Allogeneic hematopoietic stem cell transplantation (HSCT) has become the standard of care for the treatment of several life-threatening hematologic malignancies as well as certain immunodeficiency diseases. Unfortunately, as the survival rate of patients with these diseases is improved, the quality of life is negatively impacted by the development of Graft vs. Host Disease (GVHD). GVHD is a complex, multi-organ disorder arising from an immunological attack by donor allo-reactive (rx) T cells that result in damage to vital organs including the liver, skin, hematopoietic compartment and the ocular surface of the eye. Ocular GVHD occurs in >60% of these patients and is characterized by dry eye, conjunctiva damage, punctate keratopathy, corneal ulceration and perforation. Patients with ocular GVHD suffer and are incapacitated because of severe ocular discomfort, pain and poor vision. Despite the high frequency of eye involvement in patients undergoing GVHD, little is known regarding the underlying immune mechanisms responsible for ocular GVHD, limiting the ophthalmic care of these patients to palliative therapies and global anti-inflammatory drugs. Even though major advances have been made in the understanding of immune dysregulation in systemic GVHD, a critical question in the field is to understand the relationship between systemic and organ specific GVHD. More specifically, a central unanswered question regarding GVHD and subsequent damage in various tissues is the involvement of not only allo-rx, but also self-rx T cells. This is relevant as autoimmune like clinical and pathological symptoms occur in GVHD, including Sjogrens and dry eye syndrome. To understand the immune mechanisms of ocular GVHD, our group has developed a unique pre-clinical animal model, in which lethally irradiated C3H.SW mice (H2b) infused with C57BL6 (H2b) T cells + bone marrow, results in the development of systemic and ocular GVHD with kinetics of onset similar to that observed in patients who develop eye complications. Our preliminary data clearly demonstrate for the first time that ocular disease correlates with the presence of donor T cells in eye tissue and is also associated with the infiltration of macrophages (m$). Importantly, in contrast to the CD8>CD4 systemic GVHD immune phenotype, the CD4>CD8 ratio immune phenotype in the ocular compartment is distinct. Furthermore, the detection of IFN-y and TNF-a, suggests that Th1 effector allo-rx cells and M1 inflammatory m$ are involved in ocular GVHD. Interesting, these mice also exhibit thymic damage and therefore the possibility for the potential involvement of donor and/or host pathogenic T cells with self-reactivity to ocular antigens. Based on these results, we propose in Aims 1 and 2 to test the hypothesis that both allo-rx donor T cells and/ or self-rx T cells infiltrate the ocular surface and are responsible for orchestrating the recruitmet of inflammatory M1 m$ that contribute to the ocular damage. Moreover in Aim 3, we will locally regulate the T cells and m$ using antibody/cytokine conjugates, fusion proteins and novel small biomolecules to prevent and treat ocular GVHD.
In the United States ~12,000 patients annually undergo allogeneic bone marrow transplantation for the treatment of hematopoietic malignancies. Even though these patients survive their disease, they cannot enjoy life because the majority develops Graft vs. Host Disease (GVHD); a systemic inflammatory reaction where donor immune cells primarily attack the patient's liver, skin and eyes. Unfortunately, ocular GVHD occurs in more than 60% of patients and results in poor vision because of severe dry eye induced ocular surface damage. We have assembled a unique multidisciplinary team at the University of Miami Miller School of Medicine to comprehensively tackle the research and care of patients with GVHD. Our group has developed an animal model of systemic and ocular GVHD with onset kinetics similar to that observed in patients who develop eye complications. In this proposal we will use this pre-clinical model to define the immune responses in ocular GVHD and develop new targeted local immunotherapy to prevent and treat ocular GVHD. Our findings will have direct translational impact in the care of our patients to preserve their vision and improve quality of life.
