Olack Barbara J, Jaramillo Andrés, Benshoff Nicholas D, Kaleem Zahid, Swanson Carol J, Lowell Jeffrey A, Mohanakumar T
Department of Surgery, Washington University School of Medicine, St Louis, MO 63110, USA.
Xenotransplantation. 2002 Nov;9(6):393-401. doi: 10.1034/j.1399-3089.2002.01070.x.
We have previously demonstrated that human T cells responding to porcine islets are primarily CD4+ and recognized porcine major histocompatibility complex class I molecules through the indirect pathway of antigen presentation. To determine whether this mechanism is responsible for rejection of adult porcine islets xenografts, porcine islets from adult pigs were transplanted under the kidney capsule of streptozotocin-treated CD4-knockout (KO), CD8-KO, Ig-KO and normal C57BL/6 mice. Islet xenografts were acutely rejected with similar kinetics when transplanted into normal C57BL/6 (MST=17.6 +/- 3.5 days) and Ig-KO (MST=19.0 +/- 1.7 days) mice. Interestingly, islet xenografts were rejected significantly earlier when transplanted into CD8-KO mice as compared with normal C57BL/6 (MST=7.0 +/- 0.01 days, P=2 x 10-4). Histopathological analysis revealed classical acute cellular rejection with severe diffuse interstitial cellular infiltrates in all rejected islet xenografts. In contrast, islet xenografts were not rejected when transplanted into CD4-KO mice (MST >/= 100 days, P=1 x 10-9). Histopathological analysis revealed no cellular infiltrates and intact islet xenografts. CD4+ T cells from both normal C57BL/6 and CD8-KO xenograft recipients showed detectable proliferative responses to porcine islets in the presence but not in the absence of syngeneic antigen-presenting cells. In addition, the anti-islet proliferative responses observed in normal C57BL/6 mice were significantly lower than those observed in CD8-KO mice. IgG anti-porcine antibodies were readily detected in C57BL/6 and CD8-KO xenograft recipients but not in Ig-KO or CD4-KO recipients. These results indicate that indirectly activated CD4+ T cells mediate acute rejection of adult porcine islet xenografts and that xenoreactive CD8+ T cells and antibodies are not necessary in this process.
我们之前已经证明，对猪胰岛产生反应的人T细胞主要是CD4+，并通过抗原呈递的间接途径识别猪主要组织相容性复合体I类分子。为了确定这种机制是否导致成年猪胰岛异种移植的排斥反应，将成年猪的猪胰岛移植到经链脲佐菌素处理的CD4基因敲除（KO）、CD8基因敲除、Ig基因敲除和正常C57BL/6小鼠的肾包膜下。当移植到正常C57BL/6小鼠（中位生存时间[MST]=17.6±3.5天）和Ig基因敲除小鼠（MST=19.0±1.7天）中时，胰岛异种移植以相似的动力学被急性排斥。有趣的是，与正常C57BL/6小鼠相比，当移植到CD8基因敲除小鼠中时，胰岛异种移植被显著更早地排斥（MST=7.0±0.01天，P=2×10-4）。组织病理学分析显示，在所有被排斥的胰岛异种移植中均有典型的急性细胞排斥反应，伴有严重的弥漫性间质细胞浸润。相反，当移植到CD4基因敲除小鼠中时，胰岛异种移植未被排斥（MST≥100天，P=1×10-9）。组织病理学分析显示无细胞浸润，胰岛异种移植完整。来自正常C57BL/6和CD8基因敲除异种移植受体的CD4+T细胞在有同基因抗原呈递细胞存在但无同基因抗原呈递细胞不存在的情况下，对猪胰岛显示出可检测到的增殖反应。此外，在正常C57BL/6小鼠中观察到的抗胰岛增殖反应明显低于在CD8基因敲除小鼠中观察到的反应。在C57BL/6和CD8基因敲除异种移植受体中很容易检测到IgG抗猪抗体，但在Ig基因敲除或CD4基因敲除受体中未检测到。这些结果表明，间接激活的CD4+T细胞介导成年猪胰岛异种移植的急性排斥反应，并且在这个过程中异种反应性CD8+T细胞和抗体不是必需的。
