Prolonged xenograft survival of islets infected with small doses of adenovirus expressing CTLA4Ig

Background. Systemic administration of the inhibitor of costimulation, CTLA 4Ig, has been shown to prolong islet graft survival. The purpose of this st udy was to compare local and systemic expression of murine CTLA4Ig in trans plants of rat islets into mice. Methods. Murine CTLA4Ig was made by joining two polymerase chain reaction p roducts, the extracellular portion of CTLA4 and the Pc portion of IgG2a. Re combinant adenovirus expressing CTLA4Ig (AdCTLA4Ig) was generated using the strategy of Cre-lox recombination. Isolated rat islets infected with AdCTL A4Ig at multiplicities of infection (MOIs) ranging from 0.1 to 10 were tran splanted into streptozocin diabetic male B6AF1 mice. Control islets were mo ck infected or infected with AdLacZ or AdsIg, a recombinant adenovirus expr essing only the Fc portion of IgG2a. Also, AdCTLA4Ig and control viruses we re injected intramuscularly into mouse transplant recipients at the time of islet transplantation to provide CTLA41g systemically. Results. Control islets transplanted into diabetic mice were rejected in 13 -17 days. Islets infected with AdCTLA4Ig had dose-dependent prolongation of graft survival. Prolonged survival was even found with very low MOIs of 0. 1 and 0.5, with survivals of 24+/-4.2 and 25+/-2.2 days, respectively. Surv ival with an MOI of 10 was 39+/-8.7 days. With intramuscular injection, no prolongation was found at the lowest relative MOIs of 0.2 and 1, but there was dose-dependent prolongation of graft survival with larger doses. At the highest relative MOI of 400, survival was prolonged to 58+/-10 days. Conclusions. Rat islets infected with AdCTLA4Ig transplanted into mice had prolonged graft survival. Prolonged survival with MOIs as low as 0.1 and 0. 5 indicates that only a minority of islet cells need to express CTLA4Ig to exert an effect. Moreover, the results suggest that the improved islet graf t survival is due to a local influence of CTLA4Ig.