Gene therapy with adenovirus‐delivered indoleamine 2,3‐dioxygenase improves renal function and morphology following allogeneic kidney transplantation in rat

Abstract

Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the tryptophan catabolism, has recently emerged as an important immunosuppressive enzyme involved in the regulation of both physiologic (maternal tolerance), as well as pathologic (neoplasia, autoimmune diseases, asthma) processes. Accumulating evidence points to a role for IDO in suppressing T-cell responses, thereby promoting tolerance. In the present study, we investigate the effects of adenovirus-mediated gene therapy with IDO on the acute rejection of the transplanted kidneys. The experiments were performed in a rat Fisher to Lewis acute renal rejection model. RGD modified adenovirus carrying IDO gene (RGD-AdTIDO, n = 9) or RGD modified adenovirus carrying green fluorescent protein gene (RGD-AdTL, n = 8) were injected into the renal artery of the donor kidney before transplantation. A group receiving saline (n = 8) served as control. Rats were sacrificed after 7 days. Successful gene delivery was confirmed with real-time polymerase chain reaction and immunohistochemistry. RGD-AdTIDO significantly decreased elevated plasma creatinine (93.7 ± 18.9 µmol/l) compared to the RGD-AdTL (248.2 ± 43.6 µmol/l) and saline (228.3 ± 46.4 µmol/l) treated rats. Moreover, RGD-AdTIDO therapy diminished the infiltration of CD8+ T cells and macrophages into the graft and reduced renal interstitial pre-fibrosis. Also, it limited the up-regulation of kidney injury molecule-1, interleukin (IL)-2, IL-17 and transforming growth factor-β mRNA expression, and increased foxp3 mRNA expression compared to controls. RGD-AdTIDO therapy improves renal function and morphology in a clinically relevant model of acute rejection.