Recent advances in ocular graft-versus-host disease

Abstract

Ocular graft-versus-host-disease (GVHD) remains a significant clinical complication after allogeneic hematopoietic stem cell transplantation. Impaired visual function, pain, and other symptoms severely affect affected individuals' quality of life. However, the diagnosis of and therapy for ocular GVHD involve a multidisciplinary approach and remain challenging for both hematologists and ophthalmologists, as there are no unified international criteria. Through an exploration of the complex pathogenesis of ocular GVHD, this review comprehensively summarizes the pathogenic mechanism, related tear biomarkers, and clinical characteristics of this disease. Novel therapies based on the mechanisms are also discussed to provide insights into the ocular GVHD treatment.

Keywords: clinical characteristics; novel therapeutic targets; ocular graft-versus-host-disease; tear biomarkers; the pathogenic mechanism.

Figure 1

The overview of ocular GVHD and clinical management. Donor-derived immune cells (T cells, macrophage, neutrophil) cross the blood vessel barrier into the eye and drive the ocular inflammatory response, which leads to ocular tissue damage including lacrimal glands, meibomian glands, corneal, conjunctival and presents various related clinical characteristics. Based on the manifestations of different ocular impairments, it helps clinicians to take appropriate treatment measures. PEDs, persistent epithelial defects; ASEDs, autologous serum eye drops; UCS, umbilical cord serum; AMT, amniotic membrane graft; SLK, superior limbal keratoconjunctivitis. (Created with BioRender.com).

Figure 2

The pathogenic mechanism in the lacrimal glands (LG) of ocular GVHD and treatment. Donor CD4+ T cells and activated CD8+ T cells infiltrate the periductal area of the lacrimal gland causing tissue injury. In addition, fibroblasts with high expression of heat shock protein (HSP)47 are also activated and synthesize excessive collagen contributing to fibrosis in the LG and causing dry eye. The clinical therapies for ocular GVHD patients with dry eyes include artificial tears and punctal plugs. For novel therapeutic targets, it is reported that tranilast alleviates inflammation and retard fibrotic changes in LG pathology in cGVHD by preventing epithelial-mesenchymal transition. VA-lip HSP47 and Valsartan mainly reduce collagen synthesis by inhibiting or decreasing the expression of HSP47 fibroblasts. The mechanisms by which PAB, HC-HA/PTX3, and ABT-263 reduced fibrosis may involve fibroblasts. PAB specifically reduced endoplasmic reticulum stress induced by cGVHD in fibroblasts to alleviate fibrosis. HC-HA/PTX3 decreased the infiltration of fibroblasts to inhibit abnormal collagen synthesis. As for ABT-263, it selectively inhibited the antiapoptotic proteins (BCL-2 and BCL-xL), thereby mitigating the detrimental effects of senescent cells, including fibroblasts, on ocular GVHD. EMT, epithelial-mesenchymal transition; PBA, 4-phenyl butyric acid; HC-HA/PTX3, heavy chain-hyaluronan/pentraxin 3; ER, endoplasmic reticulum, VA-lip HSP4, vitamin A–coupled liposomes containing HSP47 small interfering RNA (siRNA) against HSP47. (Created with BioRender.com).

Figure 3

The pathogenic mechanism in the corneal of ocular GVHD and treatment. The corneal may appear the corneal epithelial impairment, a lower endothelial cell density, hemangiogenesis, and corneal neurosensory abnormalities in ocular GVHD. The corneal epithelial impairment including atrophy and necrosis, the vacuolization of epithelial basal cells, and stromal edema, all of which are likely associated with the infiltration of immune cells and the stimulation of inflammatory cytokines. The reduction of the corneal endothelial cells and formation of neovascularization might be associated with increased expression of the proinflammatory marker NK1R. Fosaprepitant, the inhibition of the SP-NKR1 axis, through topically applied substantially ameliorated the clinical manifestations of ocular GVHD. In addition, the aberrant complement C3/CD4+ T-cell axis activation might coordinate corneal nerve damage. However, the specific mechanism needs to be further investigated. By forming a biochemically stable convertase to rapidly hydrolyze mammalian C3, localized cobra venom factor prevents corneal sensation loss in ocular GVHD. In addition, the therapies for ocular GVHD patients with severe corneal impairment include serum eye drops, umbilical cord serum, scleral lenses, bandage soft contact lenses, amniotic membrane grafts, and keratoplasty. ASEDs, autologous serum eye drops; UCS, umbilical cord serum; AMT, amniotic membrane graft; CVF, cobra venom factor; ECD, endothelial cell density; NK1R, neurokinin-1 receptor; VEGF, vascular endothelial growth factor. (Created with BioRender.com).

Figure 4

The pathogenic mechanism in the conjunctival (A) and meibomian gland (B) of ocular GVHD and treatment. 4A: In ocular GVHD patients, the conjunctival often presents as the conjunctival injection or chronic conjunctivitis, which is related with various immune cells including T cells and neutrophils (NET). By releasing nuclear chromatin complexes as extracellular DNA webs which are termed neutrophil extracellular traps (NETs), Net and Nets cause conjunctival fibroblast proliferation and differentiation and may contribute to conjunctival fibrosis. Hence, drugs such as deoxyribonuclease I; a subanticoagulant dose of heparin; and antagonists of OSM, NGAL and TNFSF14 could be potential therapies for managing ocular GVHD. In addition, more metaplasia, fewer goblet cells, a lower mean number of mucosal microvilli, and shorter microvilli also contribute to dry eye in ocular GVHD. For ocular GVHD patients with conjunctival Involvement, the therapies also include corticosteroids, cyclosporine drops, tacrolimus drops, or ointment. 4B: Infiltration of the lymphocytes results in damage to the meibomian gland in ocular GVHD. In addition, the meibomian gland in ocular GVHD appears cystic dilatation with atrophy because of ductal epithelial hyperkeratinization, the shedding of keratinized material into the glandular ducts leading to obstructions of the orifice. Patients with ocular GVHD also develop absent meibomian glands, resulting in tear film instability. However, there is a lack of suitable animal models to explore the related mechanism of meibomian gland involvement in ocular GVHD to find specific therapeutic targets. The clinical usual treatment includes warm compresses, lid scrubs, antibiotic ointments, and steroid ointments for ocular GVHD patients with meibomian gland dysfunction. OSM, oncostatin M; NGAL, neutrophil gelatinase-associated lipocalin; TNFSF14: tumor necrosis factor superfamily member 14 (Created with BioRender.com).