Intragraft and Systemic Immune Parameters Discriminating Between Rejection and Long-Term Graft Function in a Preclinical Model of Intestinal Transplantation.

Abstract

The pathology and diagnosis of acute and chronic rejection in intestinal transplantation (ITX) are far from being completely understood. We established models of acute and chronic intestinal graft rejection and analyzed peripheral and intragraft immune responses. We performed ITX from Dark Agouti into Lewis rats applying single-dose tacrolimus (TAC) at varying concentrations. Graft histology and immunohistology were assessed on postoperative day (POD)7, 14, and 45. Intragraft and peripheral gene expressions of inflammatory and anti-inflammatory markers and lipopolysaccharide binding protein (LBP) plasma as well as alloantibodies were measured simultaneously. A 1-mg TAC resulted in acute rejection and recipient death; 3 mg and 5 mg prolonged survival and led to severe or moderate chronic rejection, respectively, with 50% of the 5-mg TAC recipients surviving the observation period. Consequently, we observed severe infiltration on POD7 in untreated and 1-mg TAC recipients compared with minor histological alterations in 3 and 5 mg TAC groups. Only 5-mg TAC treatment prevented accumulation of CD4+ T cells and ED1+ macrophages over the entire observation period. Peripheral and intragraft expressions of T cell activation inhibitor-mitochondrial were stable in long-term surviving 5-mg TAC recipients but declined before acute or chronic rejection in 1 and 3 mg TAC recipients. In contrast, LBP levels increased during acute and chronic rejections. We studied acute and chronic rejections in a preclinical model of ITX, which recapitulates clinical findings and highlights the importance of monitoring peripheral T cell activation inhibitor-mitochondrial expression, LBP levels, and antidonor antibodies for revealing rejection.