Cytokine mediators of chronic graft-versus-host disease
Kelli P.A. MacDonald, … , Bruce R. Blazar, Geoffrey R. Hill
Kelli P.A. MacDonald, … , Bruce R. Blazar, Geoffrey R. Hill
Published June 30, 2017
Citation Information: J Clin Invest. 2017;127(7):2452-2463. https://doi.org/10.1172/JCI90593.
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Review Series

Cytokine mediators of chronic graft-versus-host disease

Abstract

Substantial preclinical and clinical research into chronic graft-versus-host disease (cGVHD) has come to fruition in the last five years, generating a clear understanding of a complex cytokine-driven cellular network. cGVHD is mediated by naive T cells differentiating within IL-17–secreting T cell and follicular Th cell paradigms to generate IL-21 and IL-17A, which drive pathogenic germinal center (GC) B cell reactions and monocyte-macrophage differentiation, respectively. cGVHD pathogenesis includes thymic damage, impaired antigen presentation, and a failure in IL-2–dependent Treg homeostasis. Pathogenic GC B cell and macrophage reactions culminate in antibody formation and TGF-β secretion, respectively, leading to fibrosis. This new understanding permits the design of rational cytokine and intracellular signaling pathway–targeted therapeutics, reviewed herein.

Authors

Kelli P.A. MacDonald, Bruce R. Blazar, Geoffrey R. Hill

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Figure 2

Overview of the cytokine-driven cellular network driving cGVHD.

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Overview of the cytokine-driven cellular network driving cGVHD. cGVHD is...
cGVHD is now recognized as a Th17/Tc17- and Tfh-mediated disease. DC priming of naive allogeneic T cells in the setting of elevated IL-6 production after BMT drives RORγt expression and Th17/Tc17 differentiation and accumulation in target tissues. Increased Tfh, GC B cells, and antibody, which accumulate in target tissues, contribute to cGVHD pathology. Tfh express high levels of IL-21, which, together with elevated levels of BAFF, drive GC B cell formation and antibody secretion. CSF-1–dependent macrophages are late-phase mediators of cGVHD pathology. Th17/Tc17 are polyfunctional and coexpress high levels of multiple cytokines, including IFN-γ, TNF, IL-22, CSF-1, and GM-CSF, which are implicated in promoting the migration and differentiation of Ly6Clo monocytes into pathogenic M2 macrophages. Plasma cell–derived allo- and autoantibodies can bind to Fc receptors on macrophages, potentially contributing to their polarization. Through their secretion of TGF-β, Ly6Clo-derived macrophages promote fibroblast activation and collagen production, leading to tissue fibrosis. Adapted with permission from Blood (11).