Immunotherapy with nondepleting anti-CD4 monoclonal antibodies but no CD28antagonists protects islet graft in spontaneously diabetic nod mice from autoimmune destruction and allogeneic and xenogeneic graft rejection

Background. T-cell activation and the subsequent induction of effector func tions require not only the recognition of antigen peptides bound to MHC mol ecules by T-cell receptor (TCR) for antigen but also a costimulatory signal provided by antigen presenting cells. CD4 T-cell activation and function r equire the CD4 molecule as a coreceptor of TCR. The CD28/B7 pathway is a ma jor costimulatory signal for T-cell activation and differentiation. Methods, The effect of targeting CD4 by nondepleting anti-CD4 monoclonal an tibodies (mAbs) versus blocking CD28/B7 by CTLA4Ig, anti-CD80 mAbs, and ant i-CD86 mAbs on the prevention of recurrence of autoimmune diabetes after MH C-matched nonobese diabetes-resistant (NOR) islet transplantation in nonobe se diabetic (NOD) mice were compared. Whether nondepleting anti-CD4 mAbs pr olong allogeneic islet graft survival and xenogeneic pig islet graft surviv al in diabetic NOD mice were studied. Furthermore, the effect of nondepleti ng anti-CD4 mAbs combined with CTLA4Ig on allogeneic islet graft survival i n 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 nondepletin g 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 surviv al. Conclusions. Nondepleting anti-CD4 mAbs but not CD28 antagonists protect is let 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.