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Victor L Perez, Samantha Herretes, Stephanie Duffort, Henry Barreras, Robert Levy; Distinct Role of Donor CD4 T Cells in the Orchestration and Development of Ocular Graft versus Host Diseases. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3573.
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Graft-versus-host disease is a complication of allogeneic hematopoietic stem cell transplantation. The majority of surviving patients suffer ocular complications including severe dry eye and scarring. Although donor allo-reactive T cells are responsible for this process, their role in the immunological damage of the eye remains to be determined. Using a clinically relevant minor-mismatch bone marrow (BM) transplantation model of GVHD we study the immune response using fluorescently labeled donor cells.
After total body irradiation (10.5 cGy), C3H.SW (H2b) mice received transplantation of BM with CD4/CD8 or CD4 only T cells from C57BL/6 (H2b) mice. To monitor T cells and macrophages, transplants with BM cells from Bonzo-T cell GFP+ mice or MAFIA macrophage GFP+ mice were done. Mice were monitored weekly for systemic and ocular GVHD. Immune cell recruitment was done by mean green intensity (MGI) in vivo to detect GFP+ cells. At 7 weeks, lymphoid organs and eyes were harvested for corneal flow cytometry, and immune phenotype.
Mice transplanted with B6 T cells underwent weight loss and clinical signs of GVHD ~3wks post-HSCT. Ocular surface disease by corneal staining and ulceration occurred by week 6. Systemic immune phenotype demonstrated damaged thymus and inverted CD4/CD8 ratio in the peripheral lymphoid compartments. However, CD4/CD8 levels in the corneal infiltrates and the cervical lymph nodes had a predominant infiltration of activated CD4 T cells. Mice that were transplanted with CD4 T cells only developed systemic and ocular GVHD. GFP+ cells infiltration correlated the presence of T cells and macrophages. However, GFP+ T cells appeared early ~1wk post-HSCT, while GFP+ macrophage were detected predominantly 3wks post-HSCT correlating with the onset of ocular disease.
The development of ocular GVHD is characterized by donor macrophages and a CD4 T cell infiltrate. T cell recruitment occurs earlier post-transplantation while macrophages occurs later. This suggests that CD4 T cells play a critical role in the development of ocular GVHD by orchestrating macrophage recruitment and inflammation. Therefore, early intervention with anti T cell therapies could be used to prevent ocular complications in GVHD.
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