Jerome Ritz

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely used in the treatment of patients with hematologic malignancies, but continues to be associated with severe toxicities. Both the effectiveness and toxicity of HSCT are mediated by donor T-cells in the stem cell graft. Those T cells that target antigens expressed on recipient leukemia cells play an important role in eradicating residual tumor cells and preventing leukemia relapse after transplant. In contrast, T cells 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. My laboratory has recently focused on the assessment of donor immune function after HSCT and characterization of the immune mechanisms responsible for graft versus leukemia (GVL) and GVHD.

Although donor T cells are thought to be the primary cells responsible for GVL and GVHD, recent studies from our laboratory have provided evidence that donor B cells also play a role in both of these immunologic effects. We first examined patients with chronic myelocytic leukemia (CML) or myeloma who had clear evidence of GVL demonstrated by complete remission in response to single infusions of donor lymphocytes. These patients were found to develop antibodies to a variety of tumor-associated antigens. These antibodies were not detectable prior to transplant and the development of high titer antibodies to these proteins correlated closely with the elimination of leukemia cells. Several of these antigens represent novel proteins that are highly expressed in tumor stem cells and the selective targeting of these antigens by the donor immune system may contribute to the effectiveness of GVL in vivo.

The role of donor antibodies in GVHD was examined by testing whether HSCT patients developed antibodies specific to known minor histocompatibility antigens such as DBY and other Y-chromosome encoded proteins (H-Y antigens). While males are tolerant to these proteins, female stem cells can develop strong T cells responses to these antigens after HSCT into male recipients. Our studies demonstrated that antibodies specific for H-Y antigens were also present in approximately 50% of male recipients with female donors but not in male patients with male donors. H-Y antibodies were not present before transplant but developed 4-8 months after HSCT. Importantly, the incidence of chronic GVHD was significantly higher in patients with H-Y antibodies, but the risk of relapse was also significantly lower in these patients. Taken together, these studies provide evidence that both T and B cell responses contribute to GVHD and GVL after HSCT. In patients with severe chronic GVHD, treatments that target donor B cells may represent a novel approach to reduce this toxicity.