William R. Drobyski, MD
Professor of Medicine
Medicine - Neoplastic Diseases and Related Disorders
Medical College of Wisconsin
Research Focus: Immunobiology of bone marrow transplantation
MD: University of Rochester School of Medicine and Dentistry (1983)
The major focus of my laboratory is on the immunobiology of allogeneic bone marrow transplantation, in particular, with particular emphasis on graft versus host disease (GVHD). GVHD is the major cause of morbidity and mortality in patients undergoing allogeneic stem marrow transplantation. It is a complex pathophysiological process that is best conceptualized as a series of events that begins with the conditioning regimen and is amplified by cooperative interactions of multiple cell populations resident in the donor graft and persistent in the host. The initial event in GVHD pathophysiology derives from the conditioning regimen that results in damage to host tissues, release of proinflammatory cytokines, upregulation of MHC and adhesion molecules, and chemokine production. In the absence of alloreactive donor T cells, this is generally a self-limited process resulting in limited mortality. The induction of GVHD is therefore critically dependent upon T cells that are present in the donor stem cell graft. The process by which donor T cells recognize host alloantigens presented by host antigen-presenting cells (APCs) has been termed direct alloreactivity. As host APCs are eventually eliminated, donor T cells recognize host antigens presented on donor APCs in a process known as indirect alloreactivity. Both of these pathways of allorecognition play a role in GVHD biology. Donor T cell recognition of host alloantigens subsequently results in T cell activation, further cytokine secretion and acquisition of effector cell function that results in damage to host tissues through perforin/granzyme, fas/fas ligand and other cytotoxic pathways.
Clinically, GVHD is divided into acute and chronic phases that are primarily distinguished by their temporal onset. A longstanding, unresolved issue in the field of allogeneic stem cell transplantation has been how acute GVHD that is initiated by alloreactive donor T cells can evolve into chronic GVHD where autoreactive donor T cells are speculated to play a role in the pathophysiology of this syndrome. We have recently shown using murine models of stem cell transplantation that, during GVHD, there is a breaking of tolerance to self antigens and that this results in the development of autoimmunity. This indicates that autoreactivity is an integral component of GVHD and arises from antecedent alloreactivity. Our ongoing studies are now focused on defining the cellular basis for autoimmunity within the context of GVHD. To that end, we have recently identified a novel role for interleukin 23 in the pathophysiology of GVHD. Interleukin 23 is a proinflammatory cytokine, implicated in autoimmunity, and is secreted by activated antigen presenting cells (APCs). In the absence of donor APC-derived IL-23, we have discovered that there is selective protection in the colon from GVHD-induced pathological damage. Thus, within the context of a multi system inflammatory disorder, we have shown that a single cytokine can be responsible for directing tissue-specific pathology. Ongoing studies are now focused on downstream cytokine signaling pathways (e.g. IL-17, IL-22, IFN-γ) by which IL-23 mediates its proinflammatory effects and whether IL-23 plays a role in mediating anti leukemia effects. We are also focused on the role that regulatory T cells have in the modulation of the inflammation that occurs due to GVHD and whether these cells can be employed to prevent or attenuate GVHD-induced pathology.
Additional studies are being performed to examine strategies to modulate GVHD in order to reduce the severity of this complication without loss of the antileukemic (graft versus leukemia, GVL) effect that is conferred by the allogeneic graft and is one of the major mechanisms by which patients are cured of their underlying disease. We are using a novel mouse model that simulates human chronic myelogenous leukemia to examine strategies to enhance the GVL effect in the post transplantation period without escalating toxicity from GVHD. We are also employing biophotonic imaging to track and verify eradication of leukemia in our animal models. The overall goal of our studies is to employ cellular immunologic techniques along with standard and transgenic mouse models of stem cell transplantation to more fully understand the pathobiology of alloreactivity and, by extension, GVHD.