Abstract
Purpose:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
Keywords: 555 immunomodulation/immunoregulation •
741 transplantation •
557 inflammation