Dr. Sykes will give a Keynote address at this year's FOCIS meeting, being held June 20-23 at the San Francisco Marriott Marquis. Her presentation, Taming a Colossal Giant: The Human Allograft Response, will be Friday, June 22nd at 5:40 p.m.
Responses to allogeneic major histocompatibility antigens pose the single greatest barrier to allograft acceptance and promote severe graft-versus-host disease. Functional studies have estimated that 1 to 10% of a T cell repertoire recognizes an allogeneic donor’s HLA, making it a colossal giant that is difficult to control without paralyzing the entire immune system. Immune tolerance is the holy grail in transplantation, as it would avoid the many complications of long-term immunosuppressive therapy in organ allograft recipients. Dr. Sykes and her colleagues have achieved immune tolerance without GVHD using combined HLA-mismatched donor kidney and bone marrow transplantation (CKBMT) in a small group of patients. To understand the mechanism of tolerance, the Sykes lab developed a new strategy using high-throughput deep sequencing of TCRB chain CDR3s that provides a fingerprint of the donor-reactive T cell repertoire to track post-transplant. This method has allowed delineation of the role of gradual clonal deletion of donor-reactive T cells, combined with expansion of regulatory T cells, in the tolerance that develops in these patients. The lab has applied this technique to determine dynamics of graft-versus-host and host-versus-graft reactivity within the graft and systemically in recipients of intestinal transplants, demonstrating the interplay of these bidirectional alloresponses and their association with transplant outcomes. Studies in intestinal, kidney and liver transplant recipients are providing novel information on the localization of alloreactive T cells during rejection and establishment of tissue resident memory. Moreover, the lab has obtained new insights into the magnitude and character of the human alloresponse.