Megan Sykes, MD
Major areas of focus in the Sykes lab include hematopoietic cell transplantation, organ allograft tolerance induction, xenotransplantation tolerance, and type 1 diabetes.
Dr. Sykes and her team have developed novel strategies for achieving graft-versus-tumor effects without graft-versus-host disease following hematopoietic cell transplantation (HCT). One strategy involved their observation that graft-vs-host (GVH) alloresponses can remain within the lymphohematopoietic system, where they mediate graft-vs-leukemia (GVL) responses, without accumulating in the epithelial target tissues where graft-versus-host disease (GVHD) occurs. They demonstrated a critical role of GVHD target tissue inflammation, such as that induced by toll-like receptor stimuli, in converting a beneficial "lymphohematopoietic GVH response" to GVHD. This control by inflammation is elicited at the level of access of activated GVH-reactive T cells to the GVHD target tissues. Clinical non-myeloablative HCT trials have been carried out on the basis of this approach to separate GVL from GVHD.
The Sykes lab has pioneered minimal conditioning approaches for using HCT to achieve allograft tolerance. These include monoclonal antibodies or costimulatory blockade to eliminate host resistance to engraftment of allogeneic and xenogeneic bone marrow cells, allowing creation of a mixed chimeric state, and with it the induction of specific transplantation tolerance. Studies to understand the mechanisms of peripheral tolerance of CD4 and CD8 T cells that encounter donor antigens on bone marrow cells in the presence of costimulatory blockade provided evidence that anergy precedes specific deletion of peripheral donor-reactive T cells, and this is followed by central deletional tolerance of donor-reactive T cells that develop after chimerism is established. Insights into the roles of PD-1, LAG-3, indirect presentation and various cell-cell interactions in the peripheral tolerance processes have been published by our group.
The safety and efficacy of the above clinical approach to separating GVHD and GVL, which also involved non-myeloablative induction of mixed chimerism across HLA barriers, allowed trials of HCT for the induction of organ allograft tolerance, intentionally achieving allograft tolerance in humans for the first time. The lab has analyzed the mechanism of this tolerance, which was achieved without GVHD, but with only transient chimerism. Our studies suggested that regulatory T cells (Tregs) were involved in the initial achievement of tolerance, but that either deletion or anergy is involved in the longer term. To distinguish between the latter two mechanisms, we recently developed a novel new generation sequencing-based approach to identify and track the entire TCR repertoire of donor-specific alloreactive T cells in human transplant recipients. These studies provided evidence for eventual clonal deletion of donor-specific T cell clones in tolerant patients, provided a new window into the fate of alloreactive T cells after transplant, and may provide a new, specific biomarker that is being explored in other transplant populations. Additionally, we are now able to probe and understand the human alloresponse at a new level. Major efforts in the lab include both pre-clinical and clinical studies of non-myeloablative hematopoietic cell transplantation to improve the induction of allograft tolerance and extend it to other graft types besides the kidney. In pre-clinical studies, we are using regulatory T cells to induce mixed chimerism and tolerance to donor kidney and islet allografts.
A more recent direction for the lab is the analysis of lymphocyte turnover, chimerism, and T cell trafficking in patients receiving intestinal and liver transplants. We have obtained surprising and novel insights into the exchange and origin of human lymphoid populations in the intestinal graft and the recipient and into the fate of alloreactive lymphocytes during rejection. We are using our new TCR tracking approach to understand the interplay of GVH and host-vs-graft alloresponses in these phenomena.
Because of the inadequate supply of human organs for transplantation and the strong immune response to xenografts, another major focus of work in the Sykes lab has been the induction of xenograft tolerance. Two approaches have been pioneered in the lab, namely the induction of mixed xenogeneic chimerism and xenogeneic thymic transplantation. The latter approach has led, for the first time, to long-term kidney xenograft survival in non-human primates. The same approach is being used for combined islet and kidney xenotransplantation. The lab is now focused on using humanized mice to study the impact of differentiation in a xenogeneic (porcine) thymus on T cell homeostasis and function. We have also demonstrated that mixed xenogeneic chimerism achieves natural killer cell and natural antibody-producing B cell tolerance, in addition to T cell tolerance, and we are focused on the mechanisms by which tolerance is achieved for these innate immune components.
More recently, the Sykes lab has extended the HCT approach to the problem of reversing autoimmunity while replacing destroyed islets of Langerhans in type 1 diabetes. We have developed novel "humanized mouse" models that allow personalized analysis of human immune disorders and therapies. These models are currently being used in studies of type 1 diabetes and rheumatoid arthritis pathogenesis using the "Personalized Immune" mouse.
Please see the Columbia Center for Translational Immunology (CCTI) website for more information.