Victor H. Engelhard, PhD
T lymphocyte based immunity to antigens expressed on melanoma and other tumors
Our research centers on the structure and function of molecules encoded by the major histocompatibility complex (MHC). These cell surface molecules were discovered because they are recognized by the immune system during tissue graft rejection. However, their main function is to present peptide antigens produced from the degradation of proteins expressed in virally-infected and tumor cells to T lymphocytes. The expression of these antigens at the cell surface is critical in stimulating an immune response that results in the destruction of such cells. In collaboration with Dr. Donald Hunt in the Dept. of Chemistry, we have developed mass spectrometry approaches for the isolation and characterization of the complex mixture of peptides bound to MHC molecules. Using these techniques, we have defined a set of peptides that are recognized by T cells during immune reactions to human melanoma tumor cells. The melanoma peptides are now being used in clinical trials at UVA to develop therapeutic vaccines for melanoma. In addition, we are using transgenic mice that express human MHC molecules to model the human immune response to the melanoma peptides. This unique "preclinical" model is being used to systematically evaluate how changes in peptide structure, affinity, and mode of presentation influence the quality of the immune response generally, and its effectiveness against a modified murine melanoma. Finally, because many melanoma antigens are also expressed in normal tissue, this model allows us to evaluate the existence and impact of self-tolerance on effective anti-melanoma immune responses. Mass spectrometry is also being employed to identify peptide antigens that cause Graft-versus-host disease after bone marrow transplantation. These so-called minor histocompatibility antigens are poorly understood in terms of their origin, number, and role in this process. This work is expected to lead to the development of tools for screening donors and recipients prior to transplant, and also strategies to control transplant rejection. Finally, we are studying the mechanisms by which MHC-associated peptides are produced from the proteins that are made in cells. This work has established the existence of several different pathways by which such peptides are produced, although further work is needed to characterize them fully. We have also found that many peptides have undergone one of a set of post-translational modifications. These modifications not only provide insights into the mechanisms of peptide production, but also greatly influence the recognition of the peptides by the immune system. Collectively, work in the lab aims to provide a comprehensive understanding of how MHC-associated peptide antigens are produced, and how they can be used to ameliorate disease.