Project Summary/Abstract
Graft versus host disease (GVHD) is an immune-mediated condition affecting many organs. It is
categorized into acute and chronic subtypes. Eyes are affected in 60-90% of the patients with chronic GVHD
resulting in significant visual morbidity. About half of the ocular GVHD (oGVHD) patients develop steroid-
refractory conjunctival and lacrimal fibrosis and severe dry eye, sometimes with ocular perforation and loss of
globe. Pathophysiology of oGVHD remains incompletely understood. The current proposal will investigate the
role of host and donor macrophages, their phenotypic changes, and their crosstalk with fibroblasts and goblet
cells as mechanisms underlying oGVHD-associated ocular surface damage, fibrosis, and dry eye. The long-
term goal is to understand the immune-mediated pathophysiological basis of oGVHD for its prevention and
better therapeutic management. This proposal will use two mouse models of allogeneic bone marrow
transplantation to induce oGVHD. These models recapitulate many features of GVHD-associated ocular
surface damage, including a decrease in tear volume, signs of corneal keratopathy, conjunctival fibrosis, and
loss of goblet cells. Aim 1 will investigate whether irradiation, host macrophage activation, and the influx of
donor marrow-derived macrophages initiate and perpetuate ocular surface injury in oGVHD. Aim 2 will identify
whether profibrotic mediators released by macrophages cause transdifferentiation of conjunctival and lacrimal
gland fibroblasts to elicit oGVHD-associated fibrosis. Aim 2 will also test the role of the fibroblast-mediated
release of macrophage colony-stimulating factor-1 (CSF-1) and other chemokines in recruiting donor
macrophages to the ocular surface. Furthermore, aim 2 will evaluate whether pexidartinib, a CSF-1 receptor
inhibitor, can attenuate oGVHD by depleting conjunctival and lacrimal gland macrophages. Aim 3 will
investigate whether rescue of goblet cell loss by IL-13 can mitigate oGVHD-associated dry eye. Aim 3 will also
identify the macrophage receptors involved in mediating the biological effects of goblet cell mucins. The results
of this study will provide data on the role of host-donor macrophages, their interaction with fibroblasts and
goblet cells as underlying mechanisms in oGVHD pathology and will potentially identify novel therapeutic
approaches for the management of oGVHD.