CTLA4IG TREATMENT AMELIORATES THE LETHALITY OF MURINE GRAFT-VERSUS-HOST DISEASE ACROSS MAJOR HISTOCOMPATIBILITY COMPLEX BARRIERS

被引:118
作者
WALLACE, PM [1 ]
JOHNSON, JS [1 ]
MACMASTER, JF [1 ]
KENNEDY, KA [1 ]
GLADSTONE, P [1 ]
LINSLEY, PS [1 ]
机构
[1] BRISTOL MYERS SQUIBB PHARMACEUT RES INST, SEATTLE, WA 98121 USA
关键词
D O I
10.1097/00007890-199409150-00013
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Graft-versus-host disease (GVHD), a pathological condition associated with BMT, results from activation of donor T lymphocytes by host tissues. CD28 and CTLA-4 are structurally related T cell receptors for members of the B7 (CD80) gene family, which transmit important costimulatory signals for T cell. activation in vitro and in vivo. Here we have investigated the effects of CTLA4Ig, a soluble form of CTLA-4, on lethal GVHD in a murine model. Lethal GVHD was induced by transfer of parent C57BL/6 bone marrow and spleen cells into lethally irradiated (C57BL/6xDBA/2)F1 recipients. Short courses of treatment with CTLA4Ig did not block engraftment, but prolonged survival of BMT recipients even when administration was delayed for 6 days after transplantation. CTLA4Ig-treated survivors of GVHD maintained body weight and did not exhibit visible signs of GVHD. However, treatment regimens that maximally prolonged survival did not detectably prevent T cell-mediated hematological abnormalities associated with GVHD, including pancytopenia and abnormal cellular composition of the spleen. Our data thus show that the lethality of acute GVHD in this model system is more dependent upon CD28/CTLA-4 costimulation than are other GVHD-associated abnormalities, and can be blocked for an extended period by brief treatment with CTLA4Ig.
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页码:602 / 610
页数:9
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