Abstract
Purpose :
Graft-versus-host disease (GVHD) remains a frequent cause of morbidity following hematopoietic stem cell transplantation. GVHD often manifests with ocular surface complications that includes keratopathy. Here, we hypothesized that donor CD4 T cell that are recruited to ocular surface drive corneal nerve damage leading to ocular GVHD (oGVHD) associated keratopathy.
Methods :
An allogeneic GVHD model (minor histocompatibility antigen mismatch) was established by transferring bone marrow (BM) and purified splenic T cells from C57BL/6J (H2b) mice into lethally irradiated sex-matched C3-SW.H2b mice. Control groups were established using BM-only transfers. Systemic and ocular signs of GVHD were scored longitudinally, and corneal sensation tracked using Cochet-Bonnet esthesiometry. Whole corneal mounts were imaged using confocal imaging to study T cell and corneal nerves. Experimental groups included reconstituting recipients with BM and CD4 T cells only, CD8 T cells only, or CD4 CD8 T cells and CXCR3 -/- mice.
Results :
Corneal sensation was normal in all animals at baseline and was not impacted by irradiation as esthesiometry scores remained normal throughout the study in all BM-only recipient controls. In contrast, progressive corneal sensation loss was noted starting day 10 post-HSCT (p<0.001) in only mice that received T cells that developed oGVHD and this correlated with the onset of corneal epithelial defects. Corneal sensation loss was dependent upon CD4 T cells (p<.001), as GVHD models established with BM and CD8 T cells did not exhibit sustained corneal sensation deficits. Importantly, confocal analysis of whole mount corneas confirmed the presence of donor CD4 T cells localizing to areas where corneal nerves were damaged. Importantly, mice that were transplanted with CXCR3-/- T cells maintained normal corneal sensation throughout the study and no gross corneal pathologies were observed.
Conclusions :
Early corneal nerve damage occurs in oGVHD and this correlate with the onset of keratopathy. Significantly, donor effector CD4 T cells are responsible for the orchestration of corneal nerve destruction and signaling through CXCR3 is important in the recruitment of these population of effector T cells into the cornea. Effective local manipulation of adaptive immune responses in the cornea could be used to prevent or treat corneal nerve damage and keratopathy.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.