Posted by Marina on July 07, 2001 at 11:42:04:
Transplantation 2001 Jun 15;71(11):1656-65
Immunotherapy with nondepleting anti-cd4 monoclonal antibodies
but not cd28 antagonists protects islet graft in spontaneously
diabetic nod mice from autoimmune destruction and allogeneic
and xenogeneic graft rejection1.
Guo Z, Wu T, Kirchhof N, Mital D, Williams JW, Azuma M, Sutherland DE, Hering BJ
6 Address correspondence to: Dr. Zhiguang Guo, Department of Surgery, MMC195, University of Minnesota,
420 Delaware Street SE, Minneapolis, MN 55455. E-mail: zhiguang@tc.umn.edu.
[Medline record in process]
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS:
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.
PMID: 11435979, UI: 21329771