Desiccation Stress Triggers and Exacerbates Experimental Ocular Graft-Versus-Host-Disease

Introduction:

Ocular Graft-versus-Host Disease (oGVHD) is a rapidly progressing, sight-threatening condition of the eye following allogeneic hematopoetic stem cell transplantation (aSCT). Previously we reported in two retrospective studies, adverse environmental stress (AES) such as high air flow and low humidity during the stay on the transplant unit may be a risk factor for chronic oGVHD. To investigate which pathophysiological processes may be triggered by AES in the early phase after transplantation, we performed experiments using a mouse model of oGVHD under different environmental conditions.

Methods:

A minor mismatch-mouse model (129S2->C57BL/6) was used where mice either remained in standard housing (>50% humidity, no air flow) or were subjected to AES (<30% humidity, constant air flow) for 18 days after bone marrow transplantation (BMT). Systemic and ocular GVHD were monitored for up to 28 days and histological, immunohistochemical and flow-cytometric analyses of ocular tissue, tear film, lacrimal gland, ocular draining-lymph nodes and spleen were performed.

Results:

AES led to a significantly higher systemic and oGVHD score than in animals without AES at days 7 and days 14 after BMT. Corneal staining and blepharitis remained significantly elevated after discontinuation of AES until day 28. Tear film analysis demonstrated early elevation of Tumor Necrosis Factor (TNF), whereas increase of CD8+ T-cells, higher activation of dendritic cells and early loss of Treg activity was detected in cervical lymph nodes together with an early corneal lymphangiogenesis in desiccated animals, but not in animals kept under normal housing conditions.

Conclusions:

These data confirm the hypothesis that AES is an independent risk factor for oGvHD. Low humidity conditions after aSCT in the mouse model worsen the severity of systemic GVHD in the mouse model, implicating that AES has not only a local effect.

Therefor avoiding AES and targeting early activation of ocular surface immune mechanisms could help to reduce both oGVHD and systemic GvHD in patients undergoing aSCT.

Gehlsen:Ursapharm GmbH: Current Employment. Holtick:Roche: Honoraria. Stern:ImmunEyez: Current equity holder in private company.