Daniel H. Fowler, MD
My laboratory focuses on donor Th2 cells for modulation of graft rejection, graft-versus-host disease (GVHD), and graft-versus-tumor (GVT) effects. To generate Th2 cells ex vivo, donor CD4 cells are co-stimulated in the presence of IL-4 and IL-2; most recently, we have found that ex vivo expansion in rapamycin generates anti-apoptotic Th2 cells (Th2.rapa cells) that have increased in vivo survival and increased capacity to modulate allogeneic responses. In murine models, we found that Th2 cell allograft augmentation represents a novel approach to reduce GVHD while partially preserving a GVT effect. In murine models of fully-MHC disparate graft rejection, we found that Th2 cell allograft augmentation represents a new approach to enhance alloengraftment across genetic barriers. We have completed a first generation clinical trial that has demonstrated the safety and feasibility of Th2 cell allograft augmentation for therapy of refractory hematologic malignancy. Currently, we are testing rapamycin-generated Th2 cells in a pilot clinical at the NCI. In this trial, we have identified that Th2.rapa cells appear to promote alloengraftment, thereby permitting prompt donor chimerism after out-patient chemotherapy. Ongoing murine efforts seek to identify mechanisms of Th2 cell action, whereas clinical efforts will expand to include transplantation across increased genetic disparity.