TY - JOUR
T1 - Calcineurin inhibitor-free CD28 blockade-based protocol protects allogeneic islets in nonhuman primates
AU - Adams, Andrew B.
AU - Shirasugi, Nozomu
AU - Durham, Megan M.
AU - Strobert, Elizabeth
AU - Andersen, Dan
AU - Rees, Phyllis
AU - Cowan, Shannon
AU - Xu, Huaying
AU - Blinder, Yelena
AU - Cheung, Michael
AU - Hollenbaugh, Dianne
AU - Kenyon, Norma S.
AU - Pearson, Thomas C.
AU - Larsen, Christian P.
PY - 2002
Y1 - 2002
N2 - 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-γ 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.
AB - 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-γ 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.
UR - http://www.scopus.com/inward/record.url?scp=0036061575&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036061575&partnerID=8YFLogxK
U2 - 10.2337/diabetes.51.2.265
DO - 10.2337/diabetes.51.2.265
M3 - Article
C2 - 11812731
AN - SCOPUS:0036061575
SN - 0012-1797
VL - 51
SP - 265
EP - 270
JO - Diabetes
JF - Diabetes
IS - 2
ER -