The Risma Lab has been investigating natural killer (NK) cell and cytotoxic T lymphocyte (CTL) function and the relationship between NK cell/CTL killing and disease. NK cell and CTL function are critical to immune homeostasis, and NK cells and CTLs rely on a variety of methods to kill target cells. Our primary interest is in the perforin-granzyme–mediated pathway of cell death whereby preformed cytotoxic granules are degranulated from NK cells/CTLs at the immune synapse and initiate apoptosis via granzyme delivery to target cells. When this pathway is defective, the immune response to virally infected cells or tumor cells is impaired. The consequence of absent NK cell/CTL function in children is the development of a fatal, inflammatory disorder called hemophagocytic lymphohistiocytosis (HLH). My laboratory has been using basic, translational, and genetic research approaches to explore the relationship between defects in lymphocyte cytotoxicity and the pathogenesis of HLH, specifically as it relates to mutations in the gene encoding perforin. By studying this rare disease, we are gleaning insights into the mechanisms by which NK cells/CTLs kill target cells, allowing us to apply our findings to more common diseases such as chronic viral infections and malignancies.
HLH Research at Cincinnati Children’s
We have established a unique, multidisciplinary research team to accomplish our goals. This team includes Dr. Michael Jordan, who is determined to understand the pathogenesis of HLH in virally infected, perforin-deficient mice and who leads clinical trials for novel therapies. Other team members, Dr. Jack Bleesing, Dr. Rebecca Marsh and Dr. Ashish Kumar, all have critical roles in diagnosis and treatment of patients, development of new therapeutic protocols, and recruitment of patients to HLH research studies. Our HLH team also hosts a HLH Facebook page.