PREVENTION OF EARLY ISLET GRAFT FAILURE BY 4-AMINO-TETRAHYDROBIOPTERIN, A NOVEL, SELECTIVE INOS- INHIBITOR

Abstract

P688 Aims: Islet engraftment is highly dependent on initial control of specific and non-specific immune activation. The 4-amino analogue of tetrahydrobiopterin (ABH4) is a novel pterin-based inhibitor of NO synthases which has been shown to prolong vascularized allograft survival in rodents. In this study we investigated the effect of selective iNOS- inhibition on islet graft function in a murine transplant model. Methods: C57BL/10 (H-2b) donor islets were transplanted under the left renal capsule of streptozotocin induced diabetic C3H/He (H-2k) recipients. Cold preservation time and graft size were equal in all animals. Islet function and survival was followed by daily assessment of blood glucose (BG) concentration and rejection defined as a return of glucose levels ≥ 200 mg/dl. Animals were treated with daily doses of 150 mg/kg BW ABH4 until p.o.d. 7. Results: Mean graft survival of C57BL/10 islets into untreated C3H/He recipients was 9.7 ± 2.3 days. An eight day course of ABH4 treatment did not prolong graft survival (10.8 ± 2.05). There were no side effects of ABH4 administration noticed. However, ABH4 administration resulted in immediate graft function at p.o.day 1 in all animals (n=5) with mean serum glucose levels of 133 ± 24 mg/dl. Serum glucose levels at p.o.day 1 in unmodified recipients was 328 ± 177 mg/dl. Analysis of delta-BG prior to transplantation and p.o.day 1 demonstrated a better islet function in ABH4 treated animals with a mean delta-BG of 310±41 mg/dl as compared to 126±160 mg/dl in control animals (p=0.06, marginal significant). Conclusions: ABH4 is a new agent remarkably effective in improving primary function of murine islet allografts. As we were also able to demonstrate that survival of iNOS–deficient islet allografts is prolonged we speculate that local expression of iNOS is a major factor influencing early engraftment.