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Dr. Ritz received his MD from Chicago Medical School in 1972, followed by residency in internal medicine at the University of Wisconsin Hospital and Clinics, Madison. He completed a clinical fellowship in hematology and oncology at Beth Israel Hospital, and a research fellowship at DFCI, where he joined the staff in 1980. Since 1996, he has been director of the Connell and O'Reilly Families Cell Manipulation Core.
Hematopoietic Stem Cell Transplantation, Graft versus Host Disease, Graft versus Leukemia, Cellular Therapy and Immunotherapy
Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with hematologic malignancies, but continues to be associated with severe toxicities. Both the efficacy and toxicity of HSCT are mediated by donor immune cells. Immune responses that target antigens expressed on recipient leukemia cells (termed graft versus leukemia – GVL) play an important role in eradicating residual tumor cells and preventing leukemia relapse after transplant. In contrast, immune responses that target antigens expressed by normal tissues in the recipient are the primary mediators of graft versus host disease (GVHD) and thus lead to substantial toxicities. Although donor T cells are the primary immune cells responsible for GVL and GVHD, studies from our laboratory demonstrated that donor B cells also play a role in these responses. To examine the role of B cells we determined whether patients developed antibodies specific for minor histocompatibility antigens such as Y-chromosome encoded proteins (H-Y antigens) after HSCT. While males are tolerant to these self-proteins, female T cells develop strong responses to these antigens after transplantation into male recipients. Our studies demonstrated that antibodies specific for H-Y antigens developed in approximately 50% of male recipients with female donors but not in male patients with male donors. Importantly, the incidence of chronic GVHD was significantly higher and the risk of relapse was significantly lower in patients with H-Y antibodies. These studies provided evidence that B cell responses contribute to GVHD as well as GVL and also suggested that targeting donor B cells might offer a new therapeutic approach for chronic GVHD. This was confirmed by clinical trials demonstrating the efficacy of rituximab in patients with persistent chronic GVHD. Further studies evaluating the efficacy of rituximab for prevention of chronic GVHD are also underway. Current studies in my laboratory focus on defining the mechanisms whereby donor B cells and antibodies specific for recipient antigens contribute to GVL and GVHD.Regulatory T cells (Treg) are known to play a critical role in immune tolerance and deficiencies of Treg contribute to the development of autoimmune diseases. Studies from our laboratory demonstrated that patients with chronic GVHD were deficient in Treg and inadequate reconstitution of Treg after transplant helps explain the inability of some patients to become immunologically tolerant to their own tissues. These findings also suggested that enhancement of Treg might restore immune tolerance and control GVHD. This was recently confirmed in clinical trials showing that administration of low doses of IL-2, a critical cytokine required for maintenance of Treg, resulted in the selective expansion of Treg and significant clinical improvement in approximately 50% of patients with active chronic GVHD. Current studies in my laboratory focus on the identification of critical factors that regulate homeostasis of Treg in normal individuals and in patients after HSCT. These studies also examine the effects of exogenous IL-2 on Treg homeostasis and characterization of the mechanisms whereby IL-2 enhances Treg numbers and function in patients with GVHD.In addition to the specific projects described above, my laboratory is also interested in developing other novel immune therapies for hematologic malignancies. These would include cytokines, immune modulating antibodies or other agents, cancer vaccines and adoptive cellular therapies. Our laboratory has the ability to develop novel therapies of many types and to evaluate the immunologic effects of these new approaches in patients enrolled on the clinical trials conducted to evaluate these methods.
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