In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 10 ( 2021-10), p. 2542-2560
Abstract:
Better understanding of the regulation of auto- and alloantibody production is essential to develop hypothesis-driven therapies for autoimmune kidney diseases and graft rejection. Murine studies demonstrate that erythropoietin (EPO), a kidney-produced hormone, inhibits primary, T cell–dependent humoral immunity. EPO also diminishes autoantibodies and disease severity in murine models of lupus, and significantly reduces secondary humoral immunity in an allogeneic organ transplant model. A direct, STAT5-dependent, inhibitory effect of EPO through its receptor (EPOR) on T follicular helper (T FH ) cells that is crucial for B cell maturation mediates these effects. In vitro experiments document that EPO inhibitory effects on T FH formation apply to human cells, providing a rationale for further testing how EPOR activation affects autoimmune kidney diseases and antibody-mediated graft rejection. Background 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. Methods 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. Results 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 (T FH ). In vitro and in vivo experiments showed that EPO directly prevented T FH differentiation and function via a STAT5-dependent mechanism that reduces CD4 + T cell expression of Bcl6 . In lupus models, EPO reduced T FH , GC B cells, and autoantibody production, and abrogated autoimmune glomerulonephritis, demonstrating clinical relevance. In vitro studies verified that EPO prevents differentiation of human T FH cells. Conclusions Our findings newly demonstrate that EPO inhibits T FH -dependent antibody formation, an observation with potential implications for treating antibody-mediated diseases, including those of the kidney.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2021010098
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
2029124-3
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