No prolongation of skin allograft survival by immunoproteasome inhibition in mice
No prolongation of skin allograft survival by immunoproteasome inhibition in mice
复制标题
DOI：
10.1016/j.molimm.2017.05.022
复制
发表时间：
2017-06
影响因子：
3.6
通讯作者：
S. Mundt;Michael Basler;B. Sawitzki;M. Groettrup
中科院分区：
文献类型：
--
作者：
S. Mundt;Michael Basler;B. Sawitzki;M. Groettrup
免疫蛋白酶体是一类独特的蛋白酶体，在炎症条件下可诱导并在单核细胞和淋巴细胞中组成型表达，已知其可形成主要组织相容性复合体（MHC）I类分子上呈递的抗原库。此外，抑制免疫蛋白酶体亚单位LMP 7可改善体内自身免疫性疾病的临床症状，并显示抑制T辅助细胞（Th）1和Th 17细胞的发育，促进调节性T细胞（Treg）的产生，而不依赖于其在抗原加工中的功能。由于Th 1和Th 17细胞是有害的，Treg细胞对于移植物的接受是至关重要的，我们研究了LMP 7选择性抑制剂ONX 0914在体外混合淋巴细胞反应（MLR）中的影响，以及在体内MHC不同（C57 BL/6到BALB/c）和多种次要组织相容性抗原（miHA）不同（B10.Br到C3 H）皮肤移植模型中对同种异体移植物排斥的影响。尽管我们观察到体外T细胞的同种特异性IL-17产生减少，但我们发现选择性抑制LMP 7既不影响MHC错配模型中的同种异体移植物存活，也不影响多个轻微错配皮肤移植模型中的同种异体移植物存活。我们的结论是，在皮肤移植中，抑制免疫蛋白酶体对延长皮肤移植物存活没有效果。
The immunoproteasome, a distinct class of proteasomes, which is inducible under inflammatory conditions and constitutively expressed in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Moreover, inhibition of the immunoproteasome subunit LMP7 ameliorates clinical symptoms of autoimmune diseasesin vivoand was shown to suppress the development of T helper cell (Th) 1 and Th17 cells and to promote regulatory T-cell (Treg) generation independently of its function in antigen processing. Since Th1 and Th17 cells are detrimental and Treg cells are critical for transplant acceptance, we investigated the influence of the LMP7-selective inhibitor ONX 0914 in a mixed lymphocyte reaction (MLR)in vitroas well as on allograft rejection in a MHC-disparate (C57BL/6 to BALB/c) and a multiple minor histocompatibility antigen (miHA)-disparate (B10.Br to C3H) model of skin transplantationin vivo. Although we observed reduced allo-specific IL-17 production of T cellsin vitro, we found that selective inhibition of LMP7 had neither an influence on allograft survival in an MHC-mismatch model nor in a multiple minor mismatch skin transplantation model. We conclude that inhibition of the immunoproteasome is not effective in prolonging skin allograft survival in skin allotransplantation.