UCLA School of Medicine, 10833 Le Conte Ave., 77-120 CHS, Los Angeles, CA 90095-7054, United States.
Transpl Immunol. 2011 May;24(4):203-9. doi: 10.1016/j.trim.2011.01.002. Epub 2011 Jan 18.
Conventional immunosuppressive therapies failed to prevent allograft chronic rejection. New approaches to modulate recipient immune response are needed. Donor-like MHC class I soluble proteins demonstrated therapeutic potential to suppress chronic rejection. The present study was designed to clarify the ability of MHC class I soluble proteins to induce T regulatory cells with true regulatory potential in a fully allogeneic rat cardiac transplant model. Donor-like MHC class I proteins upregulate small population of splenic CD8(-) negative CD4(+)CD25(+)FoxP3(+) positive cells. CD4(+) splenocytes after MHC therapy suppress lymphocyte proliferation against donor antigens in vitro. ACI recipients of WF hearts treated with CD4(+) cells, induced with donor-like MHC class I proteins (CD4-MHC), demonstrated stable survival of the transplanted organ (MST >120 days; n=17). Histology revealed that grafts of recipients treated with CD4-MHC had 23.6% vessels affected 100 days postgrafting. On the contrary, hearts obtained from long-term surviving hosts treated with CD4(+) cells induced with high-dose CsA (CD4-CsA) had 50-70% of affected vessels. CD4-MHC class I treated transplants were mostly CD3(-) negative, had low level of mast and FoxP3(+) cell infiltration compared to CD4-CsA treated hearts. Intragraft CD4(+) cells were close to mast cells in morphology. The same graft tissues had similar number of CD4(+) positive cells and mast cells suggesting existence of CD4(+) positive mast cells. On the other hand, a negligible number of FoxP3(+) positive cells in the grafts after CD4-MHC treatment supports the idea of CD4(+) positive FoxP3(+) negative mast cells population. We demonstrate that donor-like MHC class I protein therapy induces population of CD4(+)CD25(+)CD8(-)FoxP3(+) cells with potential to ameliorate development of transplant vascular disease and evoke CD4(+) positive FoxP3 negative mast cells in the secondary hosts.
传统的免疫抑制疗法未能预防同种异体移植物的慢性排斥反应。需要寻找新的方法来调节受者的免疫反应。类似于供体的 MHC Ⅰ类可溶性蛋白已被证明具有抑制慢性排斥反应的治疗潜力。本研究旨在阐明类似于供体的 MHC Ⅰ类可溶性蛋白在完全同种异体大鼠心脏移植模型中诱导具有真正调节潜能的 T 调节细胞的能力。类似于供体的 MHC Ⅰ类蛋白上调了一小部分脾 CD8(-)阴性 CD4(+)CD25(+)FoxP3(+)阳性细胞。MHC 治疗后的 CD4(+) 脾细胞在体外抑制针对供体抗原的淋巴细胞增殖。用类似于供体的 MHC Ⅰ类蛋白（CD4-MHC）诱导的 ACI 受体接受 WF 心脏移植后，移植器官的稳定存活（MST>120 天；n=17）。组织学显示，用 CD4-MHC 治疗的受者的移植物在移植后 100 天有 23.6%的血管受影响。相反，用高剂量 CsA（CD4-CsA）诱导 CD4(+)细胞治疗的长期存活宿主获得的心脏有 50-70%的受影响血管。与 CD4-CsA 治疗的心脏相比，CD4-MHC Ⅰ类处理的移植物大多为 CD3(-)阴性， mast 和 FoxP3(+)细胞浸润水平较低。移植组织内的 CD4(+)细胞在形态上与肥大细胞接近。相同的移植物组织具有相似数量的 CD4(+)阳性细胞和肥大细胞，表明存在 CD4(+)阳性肥大细胞。另一方面，CD4-MHC 治疗后移植物中 FoxP3(+)阳性细胞的数量可忽略不计，支持 CD4(+)阳性 FoxP3(+)阴性肥大细胞群体的观点。我们证明，类似于供体的 MHC Ⅰ类蛋白治疗可诱导具有改善移植血管疾病发展潜力的 CD4(+)CD25(+)CD8(-)FoxP3(+)细胞群，并在次级宿主中引发 CD4(+)阳性 FoxP3 阴性肥大细胞。
