Multiple clinically relevant immunotherapies prolong the function of microencapsulated porcine islet xenografts in diabetic NOD mice without the use of anti‐CD154 mAb

• DOI: 10.1111/xen.12577
• Publication Date: 2020-01-06T08:51:00Z
• Authors: Susan A. Safley; Graham F. Barber; Robert W. Holdcraft; Lawrence S. Gazda; Stephanie Duncanson; Mark C. Poznansky; Athanassios Sambanis; Collin J. Weber
• Keywords: NOD mice; Immunosuppression; CD154; Xenotransplantation

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