Infectious Diseases
Research in this laboratory is focused on achieving an understanding of the immune response by measuring immune activity to develop disease intervention strategies against a number of new and emerging infectious diseases, including influenza virus, SARS, arena viruses, and variola virus the agent of smallpox.
Our goals are to investigate and determine cytotoxic and helper T cell epitopes derived from these infectious agents and presented by murine, non-human primate and human MHC molecules. To accomplish these goals the team is using a multidisciplinary approach based on genome wide scanning of the viruses genome, high throughput binding assays utilizing purified MHC molecules, in vitro cellular assays and in vivo assays, as feasible and appropriate. The identification and characterization of cytotoxic and helper T cell epitopes is key to the development of diagnostic reagents necessary to rigorously evaluate T cell responses associated with infection in humans, and also enable the evaluation, at the level of T cell immunity, of the performance of different vaccine candidates.
The concept of HLA supertypes and its implications for epitope identification
T cells recognize a complex between a specific MHC type and a particular pathogen-derived epitope. Thus, a given epitope will elicit a response only in individuals that express an MHC molecule capable of binding that particular epitope. MHC molecules are extremely polymorphic, with several hundred different variants known in humans. Therefore, selecting multiple peptides with different MHC binding specificities will afford increased coverage of the patient population targeted as vaccine recipient. However, the issue of population coverage in relation to MHC polymorphism is further complicated by the fact that different MHC types are expressed at dramatically different frequencies in different ethnicities. Thus, without careful consideration, a vaccine with ethnically biased population coverage could result in decreased efficacy. One means of circumventing the problem of MHC restriction in the study of immune responses in humans to infections and vaccination relies on the selection of epitopes restricted by MHC types that can be grouped in broad families or supertypes. These supertypes are characterized by largely overlapping peptide repertoires and expressed at high frequencies in all major ethnicities. Specifically, by targeting the A1, A2, A3 and A24 supertypes, population coverage in excess of 90% can be achieved, irrespective of the ethnicity of the target population. Inclusion of the B7 and B44 supertypes allows coverage of virtually 100% of the population.
A number of studies have shown that 85 to 100% of peptides which bind multiple HLA molecules with high affinity are recognized by recall responses detected in Peripheral Blood Mononuclear Cells (PBMC) from immune or infected individuals. Recognition by memory recall responses demonstrates that the epitope is not only generated in vivo in the course of natural infection, but also that a TCR repertoire exists which is capable of recognizing that particular epitope.