*Purpose: Recent studies have indicated the importance of the melanocortin pathway in the regulation of immune responses. In particular, the role that melanocortin receptors (MCRs) play in the modulation of T cell activity has gained much attention.

*Methods: Here, we examined the expression of MCRs on leukocyte subsets and dissected their contributions to the function of regulatory T cells (Tregs). We also carried out heart transplant studies using adrenocorticotropic hormone (ACTH) to assess the role of MCRs in transplant rejection.

*Results: We isolated human CD19⁺ B cells and CD3⁺ T cells, and we found that the expression of melanocortin 5 receptor (MC5R) at both the mRNA and protein levels was higher than other MCR subsets in these cells. Immunofluorescence staining of CD3⁺ T cells demonstrated the presence of MC5R on the plasma membrane. Following induction or expansion of Tregs, the expression of MC5R was increased. Addition of ACTH to a human Treg induction assay amplified the production of Tregs. Then, we tested the hypothesis that administration of ACTH would improve the survival of heart allografts in CD28^-/- mice, a strain afflicted by impaired Treg function. The mean survival time (MST) of heart allografts in the untreated CD28^-/- mice group and the CD28^-/- mice group treated with ACTH were 12 days vs. 43 days, respectively (*p<0.05). Moreover, ACTH was found to increase the synthesis of Tregs in a Treg induction assay using lymphocytes from CD28^-/- mice. As cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4-Ig) has been shown to abrogate Tregs, we tested the synergistic effects of ACTH in combination with CTLA4-Ig on the promotion of tolerance in a complete MHC-mismatched heart transplant model. The MST of the mice treated with CTLA4-Ig alone and those treated with CTLA4-Ig and ACTH were 54 days and >60 days, respectively. Further investigations are underway to assess the impact of the promotion of Tregs by ACTH in these in vivo models.

*Conclusions: In summary, these data indicate the importance of MC5R in the regulation of alloimmunity and the potential utility of stimulating the MC5R pathway to induce transplant tolerance.

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