Research Highlights
T Cell Gene Encoding
Mark Davis, PhD, professor of microbiology & immunology, played a key role in isolating the gene coding for part of the T cell receptor, a key to the immune system's functions. The discovery brings scientists closer to the goal of developing vaccines to fight cancer.
Immunology, especially as it relates to the role of T cells and antigen-presenting cells, has been an important area of research at Stanford for many years. Of the many discoveries credited to our faculty, a significant number of them have elucidated the interactions between the immune system and tumors, laying the foundation for new ways to induce clinically effective anti-tumor immunity.
- Discovery and characterization of genes encoding the T cell receptor for antigen. T cells recognize antigens with exquisite specificity on the basis of their molecular features, and they accomplish this through unique clonally expressed receptor structures on their surface. The discovery and characterization of the first T cell receptor for antigen genes by Dr. Davis has made it possible to gain critical insights into the mechanisms by which T cells recognize and respond to antigens, including tumor associated antigens (Nature 308:149, 1984, Nature 308:153, 1984, Nature 312:31 1984, Nature 434:238, 2005).
- Development of peptide/MHC reagents for staining and characterizing tumor specific T cells. The development of these critical reagents by Dr. Davis and colleagues has enabled for the first time the ability to identify, quantify, isolate and characterize antigen specific T cells (Science 274:94, 1996). Moreover, utilizing these reagents in cellular microarrays (1 :309 PLOS 2003, PLOS MED, 2005 in press) offers the potential to analyze the immune response to cancer in far greater depth than previously possible.
- Structure-based discovery and development of therapeutic entry points for the antagonism of cytokine interactions with their receptors. Cytokines are growth factors which play a key role in the proliferation of cancer cells through interactions with cell surface receptors. Dr. Garcia has determined crystal structures of the cytokines Interleukin-2 (Science 308:1477, 2005), Interleukin-6 (Science 300:2101, 2003), and Leukemia Inhibitory Factor (Molecular Cell 12:577, 2003) complexed with their receptors as a means of identifying structural elements that can be targeted for protein engineering and/or drug design. Collaborations are being formed with clinically-based colleagues to facilitate the translational potential of these experiments.
- Development of the fluorescence activated cell sorter. As the "father of flow cytometry" Dr. Leonard Herzenberg conceived the need for this instrument in the early 1960s and oversaw its development and continuous refinement over the years. When used in combination with fluorochrome coupled monoclonal antibodies, this instrument allows for the identification and isolation of cells based on their surface or intracellular phenotype. FACS based sorting and analysis is widely used by immunologists and cell biologists and represents a critical resource for virtually all of the studies performed in this Program (Science 166:747, 1969, Clin Chem 19:813, 1973, Clin Chem 48:1819, 2002).
- Development of protein and lipid microarrays for profiling antibody responses in disease. Dr. Robinson and colleagues were the first to use microarrays to profile anti-protein and anti-lipid antibody responses in patients with immune disorders and use this information to assess clinical prognosis and predict response to therapeutic intervention (Nature Medicine 8:295, 2002, Nature Medicine, in press 2005).
- Development of dendritic cell (DC) based vaccines for the treatment of cancer. The first DC vaccine based trial in humans was carried out by Dr. Engleman in collaboration with Dr. Levy (Program 6) in patients with malignant lymphoma who had failed to respond to conventional chemotherapy. This small study, together with several later studies in patients with a wide variety of solid tumors, demonstrated that syngeneic DCs loaded with tumor associated antigen can overcome immune tolerance and induce systemic anti-tumor immunity and, in some patients, regression of existing tumors (Nature Med 2:52, 1996, Proc. Natl. Acad. Sci. USA 98:8809, 2001, Science Stke pe28, 2004, J. Immunol 174:2645, 2005). The potential to harness the immune stimulating properties of DCs provides the basis for one of the key objectives of this program.
- Discovery and characterization of homing receptors and specific vascular ligands that control access of leukocytes to specific tissues. Dr. Butcher and his colleagues were the first to propose a combinatorial model of multi-step leukocyte trafficking, and have shown that lymphocyte trafficking is determined by the association and sequential operation of adhesion and chemoattractant receptors that control the multi-step processes of lymphocyte homing, chemotactic navigation, and cell-cell interactions within tissues (Science 272:60, 1996, Science 279:381, 1998, Immunity 16:1, 2002).
- Discovery of a gene that controls T cell anergy. Most cancers consist exclusively of self antigens that are only weakly immunogenic due to both deletion of autoreactive T cells in the thymus and peripheral tolerance. Understanding the molecular basis of anergy and tolerance should ultimately lead to the discovery of ways to overcome tolerance and greatly enhance anti-tumor immunity. Dr. Fathman's laboratory has recently discovered a gene in T cells, known as GRAIL, which appears to be a key determinant of T cell anergy (Immunity 18:535, 2003, J Immunol, 173: 79-85 2004, Nature Immunol 5:45, 2004). Understanding the molecular mechanisms by which GRAIL controls the anergic state could lead eventually to a breakthrough in tumor immunotherapy.
- Discovery and characterization of the CD5/Ly1 population of B cells. Dr. Leonore Herzenberg identified this new population of B cells and showed that they follow different rules of differentiation than conventional B cells. Their role in the pathogenesis of chronic lymphocytic leukemia as well as autoimmune diseases is an indication of their potential importance in anti-tumor immunity (J Exp Med 157:202, 1983, Proc Natl Acad Sci USA 81:2494, 1984, Immunol Rev 93:81, 1986, Immunol Rev 175:9-22, 2000, Proc Natl Acad Sci USA. 99:3007, 2002).
- Identification of the structural basis for differences in antigen recognition and signaling by g d T cells. Dr. Chien showed that g d T cell receptors and a b T cell receptors have profound differences in their antigen recognition requirements (Cell 76:29, 1994). Recently her group has identified the first natural ligand for these cells and together with Dr. Garcia, Dr. Chien has characterized the recognition determinants of gamma,delta T cell receptors (Science 308:252, 2005, Science 308:227, 2005).
- Discovery of the role of mast cells in innate immunity and development of methods for producing pure populations of mast cells and studying their functions in vivo . Dr. Galli has pioneered the discovery and development of reagents allowing for the direct study of Mast cells and their soluble products. Heretofore these cells were thought to be involved only in the pathogenesis of allergic diseases but new data indicate these cells are a source of both pro-inflammatory cytokines as well as chemokines and growth factors, including VEGF (Nature 346:274, 1990, J Exp Med 170:245, 1989, J Exp Med 188:1135, 1998, Proc Natl Acad Sci USA 102:6467, 2005, Blood. Jun 21, 2005 [Epub ahead of print]) doi:10.1182/blood-2005-04-1568).
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