Alters S E, Song H K, Fathman C G
Department of Medicine, Stanford University School of Medicine, California 94305-5111.
Transplantation. 1993 Sep;56(3):633-8. doi: 10.1097/00007890-199309000-00026.
Diabetic (B6) (IE-) mice treated with a depleting regimen of anti-CD4 monoclonal antibody at the time of transplantation with A/J (IEK) islets of Langerhans showed indefinite acceptance of their islet allograft, as evidenced by persistent normoglycemia. To address the mechanisms involved in such anti-CD4 induced transplantation tolerance we studied potentially IE-reactive V beta 11+ T cells from the tolerant allografted mice. Following complete repopulation of the CD4+ cells, both the CD4+V beta 11+ and CD8+V beta 11+ T cell subsets of the transplanted mice were unresponsive to anti-V beta 11 specific crosslinking. In contrast, lymphocytes tested within the first ten days following transplant were responsive to anti-V beta 11 specific crosslinking; this response decreased as a function of time and reached background levels by day 120 posttransplant. Sorting experiments indicated that the response of lymphocytes to anti-V beta 11 specific crosslinking seen during the initial 120 days posttransplant was confined to the peripheral CD8+ cells; the repopulating CD4+V beta 11+ T cells were unresponsive. In addition, administration of r-IL-2 at the time of transplantation induced rejection in anti-CD4-treated animals, again indicating that the peripheral CD8+ cells could respond shortly after transplant if provided with appropriate help. The decreasing response of CD8+ T cells from transplanted animals to anti-V beta 11 stimulation was inversely correlated with the rate of migration of cells from the thymus to the periphery, implying that new thymic migrant V beta 11+ cells, both CD4+ and CD8+, were rendered anergic upon encountering peripheral alloantigen. These data suggest the possibility that recent thymic migrants are rendered anergic upon encountering antigen in the periphery, a simple model to serve as a "fail-safe" mechanism to prevent autoreactivity.
在移植A/J（IEK）胰岛时，用抗CD4单克隆抗体清除方案处理的糖尿病（B6）（IE-）小鼠对其胰岛同种异体移植表现出无限期接受，持续正常血糖就是证据。为了探究这种抗CD4诱导的移植耐受所涉及的机制，我们研究了来自耐受同种异体移植小鼠的潜在IE反应性Vβ11 + T细胞。在CD4 +细胞完全重新填充后，移植小鼠的CD4 + Vβ11 +和CD8 + Vβ11 + T细胞亚群对抗Vβ11特异性交联无反应。相比之下，移植后前十天内检测的淋巴细胞对抗Vβ11特异性交联有反应；这种反应随时间下降，到移植后120天时达到背景水平。分选实验表明，移植后最初120天内淋巴细胞对抗Vβ11特异性交联的反应仅限于外周CD8 +细胞；重新填充的CD4 + Vβ11 + T细胞无反应。此外，移植时给予r-IL-2在抗CD4处理的动物中诱导排斥反应，再次表明如果给予适当的辅助，外周CD8 +细胞在移植后不久就会有反应。移植动物的CD8 + T细胞对抗Vβ11刺激的反应下降与细胞从胸腺迁移到外周的速率呈负相关，这意味着新的胸腺迁移Vβ11 +细胞，无论是CD4 +还是CD8 +，在遇到外周同种异体抗原后都变得无反应。这些数据表明，近期胸腺迁移细胞在遇到外周抗原后可能变得无反应，这是一种作为防止自身反应性的“故障安全”机制的简单模型。
