Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates.
Recent success using a steroid-free immunosuppressive regimen has renewed enthusiasm for the use of islet transplantation to treat diabetes. Toxicities associated with the continued use of a calcineurin inhibitor may limit the wide-spread application of this therapy. Biological agents that block key T-cell costimulatory signals, in particular the CD28 pathway, have demonstrated extraordinary promise in animal models. LEA29Y (BMS-224818), a mutant CTLA4-Ig molecule with increased binding activity, was evaluated for its potential to replace tacrolimus and protect allogeneic islets in a preclinical primate model. Animals received either the base immunosuppression regimen (rapamycin and anti-IL-2R monoclonal antibody [mAb]) or the base immunosuppression and LEA29Y. Animals receiving the LEA29Y/rapamycin/anti-IL-2R regimen (n = 5) had significantly prolonged islet allograft survival (204, 190, 216, 56, and >220 days). In contrast, those animals receiving the base regimen alone (n = 2) quickly rejected the transplanted islets at 1 week (both at 7 days). The LEA29Y-based regimen prevented the priming of anti-donor T- and B-cell responses, as detected by interferon-gamma enzyme-linked immunospot and allo-antibody production, respectively. The results of this study suggest that LEA29Y is a potent immunosuppressant that can effectively prevent rejection in a steroid-free immunosuppressive protocol and produce marked prolongation of islet allograft survival in a preclinical model.
Adams
Andrew B
AB
Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Shirasugi
Nozomu
N
Durham
Megan M
MM
Strobert
Elizabeth
E
Anderson
Dan
D
Rees
Phyllis
P
Cowan
Shannon
S
Xu
Huaying
H
Blinder
Yelena
Y
Cheung
Michael
M
Hollenbaugh
Dianne
D
Kenyon
Norma S
NS
Pearson
Thomas C
TC
Larsen
Christian P
CP
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018106:CD28 Antigens / Q000187:drug effects*; D060908:CTLA-4 Antigen; D065095:Calcineurin Inhibitors; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008253:Macaca mulatta; D015375:Receptors, Interleukin-2 / Q000276:immunology; D020123:Sirolimus / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; D065095:Calcineurin Inhibitors; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D000069594:Abatacept; D020123:Sirolimus