Indoleamine 2,3-Dioxygenase Expression in Transplanted NOD Islets Prolongs Graft Survival After Adoptive Transfer of Diabetogenic Splenocytes

Indoleamine 2,3-Dioxygenase Expression in Transplanted NOD Islets Prolongs Graft Survival After Adoptive Transfer of Diabetogenic Splenocytes Angela M. Alexander 1 , Megan Crawford 1 , Suzanne Bertera 1 , William A. Rudert 1 , Osamu Takikawa 2 , Paul D. Robbins 3 and Massimo Trucco 1 1 Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children’s Hospital of Pittsburgh, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 2 Department of Pharmacology, Hokkaido University, School of Medicine, Sapporo, Japan 3 Department of Molecular Genetics and Biochemistry, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania Abstract Indoleamine 2,3-dioxygenase (IDO) catalyzes the breakdown of the amino acid tryptophan into kyneurenine. It has been shown that IDO production by placental trophoblasts prevents the attack of maternal T-cells activated in response to the paternal HLA alleles expressed by the tissues of the fetus. In this article, we show that adenoviral gene transfer of IDO to pancreatic islets can sufficiently deplete culture media of tryptophan and consequently inhibit the proliferation of T-cells in vitro. Experiments in vivo have also demonstrated that transplantation of IDO-expressing islets from prediabetic NOD mouse donors into NOD scid recipient mice is associated with a prolongation in islet graft survival after adoptive transfer of NOD diabetogenic T-cells. This protection is attributed to the depletion of tryptophan at the transplantation site beneath the kidney capsule. These results suggest that local modulation of tryptophan catabolism may be a means of facilitating islet transplantation as a therapy for type 1 diabetes. Footnotes Address correspondence and reprint requests to Massimo Trucco, Children’s Hospital of Pittsburgh, Rangos Research Center, 3460 Fifth Ave., Pittsburgh, PA 15213. E-mail: mnt{at}pitt.edu . Received for publication 18 December 2000 and accepted in revised form 26 October 2001. BFP, blue fluorescent protein; ConA, concavalin A; CMV, cytomegalovirus; IDO, indoleamine 2,3-dioxygenase; KRH, Krebs-Ringer/HEPES buffer; MOI, multiplicity of infection; Neg, negative; STZ, streptozotocin