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Diabetes 54:443-451, 2005
© 2005 by the American Diabetes Association, Inc.

Indefinite Survival of Neonatal Porcine Islet Xenografts by Simultaneous Targeting of LFA-1 and CD154 or CD45RB

Gina R. Rayat1, and Ronald G. Gill2

1 Surgical-Medical Research Institute, University of Alberta, Edmonton, Alberta, Canada
2 Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado

A variety of transient therapies directed against molecules involved in T-cell activation and function result in long-term islet allograft survival. However, there are relatively few examples of durable islet xenograft survival using similar short-term approaches, especially regarding highly phylogenetically disparate xenograft donors. Previous studies demonstrate that combined anti-lymphocyte function-associated antigen-1 (LFA-1) plus anti-CD154 therapy results in a robust form of islet allograft tolerance not observed with either individual monotherapy. Thus, the aim of this study was to determine whether the perturbation of anti-LFA-1, either alone or in combination with targeting CD154 or CD45RB, would promote neonatal porcine islet (NPI) xenograft survival in mice. NPI xenografts are rapidly rejected in wild-type C57BL/6 mice but reproducibly mature and restore durable euglycemia in diabetic, immune-deficient C57BL/6 rag-1–/– recipients. A short course of individual anti-LFA-1, anti-CD154, or anti-CD45RB therapy resulted in long-term (>100 days) survival in a moderate proportion of C57BL/6 recipients. However, simultaneous treatment with anti-LFA-1 plus either anti-CD154 or anti-CD45RB therapy could achieve indefinite xenograft function in the majority of recipient animals. Importantly, prolongation of islet xenograft survival using combined anti-LFA-1/anti-CD154 therapy was associated with little mononuclear cell infiltration and greatly reduced anti-porcine antibody levels. Taken together, results indicate that therapies simultaneously targeting differing pathways impacting T-cell function can show marked efficacy for inducing long-term xenograft survival and produce a prolonged state of host hyporeactivity in vivo.

Address correspondence and reprint requests to Dr. Ronald G. Gill, Barbara Davis Center for Childhood Diabetes, Box-B140, University of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262. E-mail: ron.g.gill{at}uchsc.edu

Abbreviations: APC, antigen-presenting cell; ICAM-1, intracellular adhesion molecule-1; MHC, major histocompatibility complex; NPI, neonatal porcine islet


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Copyright © 2005 by the American Diabetes Association.