Ocular graft-versus-host disease (oGVHD): From A to Z

Abstract

Allogeneic hematopoietic stem cell transplantation is a definitive therapy for a variety of disorders. One of the complications is acute graft-versus-host disease (aGVHD), which has a high mortality rate. Patients can also develop chronic graft-versus-host disease (cGVHD), a more indolent yet afflicting condition that affects up to 70% of patients. Ocular involvement (oGVHD) is one of the most prevalent presentations of cGVHD and can manifest as dry eye disease, meibomian gland dysfunction, keratitis, and conjunctivitis. Early recognition of ocular involvement using regular clinical assessments as well as robust biomarkers can aid in better management and prevention. Currently, the therapeutic strategies for the management of cGVHD, and oGVHD in particular, have mainly focused on the control of symptoms. There is an unmet need for translating the preclinical and molecular understandings of oGVHD into clinical practice. Herein, we have comprehensively reviewed the pathophysiology, pathologic features, and clinical characteristics of oGVHD and summarized the therapeutic landscape available to combat it. We also discuss the direction of future research regarding a more directed delineation of pathophysiologic underpinnings of oGVHD and the development of preventive interventions.

Keywords: Allogeneic hematopoietic stem cell transplantation; Dry eye disease; GVHD; Graft-versus-host disease; Keratoconjunctivitis sicca; Meibomian gland dysfunction; Ocular graft-versus-host disease; Ocular surface.

Figure 1.

Pathological alterations in the lacrimal glands of oGVHD cases and its immunological underpinnings. The basement membrane of lacrimal ducts and lacrimal vasculature exhibits multilayering and thickening. The CD8+ and CD4+ T-cells, along with plasma cells, Th17 cells, macrophages, and neutrophils, infiltrate the peri-ductal area and contribute to fibroblast activation, myofibroblast emergence, and eventually, tissue fibrosis. In addition, activated fibroblasts perpetuate immune activation by acting as antigen-presenting cells (by expressing HLA-DR, CD34, CD40, CD54, CD80, and CD86). The involvement of other pro-fibrotic mediators and EMT-inducers, namely TGF-β, neutrophil extracellular traps, renin-angiotensin-aldosterone system, reactive oxygen species, and chemokines is also implicated in the oGVHD-related lacrimal gland destruction.

Figure 2.

Corneal manifestations of oGVHD. a. A case of oGVHD which interestingly presented with corneal perforation. MGD, prominent eyelid margin vascularization, pupil distortion, and iris prolapse in the location of corneal thinning is evident. b. A case of oGVHD with chronic involvement of cornea including neovascularization and opacity.

Figure 3.

Pathological findings of the oGVHD conjunctiva. Thinning of epithelia, loss of goblet cell microvilli and their densities; thickening, multilayering, and disruption of the basal lamina; vacuolization of basal cells; CD8+ T-cell infiltration; and fibroblast activation and myofibroblast generation are seen in the conjunctival samples of oGVHD eyes. The most prominent pathologic feature is the EMT, which is the consequence of immune activation and cytokine release.