title: Immunosuppressive effects of erythropoietin on human alloreactive T cells.
abstract: Correction of anemia with erythropoietin (EPO) is associated with improved kidney transplant outcomes. Emerging evidence, predominantly from animal models, indicates that these observations may be erythropoiesis-independent and that EPO exhibits immunosuppressive properties. We examined the effects of EPO on human T-cell alloimmunity by first documenting that CD4(+) and CD8(+) T cells express EPO receptor (EPO-R) on their surfaces. In mixed lymphocyte reactions, EPO induced a dose-dependent decrease in allogeneic CD4(+) T-cell proliferation (EPO 1000 U/ml: 44.6%±22.9% of vehicle, P<0.05; 2000 U/ml: 11.1%±4% of vehicle, P<0.001) without inducing cell death. The effects required signals transmitted directly through the EPO-R expressed on T cells, resulting in diminished Th1 differentiation without effects on regulatory T-cell induction. Mechanistic studies revealed that EPO prevented IL-2-induced proliferation by uncoupling IL-2 receptor signaling, inhibiting phosphorylation of the intracellular intermediaries AKT and extracellular signal-regulated kinase that are known to mediate T-cell expansion. EPO treatment reduced expansion of human naïve CD4(+) T cells after adoptive transfer into NOD scid γc(null) mouse recipients, verifying the effects in vivo. Although activated T cells expressed CD131, an alternative EPO receptor, addition of a specific CD131 agonist peptide, ARA290, did not alter T-cell proliferation or cytokine production. Our findings link EPO-R signaling on T cells to inhibition of T-cell immunity, providing one mechanism that could explain the observed protective effects of EPO in kidney transplant recipients.
authors.affiliation: Renal Division, Department of Medicine.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cravedi
authors.affiliation: Renal Division, Department of Medicine.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Manrique
authors.affiliation: Tisch Cancer Institute.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hanlon
authors.affiliation: Renal Division, Department of Pediatrics.
authors.forename: Jessica
authors.initials: J
authors.lastname: Reid-Adam
authors.affiliation: Tisch Cancer Institute.
authors.forename: Joshua
authors.initials: J
authors.lastname: Brody
authors.affiliation: Renal Division, Department of Medicine.
authors.forename: Praeophayom
authors.initials: P
authors.lastname: Prathuangsuk
authors.affiliation: Renal Division, Department of Medicine.
authors.forename: Anita
authors.initials: A
authors.lastname: Mehrotra
authors.affiliation: Renal Division, Department of Medicine, Recanati Miller Transplant Institute, and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York peter.heeger@mssm.edu.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D053648:Cytokine Receptor Common beta Subunit / Q000378:metabolism; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007519:Isoantigens; D016030:Kidney Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017467:Receptors, Erythropoietin / Q000276:immunology / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D014181:Transplantation Immunology / Q000187:drug effects
chemical_list: C115876:CSF2RB protein, human; D053648:Cytokine Receptor Common beta Subunit; D007166:Immunosuppressive Agents; D007519:Isoantigens; D017467:Receptors, Erythropoietin; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; D007371:Interferon-gamma