MHC-mismatched islet allografts are vulnerable to autoimmune recognition in vivo
MHC-mismatched islet allografts are vulnerable to autoimmune recognition in vivo
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DOI：
10.4049/jimmunol.175.4.2309
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发表时间：
2005-08-15
影响因子：
4.4
通讯作者：
Gill, RG
中科院分区：
文献类型：
--
作者：
Kupfer, TM;Crawford, ML;Gill, RG
当移植到1a型糖尿病受者体内时，同种异体胰岛移植物既受到常规移植物免疫的影响，又可能受到反复发生的自身免疫(胰岛特异性)的影响。重要的是，CD4T细胞在同种异体胰岛移植排斥反应和自身免疫性疾病复发导致糖尿病NOD小鼠同基因胰岛移植破坏中发挥核心作用。然而，目前尚不清楚NOD宿主MHC 11(I-A(G7))限制性、自身反应性的CD4T细胞如何也有助于识别表达不同MHC 11分子的同种异体胰岛移植物。我们假设，胰岛特异性的CD4T细胞可以通过“间接”(宿主APC依赖的)抗原识别途径来靶向MHC不匹配的同种异体胰岛移植物以进行破坏。为了验证这一假设，我们确定了NOD来源的胰岛特异性CD4T细胞(BDC-2.5TCR转基因细胞)是否会在体内损害MHC不匹配的胰岛，而不依赖于传统的同种异体移植免疫。结果表明，BDC-2.5CD4T细胞能有效地破坏NOD.SCID受者建立的完全不同的MHC-II类胰岛移植物。组织损伤是组织特异性的，因为BDC-2.5T细胞破坏了供体类型的胰岛，但不是在同一受者体内建立的同种异体甲状腺移植。此外，BDC-2.5 CD4T细胞能够在体内急性破坏MHC类H缺陷的同种异体胰岛移植物，这表明自身免疫的发病机制可以完全不依赖于供体MHC类11的表达。综上所述，这些发现表明，MHC不匹配的同种异体胰岛移植物容易受到自身反应性CD4T细胞触发的自身免疫发病的影响，可能是通过体内间接的自身抗原识别。
When transplanted into type la diabetic recipients, islet allografts are subject both to conventional allograft immunity and, presumably, to recurrent autoimmune (islet-specific) pathogenesis. Importantly, CD4 T cells play a central role both in islet allograft rejection and in autoimmune disease recurrence leading to the destruction of syngeneic islet transplants in diabetic NOD mice. However, it is unclear how NOD host MHC class 11 (I-A(g7))-restricted, autoreactive CD4 T cells may also contribute to the recognition of allogeneic islet grafts that express disparate MHC class 11 molecules. We hypothesized that islet-specific CD4 T cells can target MHC-mismatched islet allografts for destruction via the "indirect" (host APC-dependent) pathway of Ag recognition. To test this hypothesis, we determined whether NOD-derived, islet-specific CD4 T cells (BDC-2.5 TCR transgenic cells) could damage MHC-mismatched islets in vivo independent of conventional allograft immunity. Results demonstrate that BDC-2.5 CD4 T cells can vigorously destroy MHC class II-disparate islet allografts established in NOD.scid recipients. Tissue injury is tissue-specific in that BDC-2.5 T cells destroy donor-type islet, but not thyroid allografts established in the same NOD.scid recipient. Furthermore, BDC-2.5 CD4 T cells acutely destroy MHC class H-deficient islet allografts in vivo, indicating that autoimmune pathogenesis can be completely independent of donor MHC class 11 expression. Taken together, these findings indicate that MHC-mismatched islet allografts can be vulnerable to autoimmune pathogenesis triggered by autoreactive CD4 T cells, presumably through indirect autoantigen recognition in vivo.