Anti-CD40LG monoclonal antibody, clone S2/70

Background Our goal was to identify clinically relevant immunotherapies that synergize with microencapsulation to protect adult porcine islet (API) xenografts in diabetic NOD mice. We have shown previously that dual costimulatory blockade (CTLA4-Ig plus anti-CD154 mAb) combined with encapsulation protects APIs long-term in NOD mice. Since no anti-CD154 mAbs currently are approved for use in humans, we tested the efficacy of other targeted immunosuppression regimens that might be used for diabetic patients receiving encapsulated islets. Methods Microencapsulated APIs were transplanted i.p. in diabetic NOD mice given either no immunosuppression or combinations immunosuppressive reagents. Graft function was monitored by blood glucose levels, i.p. glucose tolerance tests, and histology. Mechanisms of rejection were investigated by phenotyping host peritoneal cells and measuring graft site cytokine and chemokine levels. Results New immunosuppressive therapies were compared to CTLA4-Ig plus anti-CD154 mAb, used here as a control. The most effective was triple treatment with CTLA4-Ig, anti-CD154 mAb, and intracapsular CXCL12, and the next most effective was a non-depleting anti-CD4 mAb (YTS177.9) plus intracapsular CXCL12. Three additional regimens (CTLA4-Ig plus YTS177.9, YTS177.9 alone, and anti-OX40-Ligand mAb alone) significantly prolonged encapsulated API function. Dual treatment with CTLA4-Ig plus anti-CD40 mAb was as effective as CTLA4-Ig plus anti-CD154 mAb. Five other monotherapies and three combination therapies did not augment encapsulated API survival. Most peritoneal cytokines and chemokines were either absent or minimal. At necropsy, the capsules were intact, not fibrosed, and clean when function was maintained, but were coated with host cells if rejection had occurred. Conclusions Multiple different immunotherapies which specifically inhibit CD4(+) T cells, modulate T-cell trafficking, or interfere with antigen presentation can substitute for anti-CD154 mAb to prolong encapsulated islet xenograft function in diabetic NOD mice.

The porcine cornea may be a good solution for the shortage of human donor corneas because its size and refractive properties are comparable to those of the human cornea. However, antigenic differences need to be overcome to apply xenocorneal transplantation in actual clinical practice. We aimed to investigate the feasibility of full-thickness porcine corneas as human corneal substitutes using a CD40-CD154 costimulatory pathway blocking strategy in a clinically applicable pig-to-nonhuman primate corneal transplantation model. As a result, the mean survival time of the xenocorneal grafts in recipients who received anti-CD154 antibody-based immunosuppressants (POD318 (n=4); >933, >243, 318 and >192) was significantly longer than that in controls (POD28 (n=3); 21, 28 and 29; p=0.010, log-rank test). Administration of anti-CD154 antibodies markedly reduced inflammatory cellular infiltrations (predominantly CD8 T cells and macrophages) into the xenocorneal grafts and almost completely blocked xenoantigen-triggered increases in Th1-associated cytokines, chemokines and C3a in the aqueous humor. Moreover, systemic expansion of memory T cells was effectively controlled and responses of anti-Gal/donor pig-specific antibodies were considerably diminished by programmed injection of anti-CD154 antibodies. Consequently, porcine corneas might be promising human corneal substitutes when the transplantation is accompanied by potent immunosuppression such as a CD40-CD154 costimulatory pathway blockade.