Minor antigen H60-mediated aplastic anemia is ameliorated by immunosuppression and the infusion of regulatory T cells
Minor antigen H60-mediated aplastic anemia is ameliorated by immunosuppression and the infusion of regulatory T cells
复制标题
DOI：
10.4049/jimmunol.178.7.4159
复制
发表时间：
2007-04-01
影响因子：
4.4
通讯作者：
Young, Neal S.
中科院分区：
文献类型：
--
作者：
Chen, Jichun;Ellison, Felicia M.;Young, Neal S.
由免疫系统介导的人骨髓(BM)衰竭可以在小鼠身上建立模型。在本研究中，将来自C57BL/6小鼠的淋巴结(LN)细胞输注到CB10-H2(B)/LilMed(C.B10)受体中，这些受者在多个次要组织相容抗原(包括免疫优势抗原H60)上不匹配，产生了致死性再生障碍性贫血。血细胞计数的下降与免疫优势的次要组织相容性抗原H60特异的CD8 T细胞的显著扩张和激活有关。输注来自1160相合供者的LN细胞没有在C.B10小鼠中产生骨髓衰竭，而分离的H60特异性CTL在体外对正常的C.B10细胞具有细胞毒作用。免疫抑制药物环孢素的治疗阻止了H60特异性T细胞的增殖，并将动物从致命性全血细胞减少症中拯救出来。骨髓衰竭的发生与激活的不表达FoxP3的CD4(+)CD25(+)T细胞显著增加有关，而正常的CD4(+)CD25(+)调节性T细胞与C57BL/6 LN细胞结合可中止H60特异性T细胞的扩增，防止骨髓破坏。因此，单个微小的组织相容性Ag H60不匹配就可以触发免疫反应，导致大规模的骨髓破坏。免疫抑制药物的治疗或调节性T细胞功能的增强废除了这一病理生理学，并保护动物免受骨髓衰竭的发展。
Human bone marrow (BM) failure mediated by the immune system can be modeled in mice. In the present study, infusion of lymph node (LN) cells from C57BL/6 mice into C.B10-H2(b)/LilMed (C.B10) recipients that are mismatched at multiple minor histocompatibility Ags, including the immunodominant Ag H60, produced fatal aplastic anemia. Declining blood counts correlated with marked expansion and activation of CD8 T cells specific for the immunodominant minor histocompatibility Ag H60. Infusion of LN cells from 1160-matched donors did not produce BM failure in C.B10 mice, whereas isolated H60-specific CTL were cytotoxic for normal C.B10 BM cells in vitro. Treatment with the immunosuppressive drug cyclosporine abolished H60-specific T cell expansion and rescued animals from fatal pancytopenia. The development of BM failure was associated with a significant increase in activated CD4(+)CD25(+) T cells that did not express intracellular FoxP3, whereas inclusion of normal CD4(+)CD25(+) regulatory T cells in combination with C57BL/6 LN cells aborted H60-specific T cell expansion and prevented BM destruction. Thus, a single minor histocompatibility Ag H60 mismatch can trigger an immune response leading to massive BM destruction. Immunosuppressive drug treatment or enhancement of regulatory T cell function abrogated this pathophysiology and protected animals from the development of BM failure.