June Brickey W, Felix Nathan J, Griffiths Robert, Zhang Jinghua, Wang Bo, Piskurich Janet F, Itoh-Lindstrom Yoshie, Coffman Thomas M, Ting Jenny P-Y
University of North Carolina Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Transplantation. 2002 Nov 15;74(9):1341-8. doi: 10.1097/00007890-200211150-00024.
Major histocompatibility complex (MHC) antigenic complexes trigger allogeneic T-cell responses and allograft rejection. MHC class II and related antigen processing genes, such as invariant chain (Ii) and H2-DM accessory molecules, are controlled by the master transcriptional regulator, class II transactivator (CIITA). CIITA also up-regulates MHC class I gene expression in vitro. Thus, disruption of a single factor, namely CIITA, represents an ideal strategy for reducing transplant rejection.
We studied the immunological advantages of transplanting CIITA deficient hearts into mismatched recipients in comparison to wild-type (B6) allografts or MHC class II-deficient (Abeta ) hearts.
Elimination of CIITA greatly enhanced graft survival (median survival time [MST] 36 days) over the survival of wild-type (MST 9 days) and even over Abeta (MST 20 days) cardiac grafts. This was accompanied by greatly reduced mixed lymphocyte reactivity and in vivo antigen priming capacity. Analyses for CD4, CD8, and other inflammatory cells, plus cytotoxic T-cell activity and MHC class I specific alloantibody production, did not reveal significant differences in CIITA allograft tissues. Some cytokines that may support immunosuppression, such as transforming growth factor (TGF)-beta, were increased in mice receiving either Abeta or CIITA cardiac grafts.
We conclude that disruption of CIITA function plays a beneficial role in preventing normal allogeneic T-cell responses. Even though inflammatory cells are present in CIITA allografts, the dramatic prolongation in allograft survival of CIITA hearts as compared with wild-type grafts provides a foundation for designing molecular therapies to interfere with MHC class II function and thereby reduce transplantation rejection.
主要组织相容性复合体（MHC）抗原复合物引发同种异体T细胞反应和同种异体移植排斥。MHC II类及相关抗原加工基因，如恒定链（Ii）和H2-DM辅助分子，受主要转录调节因子II类反式激活因子（CIITA）控制。CIITA在体外也上调MHC I类基因表达。因此，破坏单一因子CIITA是减少移植排斥的理想策略。
我们研究了将CIITA缺陷心脏移植到不匹配受体中的免疫优势，并与野生型（B6）同种异体移植或MHC II类缺陷（Abeta）心脏进行比较。
与野生型（中位生存时间[MST]9天）甚至Abeta（MST 20天）心脏移植相比，消除CIITA大大提高了移植物存活率（MST 36天）。这伴随着混合淋巴细胞反应性和体内抗原启动能力的大幅降低。对CD4、CD8和其他炎症细胞的分析，以及细胞毒性T细胞活性和MHC I类特异性同种异体抗体产生，在CIITA同种异体移植组织中未发现显著差异。一些可能支持免疫抑制的细胞因子，如转化生长因子（TGF）-β，在接受Abeta或CIITA心脏移植的小鼠中增加。
我们得出结论，CIITA功能的破坏在预防正常同种异体T细胞反应中起有益作用。尽管CIITA同种异体移植中存在炎症细胞，但与野生型移植物相比，CIITA心脏同种异体移植存活时间的显著延长为设计干扰MHC II类功能从而减少移植排斥的分子疗法提供了基础。
