Many of the most common autoimmune diseases result from T cell attacks via self-antigens expressed in specific organs. Likewise, in many cancers, it is common to identify T cells that recognize self-antigens over-expressed in tumor cells. Therefore, understanding the biological mechanisms that determine how self-peptide/MHC complexes drive the immune response of T cells, may help to uncover therapeutics for treating these devastating diseases. Dr. John Kappler, Distinguished Professor for National Jewish Health and the University of Colorado, Denver, studies the way in which T cells recognize self-antigens in order to translate fundamental research into translational projects that identify how T cells participate in a number of diseases. His knowledge and experience with how peptide and MHC complexes drive the immune response of T cells, allow him and his team to design novel ways to harness the immune system in the treatment of autoimmune diseases and cancer.

Recently awarded the Wolf Award alongside his wife and long term collaborator, Dr. Kappler is a leader in the field having contributed to seminal knowledge about T cells and the immune system. With over thirty years of experience in studying T cell receptor and MHC-peptide structure and function, Dr. Kappler and his team have accumulated a wide set of tools that allow them to address any aspect of this area -- all the way from the in vivo immune responses to the atomic x-ray structures of T cell receptors and MHC/peptide complexes. Their groundbreaking findings, including the discovery of the nature of T cell antigen receptor, the role of antigen processing in generating the peptides required for creating MHC/peptide complexes, and the phenomenon of thymic elimination of self-reactive T cells during T cell development, have helped them to develop tools that are now commonly used around the world to study these molecules. Thus, Dr. Kappler’s projects have taught the scientific community that the T cell branch of the immune system is exquisitely able to detect and respond to slight variants of self-antigens and that this knowledge can be used to develop strategies either to prevent or provoke immune responses to self-antigens.

Current research includes:

• Type-1 Diabetes (T1D): T1D is an autoimmune disease in which T cells infiltrate the pancreas and destroy the beta cells that produce insulin. Exactly how peptides from these proteins bind to self MHC, and why these peptide-MHC complexes do not eliminate the self-reactive T cells during thymic development has remained a mystery. Dr. Kappler and his team have identified the pathogenic peptides and shown that they bind very poorly to the relevant MHC molecules unless they have been chemically modified in a process that is unique to the pancreas. T cells specific for these peptides fail to find these peptide-MHC complexes in the thymus. They escape to encounter the modified self-peptides bound to MHC for the first time in the pancreas, thus initiating disease. Recently Dr. Kappler and his collaborators have been accumulating evidence that the same process occurs in the human disease that they have previously observed mouse models. His work has pointed to the possibility of prevention or treatment based on self-antigen therapy.

• Cancer Vaccines: The prospect of using the body’s immune system to fight cancer, first envisioned many decades ago, has been an elusive goal. In collaboration with others Dr. Kappler has taken the approach of creating a vaccine using a modified version of the tumor antigenic peptide that is much more effective than the natural one in eliciting an immune response from these T cells, driving them to a highly active differentiation state. These fully activated T cells can now destroy the tumor cells that express only the natural, unmodified tumor antigen. He and his team worked out the general principles for this approach in a mouse tumor model and are now involved in a multi-center program attempting to apply these methods to human lung and breast cancer. His work is not designed to replace any therapy, but by creating “super-agonist” peptides that strongly stimulate tumor specific T cells, he and his team hope to provide synergistic tools that can be combined with other therapies. The specific immune boosting effect of these peptides may mean that lower doses of the more toxic non-specific therapies can be used.