Indoleamine 2,3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes.
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 NODscid 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.
Alexander
Angela M
AM
Division of Immunogenetics, Department of Pediatrics, Rangos Research Center, Children's Hospital of Pittsburgh, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Crawford
Megan
M
Bertera
Suzanne
S
Rudert
William A
WA
Takikawa
Osamu
O
Robbins
Paul D
PD
Trucco
Massimo
M
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D003470:Culture Media / Q000737:chemistry; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D018014:Gene Transfer Techniques; D006085:Graft Survival / Q000187:drug effects*; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000637:transplantation*; D013997:Time Factors; D014364:Tryptophan / Q000032:analysis / Q000037:antagonists & inhibitors; D014366:Tryptophan Oxygenase / Q000494:pharmacology*
D003470:Culture Media; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007328:Insulin; D003208:Concanavalin A; D014364:Tryptophan; D014366:Tryptophan Oxygenase