Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

Abstract

With the increasing use of mismatched, unrelated, and granulocyte colony-stimulating factor-mobilized peripheral blood stem cell donor grafts and successful treatment of older recipients, chronic graft-versus-host disease (cGVHD) has emerged as the major cause of nonrelapse mortality and morbidity. cGVHD is characterized by lichenoid changes and fibrosis that affects a multitude of tissues, compromising organ function. Beyond steroids, effective treatment options are limited. Thus, new strategies to both prevent and treat disease are urgently required. Over the last 5 years, our understanding of cGVHD pathogenesis and basic biology, born out of a combination of mouse models and correlative clinical studies, has radically improved. We now understand that cGVHD is initiated by naive T cells, differentiating predominantly within highly inflammatory T-helper 17/T-cytotoxic 17 and T-follicular helper paradigms with consequent thymic damage and impaired donor antigen presentation in the periphery. This leads to aberrant T- and B-cell activation and differentiation, which cooperate to generate antibody-secreting cells that cause the deposition of antibodies to polymorphic recipient antigens (ie, alloantibody) or nonpolymorphic antigens common to both recipient and donor (ie, autoantibody). It is now clear that alloantibody can, in concert with colony-stimulating factor 1 (CSF-1)-dependent donor macrophages, induce a transforming growth factor β-high environment locally within target tissue that results in scleroderma and bronchiolitis obliterans, diagnostic features of cGVHD. These findings have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition. This new understanding of cGVHD finally gives hope that effective therapies are imminent for this devastating transplant complication.

Figure 1.

Schematic overview of the cellular and molecular mediators, known and implicated, contributing to the continuum of aGVHD and cGVHD pathology. Both naive T cells (T_N) and their precursors (HSCs, common lymphoid progenitor [CLP]) contained within the stem cell graft contribute to cGVHD pathology. Mature donor T cells within the graft contribute to thymic destruction resulting in disrupted immune reconstitution. Thymic dysfunction favors the selection of autoreactive and alloreactive T cells polarized toward Th17/Tc17 lineages. Donor-derived DC APC function is corrupted during aGVHD, reducing their capacity to expand and maintain Tregs in the periphery. T-follicular helper cell (T_FH)-derived IL-21, together with elevated levels of BAFF, result in aberrant B-cell reconstitution favoring GC B-cell (GBC) expansion. Polyfunctional Th17/Tc17 cells migrate to target organs where secreted IL-17 may function as a chemokine for Ly6Clo monocytes. CSF-1 derived in part from Th17/Tc17 promotes the differentiation of Ly6Clo monocytes into tissue-resident macrophages (MΦ), which are polarized toward an M2 phenotype under the influence of multiple proinflammatory cytokines (GM-CSF, IL-22, IL-13, and IFNγ) produced by Th17/Tc17. Plasma cell–derived allo/autoantibodies (Ab) can bind to Fc receptors on macrophages, contributing to their polarization and promotion of TGFβ secretion, which promotes fibroblast activation and collagen production. Fc, receptor for immunoglobulins; T_allo, alloreactive T cell; T_EFF, effector T cell.