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Erythropoietin Reduces Auto- and Alloantibodies by Inhibiting T Follicular Helper Cell Differentiation

2021; American Society of Nephrology; Volume: 32; Issue: 10 Linguagem: Inglês

10.1681/asn.2021010098

1533-3450

Chiara Guglielmo, Sofia Bin, Chiara Cantarelli, Susan Hartzell, Andrea Angeletti, Chiara Donadei, Arun Čumpelik, Lisa Anderson, Evan Cody, Peter T. Sage, Gaetano La Manna, Enrico Fiaccadori, Peter S. Heeger, Paolo Cravedi,

Immune Cell Function and Interaction

Although high-affinity IgG auto- and alloantibodies are important drivers of kidney inflammation that can result in ESKD, therapeutic approaches that effectively reduce such pathogenic antibodies remain elusive. Erythropoietin (EPO) has immunomodulatory functions, but its effects on antibody production are unknown.We assessed the effect and underlying mechanisms of EPO/EPO receptor (EPOR) signaling on primary and secondary, T cell-dependent and T-independent antibody formation using in vitro culture systems, murine models of organ transplantation and lupus nephritis, and mice conditionally deficient for the EPOR expressed on T cells or B cells.In wild-type mice, recombinant EPO inhibited primary, T cell-dependent humoral immunity to model antigens and strong, polyclonal stimuli, but did not alter T-independent humoral immune responses. EPO also significantly impaired secondary humoral immunity in a potent allogeneic organ transplant model system. The effects required T cell, but not B cell, expression of the EPOR and resulted in diminished frequencies of germinal center (GC) B cells and T follicular helper cells (TFH). In vitro and in vivo experiments showed that EPO directly prevented TFH differentiation and function via a STAT5-dependent mechanism that reduces CD4+ T cell expression of Bcl6. In lupus models, EPO reduced TFH, GC B cells, and autoantibody production, and abrogated autoimmune glomerulonephritis, demonstrating clinical relevance. In vitro studies verified that EPO prevents differentiation of human TFH cells.Our findings newly demonstrate that EPO inhibits TFH-dependent antibody formation, an observation with potential implications for treating antibody-mediated diseases, including those of the kidney.