低剂量CTLA4IgM联合FK506诱导主要组织相容性复合体不匹配心脏同种异体移植的长期接受

Long-term acceptance of major histocompatibility complex-mismatched cardiac allograft induced by a low dose of CTLA4IgM plus FK506.

作者信息

Yamada A, Murakami M, Ijima K, Yagita H, Okumura K, Komatsu S, Uede T

机构信息

Section of Immunopathogenesis, Hokkaido University, Japan.

出版信息

Microbiol Immunol. 1996;40(7):513-8. doi: 10.1111/j.1348-0421.1996.tb01102.x.

DOI:10.1111/j.1348-0421.1996.tb01102.x

PMID:8865157

Abstract

The immunosuppressant FK506 prolongs allograft survival. However, at therapeutic doses it has significant side effects. A fusion protein consisting of the extracellular portion of CTLA4 and the Fc portion of human IgG (CTLA4IgG) also prolongs allograft survival, but large doses of CTLA4IgG are required for the induction of cardiac allograft acceptance. Therefore, we constructed a pentameric form of a new CTLA4 fusion protein, CTLA4IgM. We tested whether low doses of CTLA4IgG or CTLA4IgM in combination with subtherapeutic doses of FK506 can prolong allograft survival in a synergistic fashion. C57BL/6 (H-2b) neonatal hearts were transplanted to CBA/J (H-2b) mice in a heterotopic, nonvascularized cardiac allograft model. The findings demonstrate that a combination of low doses of FK506 plus a pentameric form of CTLA4Ig, CTLA4IgM, leads to significant graft survival, while a combination of FK506 plus CTLA4IgG does not.

摘要

免疫抑制剂FK506可延长同种异体移植物的存活时间。然而，在治疗剂量下它具有显著的副作用。一种由CTLA4的细胞外部分与人IgG的Fc部分组成的融合蛋白（CTLA4IgG）也能延长同种异体移植物的存活时间，但诱导心脏同种异体移植接受需要大剂量的CTLA4IgG。因此，我们构建了一种新型CTLA4融合蛋白CTLA4IgM的五聚体形式。我们测试了低剂量的CTLA4IgG或CTLA4IgM与低于治疗剂量的FK506联合使用是否能以协同方式延长同种异体移植物的存活时间。在异位、非血管化心脏同种异体移植模型中，将C57BL/6（H-2b）新生心脏移植到CBA/J（H-2b）小鼠体内。研究结果表明，低剂量FK506与五聚体形式的CTLA4Ig即CTLA4IgM联合使用可显著延长移植物存活时间，而FK506与CTLA4IgG联合使用则不能。