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 rejection.
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.
Guo
Z
Z
Department of Surgery, MMC195, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455, USA. zhiguang@tc.umn.edu
Wu
T
T
Kirchhof
N
N
Mital
D
D
Williams
J W
JW
Azuma
M
M
Sutherland
D E
DE
Hering
B J
BJ
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000187:drug effects / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use; D015551:Autoimmunity / Q000187:drug effects*; D018106:CD28 Antigens / Q000187:drug effects; D015704:CD4 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D003920:Diabetes Mellitus / Q000235:genetics / Q000601:surgery*; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology / Q000601:surgery; D006084:Graft Rejection / Q000517:prevention & control*; D018796:Immunoconjugates; D007167:Immunotherapy; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D055502:Secondary Prevention; D016019:Survival Analysis; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D000069594:Abatacept