Intralipid® attenuates acute cardiac allograft rejection in relation to promoting CD4+CD25+Foxp3+ regulatory T-cells and inhibiting toll-like receptor 4 expression

Abstract

Clinically available agents that promote the suppression of inflammatory processes with minimal adverse effects are highly desired. An FDA-approved nutrition supplement, Intralipid®, has shown its immunomodulatory potential. However, its influence on organ transplant rejection has not been tested. Here, we have investigated whether Intralipid® affect allograft outcome in a fully major histocompatibility complex (MHC)-mismatched rat model of heterotopic working-heart transplantation. Recipients were treated intravenously with Intralipid® (1.5g/kg, clinical dosage) or saline (untreated control) on post-transplantation days (PODs) 1, 3, and 6. Treatment with Intralipid® results in a significant prolongation of median graft survival from 7 days to 12 days. On POD 7, while the allografts from our untreated (i.e., control) group exhibit severe rejection, the allografts from Intralipid®-treated group show milder rejection demonstrating preserved myocardium integrity and decreasing infiltration of inflammatory cells (ED1+ and CD3+ cells). Flow cytometry analysis reveals a marked increase of CD4+CD25+Foxp3+ regulatory T-cells (Tregs) in the peripheral blood of Intralipid®-treated recipients beginning on POD 3 (7.0% vs. 14.4%, untreated vs. Intralipid®-treated). Intralipid® treatment also promotes Tregs in the spleens and allograft hearts. Toll-like receptor 4 expression is markedly suppressed in the Intralipid®-treated allografts. Our results suggest a new use of Intralipid® to modulate immune responses in the setting of heart transplantation. This study could stimulate further mechanistic as well as treatment studies leading to the clinical application of Intralipid® as an adjunctive therapy with current immunosuppression agents to manage organ rejection.