Pioneering a New Approach to Vaccines: Targeting Dendritic Cells

Steinman, Ralph

An antigen is a substance that stimulates immunity. It can be a bacterium, a pollen grain, or a protein on a pathogen. Vaccines work by presenting such antigens to the immune system in a way that elicits a long-lasting response without making a person sick. To do this, antigens must get into cells called dendritic cells—the sentinel cells of the immune system—which initiate the immune response and orchestrate later steps in the process. Rockefeller scientists led by Ralph Steinman (1943 - 2011) have unraveled many of the molecular details of how dendritic cells capture antigens, and they have introduced a new rational approach to developing vaccines that targets dendritic cells. The first of these vaccines to be tested in human subjects is aimed at HIV, the virus that causes AIDS, the immune disorder that has already killed 25 million people. Phase 1 clinical trials directed by Sarah Schlesinger (1960 - ) are under way at the Rockefeller Hospital.

Dendritic Cell from original description by Steinman and Cohn.

The Rockefeller Hospital has been at the center of dendritic cell research since the discovery of these cells by Steinman in 1973. Steinman and Rockefeller immunologist Michel Nussenzweig (1955 - ) later found a marker known as DEC-205 that is unique to dendritic cells. The vaccine created by Steinman’s group uses a monoclonal antibody against DEC-205 to deliver an HIV antigen called gag to immature dendritic cells. The cells also are targeted with a synthetic form of double-stranded RNA known as poly IC, which prompts the maturation of dendritic cells into their fully functional mature form. In experiments with mice, this approach enhanced the presentation of the antigen to the immune system, leading to a 100-fold increase in the immune response. The Steinman laboratory is using the same strategy to study potential vaccines against tuberculosis, malaria, Epstein-Barr virus, and other pathogens, as well as to combat cancer.

Ralph M. Steinman received the BS from McGill University (1963) and the MD from Harvard University (1968). He joined The Rockefeller University in 1970, after an internship and residency at Massachusetts General Hospital. He has remained at Rockefeller since then, becoming professor in 1988 and Henry G. Kunkel Professor in 1995. Steinman’s achievements have been recognized with, among others, the Gairdner Foundation International Award (2003) and the Albert Lasker Award for Basic Medical Research (2007). He is the recipient of four honorary degrees and has been elected to the U.S. National Academy of Sciences and its Institute of Medicine. Steinman also is an editor of the Journal of Experimental Medicine.

Schlesinger, Sarah

Sarah J. Schlesinger received the AB from Wellesley College (1981), spending her college summers doing research in the Steinman laboratory, and the MD from Rush Medical College (1985). After an internship at Albert Einstein College of Medicine, she took a residency at New York Hospital, where she later was selected to be chief resident in the department of pathology. In 1996, she became a research physician/pathologist in the division of retrovirology at the Walter Reed Army Institute of Research, and later worked as a scientist in vaccine research and design at the International AIDS Vaccine Initiative. In 2003, she returned to Rockefeller as a research associate professor and clinical director of the Steinman laboratory, with a joint appointment at the Aaron Diamond AIDS Research Center. She has been involved in the clinical trials of four HIV vaccines, including ADVAX and ADMVA. In 2007, Schlesinger became associate professor of clinical investigation at Rockefeller.

Selected Publications

Nussenzweig MC, Steinman RM, Witmer MD, and Gutchinov B. A monoclonal antibody specific for mouse dendritic cells. Proc Natl Acad Sci USA, 1982, 79: 161-165

Guo M, Gong S, Maric S, Misulovin Z, Pack M, Mahnke K, Nussenzweig MC, and Steinman RM. A monoclonal antibody to the DEC-205 endocytosis receptor on human dendritic cells. Hum Immunol, 2000, 61: 729-738

Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii SI, Soares H, Brimnes MK, Moltedo B, Moran TM, and Steinman RM. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med, 2004, 199: 815–824
http://jem.rupress.org/cgi/reprint/199/6/815

