Guo Z, Wu T, Kirchhof N, Mital D, Williams J W, Azuma M, Sutherland D E, Hering B J
Department of Surgery, MMC195, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Transplantation. 2001 Jun 15;71(11):1656-65. doi: 10.1097/00007890-200106150-00027.
T-cell activation and the subsequent induction of effector functions require not only the recognition of antigen peptides bound to MHC molecules by T-cell receptor (TCR) for antigen but also a costimulatory signal provided by antigen presenting cells. CD4 T-cell activation and function require the CD4 molecule as a coreceptor of TCR. The CD28/B7 pathway is a major costimulatory signal for T-cell activation and differentiation.
The effect of targeting CD4 by nondepleting anti-CD4 monoclonal antibodies (mAbs) versus blocking CD28/B7 by CTLA4Ig, anti-CD80 mAbs, and anti-CD86 mAbs on the prevention of recurrence of autoimmune diabetes after MHC-matched nonobese diabetes-resistant (NOR) islet transplantation in nonobese diabetic (NOD) mice were compared. Whether nondepleting anti-CD4 mAbs prolong allogeneic islet graft survival and xenogeneic pig islet graft survival in diabetic NOD mice were studied. Furthermore, the effect of nondepleting anti-CD4 mAbs combined with CTLA4Ig on allogeneic islet graft survival in NOD mice was investigated.
Recurrence of autoimmune diabetes can be prevented by nondepleting anti-CD4 mAbs. Blocking the CD28/B7 costimulatory pathway by CTLA4Ig or by anti-CD80 mAbs and anti-CD86 mAbs cannot prevent recurrence of autoimmune diabetes after islet transplantation. Short-term treatment with nondepleting anti-CD4 mAbs significantly prolongs allogeneic islet graft survival and xenogeneic pig islet graft survival in diabetic NOD mice. But nondepleting anti-CD4 mAbs combined with CTLA4Ig decreased allogeneic islet graft survival.
Nondepleting anti-CD4 mAbs but not CD28 antagonists protect islet grafts in diabetic NOD mice from autoimmune destruction and allogeneic and xenogeneic graft rejection. The efficacy of nondepleting anti-CD4 mAbs is compromised when it combines with CTLA4Ig.
T细胞活化及随后效应功能的诱导不仅需要T细胞受体（TCR）识别与MHC分子结合的抗原肽，还需要抗原呈递细胞提供的共刺激信号。CD4 T细胞的活化和功能需要CD4分子作为TCR的共受体。CD28/B7途径是T细胞活化和分化的主要共刺激信号。
比较了非耗竭性抗CD4单克隆抗体（mAb）靶向CD4与CTLA4Ig、抗CD80 mAb和抗CD86 mAb阻断CD28/B7对非肥胖糖尿病（NOD）小鼠在MHC匹配的非肥胖糖尿病抵抗（NOR）胰岛移植后预防自身免疫性糖尿病复发的作用。研究了非耗竭性抗CD4 mAb是否能延长糖尿病NOD小鼠的同种异体胰岛移植存活时间和异种猪胰岛移植存活时间。此外，还研究了非耗竭性抗CD4 mAb与CTLA4Ig联合应用对NOD小鼠同种异体胰岛移植存活的影响。
非耗竭性抗CD4 mAb可预防自身免疫性糖尿病的复发。CTLA4Ig或抗CD80 mAb和抗CD86 mAb阻断CD28/B7共刺激途径不能预防胰岛移植后自身免疫性糖尿病的复发。非耗竭性抗CD4 mAb短期治疗可显著延长糖尿病NOD小鼠的同种异体胰岛移植存活时间和异种猪胰岛移植存活时间。但非耗竭性抗CD4 mAb与CTLA4Ig联合应用可降低同种异体胰岛移植存活时间。
非耗竭性抗CD4 mAb而非CD28拮抗剂可保护糖尿病NOD小鼠的胰岛移植免受自身免疫破坏以及同种异体和异种移植排斥。非耗竭性抗CD4 mAb与CTLA4Ig联合应用时其疗效会受到影响。
