Thomas Kepler PhD
The Kepler laboratory develops computational tools and applies them in the context of systems-level experimentation to address outstanding questions in immunology and vaccine development. Much of their work is centered on antibodies and the cells (B cells) that produce them.
Antibodies are genetically extraordinary: their genes are encoded only as fragments in the genome. The B cell’s genome must be cut, rearranged and re-ligated in several places to make the genes required for antibody production. Furthermore, after a B cell has encountered a molecule that binds its antibody (whether on a pathogen, an infected cell, tumor, or, in the case of autoimmune disease, normal tissue) the B cell directs mutations into its rearranged antibody genes, and is then subject to competitive selection for improved ability to bind the eliciting molecule. In this Darwinian process, known as affinity maturation, the antibody response is rapidly improved and prepared as the memory response that confers long-term immunity and serves as the basis for vaccination.
The Kepler group works with multiple collaborating laboratories to generate and integrate data from many different assays, each of which provides one perspective on the workings of affinity maturation. By using computational means to coordinate the integration of these diverse data, a comprehensive picture of the process at a systems level emerges.
Professor Kepler, in partnership with colleagues at Duke and Harvard Universities, has developed a new approach to vaccination that uses computational methods to select combinations of immunogens to use in vaccines that drive affinity maturation in specific directions. These methods are being used to develop vaccines against HIV, influenza, and anthrax.
- Haynes BF, G Kelsoe, SC Harrison, TB Kepler (2012) B Cell Lineage Immunogen Design: A New Approach To Vaccine Development. Nat Biotech, 30: 423-433.
- Manolopoulou I, Matheu MP, Cahalan MD, West M, Kepler TB (2012) Bayesian spatio-dynamic modelling in cell motility studies: Learning nonlinear taxic fields guiding the immune response. J Am Stat Assoc, in press.
- Liao H-X, X Chen,S Munshaw, R Zhang, DJ Marshall, N Vandergrift, JF Whitesides, X Lu, J-S Yu, K-K Hwang, F Gao, M Markowitz, SL Heath, KJ Bar, PA Goepfert, DC Montefiori, GC Shaw, SM Alam, DM Margolis, TN Denny,SD Boyd, E Marshal, M Egholm, BB Simen, B Hanczaruk, AZ Fire, G Voss, G Kelsoe, GD Tomaras, MA Moody, TB Kepler, BF Haynes (2011) Initial antibodies binding to HIV-1 gp4 in acutely infected subjects are polyreactive and highly mutated. J Exp Med 208:2237-49.
- Munshaw S, TB Kepler (2010) SoDA2: A Hidden Markov Model Approach for Inference of Immunoglobulin Rearrangements. Bioinformatics 26:867-72.
- Ciupe SM, BH Devlin, ML Markert, TB Kepler (2009) The dynamics of T-cell receptor repertoire diversity following thymus transplantation for DiGeorge Anomaly. PLOS Comp. Biol. 5: e1000396