Unraveling the Mechanisms of Cutaneous Graft-Versus-Host Disease

Abstract

The skin is the most common target organ affected by graft-versus-host disease (GVHD), with severity and response to therapy representing important predictors of patient survival. Although many of the initiating events in GVHD pathogenesis have been defined, less is known about why treatment resistance occurs or why there is often a permanent failure to restore tissue homeostasis. Emerging data suggest that the unique immune microenvironment in the skin is responsible for defining location- and context-specific mechanisms of injury that are distinct from those involved in other target organs. In this review, we address recent advances in our understanding of GVHD biology in the skin and outline the new research themes that will ultimately enable design of precision therapies.

Keywords: B cells; T cells; antigen-presenting cells; cutaneous graft-versus-host disease; microbiome; pathophysiology; repair mechanisms.

Figure 1

Pathogenesis of cutaneous graft-versus-host disease (GVHD). (A) Diagram depicting cellular and structural elements of normal skin. (B) During acute GVHD, the local production of IFN-γ inducible chemokines in response to tissue injury promotes the recruitment of CXCR3⁺ alloreactive T cells into the skin (34). Upon in situ interaction with host-type Langerhans cells, alloreactive T cells are reprogramed to differentiate into pathogenic effector cells characterized by enhanced survival and generation of IFN-γ (35). Pathogenic T cells kill Lgr5⁺ epidermal stem cells (36), thus disabling normal repair mechanisms and epidermopoiesis; these effects are manifested by vacuolar degeneration and apoptosis of the basal and suprabasal epidermal cells, focal dermo-epidermal separation, and necrosis of the epidermis with denudation. Distortion of the local microbiome as a consequence of the conditioning regimen and antibiotic therapy may also be an important factor driving skin inflammation (37). (C) During the evolution of chronic GVHD, donor T cell-derived IL-17 is required for recruitment of Ly6C^low monocytes to the skin, which then differentiate into macrophages (38). Generation of transforming growth factor (TGF)-β by activated macrophages induces fibroblasts to differentiate into myofibroblasts that promote collagen deposition through a heat shock protein 47-dependent mechanism (39). Binding of allo- or auto-antibodies to macrophage Fc receptors induces their polarization toward the M2 phenotype and production of TGF-β (27), thus amplifying the process of myofibroblast generation of collagen. IL-21 generation by follicular helper-like cells recruited to the skin may also have direct effects upon skin fibroblast differentiation (40). Collectively, these mechanisms lead to thickening and homogenization of collagen bundles throughout the dermis.