam W, Wang Yinong, Gao Ge, Deng Songyan, Diggs Lonnette, Rothstein David M, Tellides George, Lakkis Fadi G, Dai Zhenhua
Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
J Immunol. 2005 May 15;174(10):6161-8. doi: 10.4049/jimmunol.174.10.6161.
Immune responses are suppressed in immunologically privileged sites, which may provide a unique opportunity to prolong allograft survival. However, it is unknown whether testicular immune privilege promotes transplantation tolerance. Mechanisms underlying immune privilege are also not well understood. Here we found that islet transplantation in the testis, an immunologically privileged site, generates much less memory CD8(+) T cells but induces more Ag-specific CD4(+)CD25(+) regulatory T cells than in a conventional site. These CD4(+)CD25(+) cells exhibited the suppression of alloimmune responses in vivo and in vitro. Despite the immune regulation, intratesticular islet allografts all were rejected within 42 days after transplantation although they survived longer than renal subcapsular islet allografts. However, blocking CD40/CD40L costimulation induced the tolerance of intratesticular, but not renal subcapsular, islet allografts. Tolerance to intratesticular islet allografts spread to skin allografts in the non-privileged sites. Either transfer of memory CD8(+) T cells or deletion of CD25(+) T cells in vivo broke islet allograft tolerance. Thus, transplantation tolerance requires both costimulatory blockade, which suppresses acute allograft rejection, and a favorable balance between memory and regulatory T cells that could favorably prevent late allograft failure. These findings reveal novel mechanisms of immune privilege and provide direct evidence that testicular immune privilege fosters the induction of transplantation tolerance to allografts in both immunologically privileged and non-privileged sites.
免疫反应在免疫特惠部位受到抑制，这可能为延长同种异体移植物存活提供独特机会。然而，睾丸免疫特惠是否促进移植耐受尚不清楚。免疫特惠的潜在机制也尚未完全了解。在此我们发现，在免疫特惠部位睾丸内进行胰岛移植，与在传统部位相比，产生的记忆性CD8(+) T细胞少得多，但诱导产生的抗原特异性CD4(+)CD25(+)调节性T细胞更多。这些CD4(+)CD25(+)细胞在体内和体外均表现出对同种异体免疫反应的抑制作用。尽管存在免疫调节，但睾丸内胰岛同种异体移植物在移植后42天内均被排斥，尽管它们的存活时间比肾被膜下胰岛同种异体移植物长。然而，阻断CD40/CD40L共刺激可诱导睾丸内而非肾被膜下胰岛同种异体移植物产生耐受。对睾丸内胰岛同种异体移植物的耐受可扩展至非特惠部位的皮肤同种异体移植物。体内记忆性CD8(+) T细胞的转移或CD25(+) T细胞的缺失均可打破胰岛同种异体移植物的耐受。因此，移植耐受既需要共刺激阻断以抑制急性同种异体移植排斥，也需要记忆性T细胞和调节性T细胞之间的良好平衡，以有效预防晚期同种异体移植失败。这些发现揭示了免疫特惠的新机制，并提供了直接证据表明睾丸免疫特惠促进在免疫特惠和非特惠部位对同种异体移植物诱导移植耐受。