Boscardin SB, Hafalla JC, Masilamani RF, Kamphorst AO, Zebroski HA, Rai U, Morrot A, Zavala F, Steinman RM, Nussenzweig RS, and Nussenzweig MC. Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses. J Exp Med, 2006, 203: 599-606
http://jem.rupress.org/cgi/reprint/203/3/599

Trumpfheller C, Finke JS, López CB, Moran TM, Moltedo B, Soares H, Huang Y, Schlesinger SJ, Park CG, Nussenzweig MC, Granelli-Piperno A, and Steinman RM. Intensified and protective CD4+ T cell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine. J Exp Med, 2006, 203: 607-617
http://jem.rupress.org/cgi/reprint/203/3/599

Bozzacco L, Trumpfheller C, Siegal FP, Mehandru S, Markowitz M, Carrington M, Nussenzweig MC, Piperno AG, and Steinman RM. DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes. Proc Natl Acad Sci USA, 2007, 104: 1289-1294
http://www.pnas.org/content/104/4/1289.full.pdf+html

Trumpfheller C, Caskey M, Nchinda G, Longhi MP, Mizenina O, Huang Y, Schlesinger SJ, Colonna M, and Steinman RM. The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Aca. Sci USA, 2008, 105: 2574-2579
http://www.pnas.org/content/105/7/2574.full.pdf+html

Nchinda G, Kuroiwa J, Oks M, Trumpfheller C, Park CG, Huang Y, Hannaman D, Schlesinger SJ, Mizenina O, Nussenzweig MC, Uberla K, and Steinman RM. The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells. J Clin Invest, 2008, 118: 1427-1436
http://www.jci.org/articles/view/34224/pdf

S. Vasan, S.J. Schlesinger, Y. Huang, A. Hurley, A. Lombardo, Z. Chen, S. Than, P. Adesanya, C. Bunce, M. Boaz, R. Boyle, E. Sayeed, L. Clark, D. Dugin, C. Schmidt, Y. Song, L. Seamons, L. Dally, M. Ho, C. Smith, M. Markowitz, J. Cox, D.K. Gill, J. Gilmour, M. C. Keefer, P. Fast, D. D. Ho. Phase 1 Safety and Immunogenicity Evaluation of ADVAX, a Multigenic, DNA-based Clade C/B’ HIV-1 Candidate Vaccine PLOS One, 2010

S. Vasan, S. J. Schlesinger, Z. Chen, A. Hurley, A. Lombardo, S. Than, P. Adesanya, C. Bunce, M. Boaz, R. Boyle, E. Sayeed, L. Clark, D. Dugin, M. Boente-Carrera, C. Schmidt, Q. Fang, L. Ba, Y. Huang, G.J. Zaharatos, D.F. Gardiner, M. Caskey, L. Seamons, M. Ho, L.Dally, C. Smith, J. Cox, D.K. Gill, J. Gilmour, M.C. Keefer, P. Fast, D. D. Ho. Phase 1 Safety and Immunogenicity Evaluation of ADMVA, a Multigenic, Modified Vaccinia Ankara-HIV-1 B’/C Candidate Vaccine PLOS One, 2010

Further Reading

Bashyam H. Ralph Steinman: Dendritic cells bring home the Lasker. J Exp Med, 2007, 204: 2245-2248
http://jem.rupress.org/cgi/reprint/204/10/2245

Links

Ralph M. Steinman, Laboratory of Cellular Physiology and Immunology
http://www.rockefeller.edu/labheads/steinman/steinman-lab.php

Sarah J. Schlesinger, Research Affiliate
http://www.rockefeller.edu/research/resaff_schlesinger.php

2007 Lasker Award Description
http://www.laskerfoundation.org/awards/2007_b_description.htm

Sarah J. Schlesinger, Race for the Cure
http://bigthink.com/drsarahschlesinger/race-for-the-cure

In The Life
"Creating Solutions" Episode
http://www.inthelifetv.org/html/episodes/81.html