ACTH treatment promotes murine cardiac allograft acceptance

JCI Insight. 2021 Jul 8;6(13):e143385. doi: 10.1172/jci.insight.143385.


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.

Keywords: Immunology; Organ transplantation; T cell receptor; Tolerance; Transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenocorticotropic Hormone* / immunology
  • Adrenocorticotropic Hormone* / pharmacology
  • Animals
  • CD4 Antigens / immunology
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Graft Rejection* / drug therapy
  • Graft Rejection* / immunology
  • Graft Rejection* / pathology
  • Graft Survival / drug effects
  • Graft Survival / immunology
  • Heart Transplantation / adverse effects*
  • Hormones / pharmacology
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Membrane Proteins / immunology*
  • Mice
  • STAT5 Transcription Factor / immunology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*
  • Transplantation Tolerance / drug effects
  • Transplantation Tolerance / immunology


  • CD4 Antigens
  • Hormones
  • Interleukin-2 Receptor alpha Subunit
  • MRAP protein, mouse
  • Membrane Proteins
  • STAT5 Transcription Factor
  • Stat5a protein, mouse
  • Adrenocorticotropic Hormone