Eckhard R. Podack, M.D., Ph.D.
Professor and Chair of Microbiology & Immunology
Description of Research
Induction of Immunity by Heat Shock Protein gp96-Ig Heat shock protein gp96 is a natural adjuvant and a peptide chaperone binding to antigen presenting cells (APC) inducing APC activation and maturation, and channeling gp96-associated peptides into the Class I major histocompatability complex (MHC) presentation pathway for priming CD8 cytotoxic T lymphocyte (CTL) responses. Gp96 is unique in that it provides antigenicity and peptide-specificity through its peptide chaperone function and adjuvanticity through its ability to bind to scavenging receptors and toll-like receptors (TLRs) and to activate APC. Realizing the potential of gp96 as a vaccine, Dr. Podack’s laboratory had previously created a gp96-Ig fusion protein that is secreted from tumor cells upon transfection. In murine studies, tumor secreted gp96-Ig induced specific CD8 CTL expansion and, when used as a vaccine, mediated tumor rejection and long-lasting tumor immunity by CD8 cells with the help of natural killer (NK) cells. Murine preclinical data suggest that human tumor cells secreting gp96-Ig will be a powerful, therapeutic CD8 CTL vaccine, because gp96-Ig provides both the adjuvant effect and the specific peptides for dendritic cell (DC) activation and presentation. Tumor secreted gp96-Ig recruits and activates DC and NK cells, and causes CD8 CTL expansion. The molecular determinants of the three-way cell interaction are studied by Dr. Podack and his colleagues. The potential of gp96-Ig to break immune tolerance to tumors also is under investigation. In studies funded by independent resources, Dr. Podack recently performed an experiment with mice and the results were indicative that the combination of gp96 and oxygen as proposed in his clinical trial may also be successful in NSCL patients.
TNF Receptor Superfamily Member #25 and its Ligand TL1a Mediate TH2 Switch and Contribute to Asthma The biological function of TNFRSF25 (TNFR25), also known as death receptor-3 (DR3), is not known. TNFR25-transgenes expressed on T cells were used to determine the physiological function of TNFR25, a member of the tumor necrosis factor- (TNF) receptor family expressing an intracellular death domain. The full length form of TNFR25, a dominant negative form of TNFR25 (TNFR25-DN) lacking the intracellular death domain, and an alternatively spliced form of TNFR25 TNFR25-5, 6) lacking exon 5 and 6 encoding the fourth extracellular cysteine rich domain, were analyzed by Dr. Podack’s laboratory. Transgenic expression of TNFR25 on T cells mediated TH2 polarization of cytokine and antibody production upon T-cell activation and antigen exposure. Apparently TNFR25 signals may be important in effector responses to pathogens by shaping the ensuing polarization towards TH2 or towards a mixed TH1/TH2 response. TNFR25-transgenic mice were highly susceptible to antigen-induced airway hyper-reactivity in an asthma model in mice and produced increased quantities of interleukin-13 (IL-13) and eosinophils in the lung upon antigen exposure by inhalation. Transgenic mice expressing a dominant negative form of TNFR25 showed increased resistance to airway hyper-reactivity when compared to wild type (wt) mice. Similarly, a blocking anti TL1a antibody was able to ameliorate asthma in wt mice indicating that DR3 and TL1a are involved in the pathogenesis of asthma.
TL1A and TNFR25 are important components of the mucosal immune system. TL1A is highly expressed in the intestinal mucosa in Crohn’s disease, an autoimmune inflammatory bowel disease. In murine models anti-TL1A blocked development of inflammatory bowel disease indicating a critical role of this receptor ligand pair in the gut associated lymphoid compartment.
- Completed successful lung tumor vaccine trial.
- Discovered that Perforin-2, a new member of the Perforin family, promises interesting discoveries.
- Discovered that TNFRSF25 is a powerful regulator of T regulatory cells, in addition to elucidating the role of TL1A and TNFRSF25 as co-stimuli for conventional T cell responses.
- Realized the potential of heat shock proteins to enter the clinical field of immunotherapy using both cancer and HIV/SIV models of disease.
- Established NOD,SCID,γc-/- humanized mouse model system for the testing of gp96 mediated human vaccine responses.
Selected Cancer-Related Publications
- Podack ER. How to Polymerize in Order to Survive. Immunity 30:668-670, 2009. Read more »
- Schreiber TH, Deyev VV, Rosenblatt JD, Podack ER. Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination. Cancer Res 69:2026-33, 2009. Read more »
- Schreiber TH, Podack ER. A critical analysis of the tumour immunosurveillance controversy for 3-MCA-induced sarcomas. Br J Cancer 101:381-6, 2009. Read more »