ACTH treatment promotes murine cardiac allograft acceptance.

Jing Zhao,Stefan G Tullius,Naima Banouni,Vivek Kasinath,Xiaofei Li,Mayuko Uehara,Liwei Jiang,Paolo Fiorina,Basmah S Al Dulaijan,Takaharu Ichimura,Reza Abdi,Jamil Azzi,Joren C Madsen,Petr Jarolim

doi:10.1172/jci.insight.143385

Abstract

Heart transplantation is the optimal therapy for patients with end-stage heart disease, but its long-term outcome remains inadequate. Recent studies have highlighted the importance of the melanocortin receptors (MCRs) in inflammation, but how MCRs regulate the balance between alloreactive T cells and Tregs, and whether they impact chronic heart transplant rejection, is unknown. Here, we found that Tregs express MC2R, and MC2R expression was highest among all MCRs by Tregs. Our data indicate that adrenocorticotropic hormone (ACTH), the sole ligand for MC2R, promoted the formation of Tregs by increasing the expression of IL-2Rα (CD25) in CD4+ T cells and activation of STAT5 in CD4+CD25+ T cells. ACTH treatment also improved the survival of heart allografts and increased the formation of Tregs in CD28KO mice. ACTH treatment synergized with the tolerogenic effect of CTLA-4–Ig, resulting in long-term survival of heart allografts and an increase in intragraft Tregs. ACTH administration also demonstrated higher prolongation of heart allograft survival in transgenic mouse recipients with both complete KO and conditional KO of PI3Kγ in T cells. Finally, ACTH treatment reduced chronic rejection markedly. These data demonstrate that ACTH treatment improved heart transplant outcomes, and this effect correlated with an increase in Tregs.

Highlights

Heart transplantation is a life-saving strategy; numerous challenges must be met to improve allograft and recipient survival [1, 2]
We measured the gene expression of MC1R, MC2R, MC3R, MC4R, and MC5R in the CD4+CD25+ T cells, and we found by quantitative PCR that MC2R was expressed more highly than the other melanocortin receptors (MCRs) (Figure 1A)
We found that human CD4+CD25+Foxp3+ Tregs expressed MC2R significantly more robustly than naive T cells, as measured by quantitative PCR (qPCR) (Figure 1C)

Summary

Introduction

Heart transplantation is a life-saving strategy; numerous challenges must be met to improve allograft and recipient survival [1, 2]. Despite an improvement in short-term outcomes, a high percentage of heart transplant recipients develop chronic rejection [3, 4]. Cardiac allograft vasculopathy (CAV) refers to the development of diffuse coronary artery disease of the allograft that rises in incidence 1 year following transplantation and represents an important sequela of excessive inflammation related to graft rejection [5, 6]. CAV is a typical cause of graft dysfunction, affecting about 30% of patients at 5 years after transplantation [5]. CAV causes the most deaths in heart transplant recipients after the third year after transplantation [5]. Moderate or severe coronary artery disease that is diagnosed within 1 year after transplantation, termed early CAV, is an independent predictor of a mortality rate of 50% at 3 years after transplantation [7]. CAV persists as a major hindrance against long-term survival of the transplant [7]

Methods

Results

Conclusion