David Lewinsohn, M.D., Ph.D.

Biography
After receiving his B.S. in biology from Haverford College, David Lewinsohn attended Stanford University School of Medicine. In 1989 he received his Ph.D. in cancer biology and received his M.D. the same year. Dr. Lewinsohn was a Fellow of Pulmonary and Critical Care Medicine at the University of Washington, Seattle, WA, from 1993-1996, and a senior fellow and acting instructor from 1996-1998. During 1996-1998 he was also an investigator at the Infectious Disease Research Insititute in Seattle, WA. At present, he is adjunct Assistant Professor at the OHSU Department of Molecular Microbiology and Immunology, an Assistant Professor in Pulmonary and Critical Care Medicine at the Portland VA Medical Center, Portland, OR, and an Assistant Scientist at the Vaccine and Gene Therapy Institute.

Research Overview
Tuberculosis is the leading single cause of infectious disease mortality worldwide. Immunity to tuberculosis depends upon the cellular immune system. Hence, developing an improved vaccine will require an understanding of the mechanisms by which T cells recognize cells infected with the bacterium Mycobacterium tuberulosis (Mtb). Because Mtb is a facultative intracellular pathogen, cytotoxic cells may be important in the recognition and elimination of infected cells. My laboratory has used Mtb-infected peripheral blood-derived dendritic cells (DC) to elicit human CD8+ T cells capable of lysing cells infected with Mtb. The long term objectives of the laboratory are to investigate the basic cellular and molecular mechanisms of human CD8+ T cell responses to tuberculosis infection. These T cells recognize antigen in the context of a "restricting molecule", so that understanding the nature of this restriction may aid in designing effective vaccine strategies. Recently, we have characterized CD8+ T cells that are non-classically restricted in that they are neither HLA-A-, B-, or C-restricted, nor do they appear to utilize molecule CD1. At present, little is known about the relative contribution of each of these restriction specificities in the overall CD8+ response to Mtb. In order to determine the precursor frequencies of classically, CD1, and non-classically restricted cells, an ELISPOT-based limiting dilution analysis is underway. In one PPD+ subject, the majority of the Mtb-specific CD8+ T cells were non-classically restricted, while a minority were classically HLA-restricted. Using T cell clones derived from this approach, areas of active investigation in the laboratory include defining the molecular requirements for non-classical antigen presentation, defining antigens recognized by Mtb-specific CD8+ T cells, and defining the pathway by which Mtb-derived proteins gain access to the HLA class I processing pathway. It is hoped that this work may aid development of an effective vaccine against tuberculosis.

Selected References:

Lewinsohn, D. M., L. Zhu, V. J. Madison, D. C. Dillon, S. P. Fling, S. G. Reed, K. H. Grabstein, and M. R. Alderson. 2001. Classically restricted human CD8+ T lymphocytes derived from Mycobacterium tuberculosis-infected cells: definition of antigenic specificity. J. Immunol. 166:439.

Lewinsohn, D. M., A. L. Briden, S. G. Reed, K. H. Grabstein, and M. R. Alderson. 2000. Mycobacterium tuberculosis-reactive CD8+ T lymphocytes: the relative contribution of classical versus nonclassical HLA restriction. J. Immunol. 165:925.

Tomazin, R., J. Boname, N. R. Hegde, D. M. Lewinsohn, Y. Altschuler, T. R. Jones, P. Cresswell, J. A. Nelson, S. R. Riddell, and D. C. Johnson. 1999. Cytomegalovirus US2 destroys two components of the MHC class II pathway, preventing recognition by CD4+ T cells. Nat. Med. 5:1039.

Lewinsohn, D. M., T. T. Bement, J. Xu, D. H. Lynch, K. H. Grabstein, S. G. Reed, and M. R. Alderson. 1998. Human purified protein derivative-specific CD4+ T cells use both CD95-dependent and CD95-independent cytolytic mechanisms. J. of Immunol. 160:2374.

Lewinsohn, D. M., M. R. Alderson, A. L. Briden, S. R. Riddell, S. G. Reed, and K. H. Grabstein. 1998. Characterization of human CD8+ T cells reactive with Mycobacterium tuberculosis-infected antigen-presenting cells. J. Exp. Med. 187:1633.

A more complete listing of publications by Dr. Lewinsohn is available from the National Library of Medicine [PubMed]