Linking erythropoietin to Treg-dependent allograft survival through myeloid cells.

Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE

Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-

Erythropoietin*/genetics ; Erythropoietin*/metabolism ; T-Lymphocytes, Regulatory*; Abatacept ; Allografts ; Animals ; Epoetin Alfa ; Mice ; Myeloid Cells

Erythropoietin (EPO) has multiple nonerythropoietic functions, including immune modulation, but EPO's effects in transplantation remain incompletely understood. We tested the mechanisms linking EPO administration to prolongation of murine heterotopic heart transplantation using WT and conditional EPO receptor-knockout (EPOR-knockout) mice as recipients. In WT controls, peritransplant administration of EPO synergized with CTLA4-Ig to prolong allograft survival (P < 0.001), reduce frequencies of donor-reactive effector CD8+ T cells in the spleen (P < 0.001) and in the graft (P < 0.05), and increase frequencies and total numbers of donor-reactive Tregs (P < 0.01 for each) versus CTLA4-Ig alone. Studies performed in conditional EPOR-knockout recipients showed that each of these differences required EPOR expression in myeloid cells but not in T cells. Analysis of mRNA isolated from spleen monocytes showed that EPO/EPOR ligation upregulated macrophage-expressed, antiinflammatory, regulatory, and pro-efferocytosis genes and downregulated selected proinflammatory genes. Taken together, the data support the conclusion that EPO promotes Treg-dependent murine cardiac allograft survival by crucially altering the phenotype and function of macrophages. Coupled with our previous documentation that EPO promotes Treg expansion in humans, the data support the need for testing the addition of EPO to costimulatory blockade-containing immunosuppression regimens in an effort to prolong human transplant survival.

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P01 HL158504 United States HL NHLBI NIH HHS; R01 AI132949 United States AI NIAID NIH HHS; T32 AI007529 United States AI NIAID NIH HHS; U01 AI131470 United States AI NIAID NIH HHS; U01 AI063594 United States AI NIAID NIH HHS; P01 AI123086 United States AI NIAID NIH HHS

Keywords: Adaptive immunity; Cellular immune response; Mouse models; Transplantation

11096-26-7 (Erythropoietin)
64FS3BFH5W (Epoetin Alfa)
7D0YB67S97 (Abatacept)

Date Created: 20220407 Date Completed: 20220524 Latest Revision: 20230531

20240829

PMC9220923

10.1172/jci.insight.158856

35389892