Molecular Microbiology & Immunology, Neurology
Keck School of Medicine
Research OverviewMolecular Immunology Approaches to Combat Disease
The major histocompatibility complex (MHC) control immune responsiveness and greatly affect many aspects of modern medicine. Understanding their action in molecular terms will lead to rational therapies to combat transplant rejection, autoimmune disease and cancer as well as the development of new vaccines to protect from viruses including HIV. MHC class I molecules associate with fragments or peptides derived from foreign, often viral, antigens and present them for recognition by membrane-bound T cell receptors (TCR) expressed on the surface of cytotoxic or helper T lymphocytes. This antigen-specific interaction initiates a cascade of events which results in the destruction of aberrant or infected cells. At present my research program comprises three projects - all focusing on MHC-TCR interactions.
We have used cassette mutagenesis to create class I molecules to study TCR recognition and have evidence that TCR recognition of foreign class I molecules(allorecognition), differs from viral-specific CTL recognition in that residues outside the cleft of class I molecules play a role in this interaction and that some alloreactive TCR are peptide-promiscuous not peptide-specific. We are presently generating hybrid TCRs with the goal of determining the geometry of TCR-class I interactions. The long term goal of this project is to understand the molecular basis of allograft rejection in order to design molecules to specifically combat graft destruction.
Vaccination has provided protection from many infectious diseases for centuries, and attenuated viruses are particularly effective at this. For protection from the HIV virus, similar approaches are not very appealing and are probably not practical. To overcome these problems, we have begun to design, DNA expression vectors containing the minimal information to elicit an immune response specific for HIV. Our results suggest that we can obtain a robust cellular and weak humoral response to an HIV-specific epitope (of gp120), encoded in ~200bp, and we are presently redesigning the molecule (by adding a T helper epitope) to produce a vigorous antibody response as well.
We are also using this mini-gene approach of using minimal sequences to modify the immune response to control autoimmune T cells. In this work, I have designed a mini-protein, derived from a membrane-bound myelin protein, which is secreted. In collaboration with Dr. Leslie Weiner and Dr. W. French Anderson we have used this mini-protein sequence in a gene therapy approach to treat mice with experimental autoimmune encephalomyelitis - the animal model for multiple sclerosis. Preliminary results are extremely promising and Dr. Weiner is most anxious to translate this methodology to the clinic for treatment of MS as soon as possible.
I also believe that we can extend the mini-gene approach to design agents which may well be effective at generating immune responses to malignancies and plan to pursue this idea in the future.