Area of interest
The goal of our lab is to discover new leukemia antigens and develop methods for analyzing their ability to induce an immune response.
Minor histocompatibility antigens (mHAgs) are thought to play a significant role in donor-derived immunity in the setting of allogeneic transplant. The antigens result from the genetic differences, or cSNPs, between the donor and patient. If the donors immune system has never been exposed to a peptide antigen containing the patients cSNP the donors immune system can recognize the patients cSNP as foreign and mount an immune response. By applying this general concept, we have been able to identify 2 new mHAgs through a relatively fast multi-step screening process. While the process involves 4 steps 1) collecting a large cohort of donor and matched patient DNA samples, 2) ranking cSNP differences with respect to patient outcomes, 3) predicting antigens using binding algorithm software, 4) confirming mHAg-specific T cells in posttransplant patients using tetramers, the overall process is far faster and less expensive than traditional mHAg discovery methods. Our aim will be to use this general approach to identify mHAgs that are derived from hematopoietically restricted genes or genes expressed in leukemia stem cells. To do this we will use the same DNA samples in the original study, but will perform deep resequencing at the genes of interest to identify cSNP disparities associated with an immune response.
Additional studies will be performed to characterize the immune responses elicited by the mHAgs discovered. The first mHAg discovered in our initial study, T4A, has several characteristics that make it a good candidate antigen for targeted immunotherapy. The source protein, TRIM42, is present in leukemia, but not normal granulocytes. Apart from hematopoietic tissue, TRIM42 mRNA is only detectable in testis suggesting that the T4A epitope may not confer significant graft versus host disease. Our lab will investigate the biological function of TRIM42 in hematopoietic development and leukemogenesis. In collaboration with Dr. Glish and Dr. Jorgenson in the Department of Chemistry, we will also work on new HPLC/MS based methodologies to confirm the presence of the T4A peptide on leukemia, and hopefully discover other leukemia-associated antigens. We will also work on developing new assays to measure T4A mediated cytotoxicity using micropallet technology developed in the laboratory of Dr. Nancy Allbritton. By using these assays we hope to be able to simultaneously assess antigen-specific T cell number and their ability to kill antigen-presenting targets with subsequent single-cell cloning of the most active cytotoxic T cells. These studies will hopefully lead to the identification and characterization of new immune targets in leukemia.
Awards and Honors
1991-1995 Morehead Scholar, University of North Carolina at Chapel Hill, NC
1992 Phi Eta Sigma
1995 Phi Beta Kappa
1996-1997 Sarah Kenan Merit Scholar, University of North Carolina School of Medicine at Chapel Hill, NC
1998 MitchikoKuno Research Award, University of North Carolina at Chapel Hill, NC
2001 Alpha Omega Alpha
2005 Tufts Excellence in Teaching Award, Brigham and Womens Hospital, Boston MA.
2008 Presenter MD Anderson Hematology/Oncology Fellwoship Research Forum, Houston TX