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Research Interests - Curriculum Vitae
Transplant recipients today are living longer and have better quality of life than ever before. Unfortunately, one of the complications of life-long immunosuppression therapy is an increased risk for developing malignancies. Studies indicate that all cancers are slightly increased in transplant recipients. However, the two most common malignancies are non-melanoma skin cancer and post-transplant lymphoproliferative disorder (PTLD). These two cancers are increased 60-250 fold and 20-fold, respectively, compared to the general population. My laboratory is interested in the mechanisms of these two post-transplant malignancies, with an eye to ultimately being able to harness the immune system to not only treat them, but prevent them from occurring. These studies are a natural outgrowth of my earlier interests in allograft acceptance and transplantation tolerance, as I consider post-transplant malignancies to be the "flip side' of clinical transplant acceptance.
PTLD tends to occur fairly early after transplantation, is often associated with the Epstein-Barr virus and can have significant mortality. My laboratory's work in PTLD has focused predominantly on the link between cytokine gene polymorphisms and the development of PTLD. We initially observed, in a small cohort of patients, an association of the A/A genotype at position +874 of the IFN- g gene (thought to be indicative of low cytokine production) with PTLD (VanBuskirk et al, Transplant Proceedings). We have added to this cohort, but the numbers are still too small to determine with 80% power whether the association truly exists in humans. We put together a multi-center team to acquire the necessary PTLD and control samples, and received pilot project funding from the National Cancer Institute to perform a multi-institutional study to answer this important question. As an alternative to the clinical trial, we performed a prospective trial in the xenogeneic animal model of PTLD, the hu PBL SCID mouse. We observed a similar association of the A/A genotype with rapid, high penetrance tumor production. In exploring the relationship between IFN- g genotype and TGF- b , we determined that TGF- b can reduce memory CTL restimulation to the effector phase in A/A genotype peripheral blood cells. Further, neutralization of TGF- b in hu PBL SCID mice prolonged survival and resulted in an expansion of CD8+ T cells. These studies were funded by a pilot project grant from NIAID and resulted in filing of a provisional patent and a manuscript published in the journal, Blood . Our current experiments are focused on defining the mechanisms by which TGF- b inhibits the restimulation of CTL, and how the balance between TGF- b and IFN- g can be manipulated to prevent PTLD. These studies have been funded by the Roche Organ Transplant Research Foundation, and are the subject of a pending R01 application.
The incidence of non-melanoma skin cancer in transplant recipients is 65-250 times that of the general population. Indeed, skin cancer is estimated to be the cause of death in 27% of Australian heart transplant recipients who had survived greater than 4 years post transplant. Because skin cancer appears several years after transplantation, the extent of the clinical problem has only recently been appreciated. As a consequence, the immunobiology underlying post-transplant skin cancer has not been systematically investigated. My laboratory, along with the laboratories of Dr. Tatiana Oberyszyn and Donna Kusewitt, is investigating post-transplant skin cancer. One project is investigating the role of CD4+ T cells in ultraviolet light-induced skin inflammation and carcinogenesis. Transplant patients often have reduced numbers of circulating CD4+ T cells and this reduction in CD4+ cells is reported to associate with increased skin cancer. We have shown that CD4+ T cells are important in controlling tumor growth and that mice with reduced CD4+ T cell levels are more susceptible to UV-induced skin inflammation and develop significantly more skin tumors than non-immunosuppressed mice (VanBuskirk et al Anticancer Research; Hatton et al, in preparation). One current study investigates the possible role of CD4+ NKT cells in the modulation of UV-induced skin inflammation and carcinogenesis, and is funded by the American Cancer Society, Ohio Division. Through an NCI-funded pilot project, we are also developing an animal model for post-transplant skin cancer using clinically relevant immunosuppressants. Our initial data indicate that cyclosporine treatment, like CD4-depletion, greatly exacerbates UV-induced skin inflammation, indicating one mechanism by which cyclosporine could increase skin cancer development. Once fully defined, this animal model will be invaluable in assessing prevention and treatment strategies under immunosuppressive conditions.
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