Daniel Douek, M.D., MRCP, Ph.D.
Human Immunology Section
Description of Research Program
The Human Immunology Section studies the processes that determine the course of human diseases in which the immune system, particularly its T cell arm, plays a central role in their pathogenesis and outcome. Furthermore, our aim is to use the knowledge gained through these studies to initiate clinical studies of new therapeutic and vaccine approaches. Our overriding philosophy is to address questions of human disease directly in humans, with as little in vitro manipulation as possible, using state-of-the art technologies to measure a multitude of different parameters.
Our studies of HIV explore the mechanisms by which CD4 T cells are depleted, appreciating that there are likely to be many such mechanisms which operate with varying predominance at different stages of infection from the acute phase through to AIDS. A major aspect of these studies is to examine the roles of target cell type and availability, direct infection, chronic immune activation, and lymphoid tissue architectural integrity. Our findings have led to a new understanding of the timing, extent, and anatomical distribution of CD4 T cell depletion in HIV infection, which we believe will result in novel therapeutic and vaccine approaches to treatment of exposed and infected individuals, and they also highlight the anatomical sites where first-line prophylactic vaccines would need to be effective. Furthermore, we are pursuing studies of therapeutic agents that we hope will improve immune reconstitution once HIV-infected individuals are treated with antiretroviral drugs.
Another aspect of our work in HIV infection involves analysis of the clonal composition of CD8 T cells that respond to HIV. Escape from adaptive T cell immunity through viral epitope mutation is considered to be a major obstacle to the development of vaccines that aim to elicit cellular immunity. We are thus investigating the molecular determinants of this phenomenon at the level of the T cell receptor–epitope contact interface, and defining structural motifs that govern the pace and pattern of epitope escape. The practical consequences of our findings suggest that vaccine strategies should elicit responding T cells that are qualitatively superior, in terms of clonotypic composition, to those elicited in natural infection.
We also have an interest in hematological malignancies, such as chronic myeloid leukemia, that we pursue in collaboration with other investigators at the National Institutes of Health. Our studies aim to characterize the origin, activity, and functional properties of leukemia antigen-specific T cell clones and GVH-associated T cell clones in transplant recipients.
Selected Publications
Venturi V, Quigley MF, Greenaway HY, Ng PC, Ende ZS, McIntosh T, Asher TE, Almeida JR, Levy S, Price DA, Davenport MP and Douek DC. A Mechanism for TCR Sharing between T Cell Subsets and Individuals Revealed by Pyrosequencing. J Immunol 186:4285-4294 (2011).
Sandler NG, Wand H, Roque A, Law M, Nason MC, Nixon DE, Pedersen C, Ruxrungtham K, Lewin SR, Emery S, Neaton JD, Brenchley JM, Deeks SG, Sereti I and Douek DC. Plasma Levels of Soluble CD14 Independently Predict Mortality in HIV Infection. J Infect Dis 203:780-790 (2011).
Sandler NG, Koh C, Roque A, Eccleston JL, Siegel RB, Demino M, Kleiner DE, Deeks SG, Liang TJ, Heller T and Douek DC. Host Response to Translocated Microbial Products Predicts Outcomes of Patients with HBV or HCV infection. Gastroenterology 114: 1220-1230 (2011).
Scheinberg P, Melenhorst JJ, Brenchley JM, Hill BJ, Hensel NF, Chattopadhyay PK, Roederer M, Picker LJ, Price CA, Barrett AJ, Douek DC. The transfer of adaptive immunity to cytomegalovirus (CMV) during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor. Blood. 114:5071-5080 (2009).
Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, Scheinberg P, Price DA, Hage CA, Kohli LM, Khoruts A, Frank I, Else J, Schacker T, Silvestri G, Douek DC. Differential Th17 CD4 T cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood. 112:2826-2835 (2008).
Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C. Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O’Shea J, Holland SM, Paul WE, Douek DC. Impaired Th17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. 452:773-776 (2008).
Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 12:1365-1371 (2006).
Price DA, Brenchley JM, Ruff LE, Betts MR, Hill BJ, Roederer M, Koup RA, Migueles S, Gostick E, Wooldridge L, Sewell AK, Connors M, Douek DC. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J Exp Med. 202:1349-1361 (2005).
Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 434:1093-1097 (2005).
Price DA, West SM, Betts MR, Ruff LE, Brenchley JM, Ambrozak DR, Edghill-Smith Y, Kuroda MJ, Bogdan D, Kunstman K, Letvin NL, Franchini G, Wolinsky SM, Koup RA, Douek DC. T Cell receptor recognition motifs govern immune escape patterns in acute SIV Infection. Immunity. 21:793-803 (2004).
Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, Douek DC. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 200:749-759 (2004).
Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, Casazza JP, Kuruppu J, Kunstman K, Wolinsky S, Grossman Z, Dybul M, Oxenius A, Price DA, Connors M, Koup RA. HIV preferentially infects HIV-specific CD4+ T cells. Nature. 417:95-98 (2002).
Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, Berenson JR, Collins RH, Koup RA. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet. 355:1875-1881 (2000).
Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA. Changes in thymic function with age and during the treatment of HIV infection. Nature. 396:690-695 (1998).
Douek DC, Altmann DM. HLA-DO is an intracellular class II molecule with distinctive thymic expression. Int Immunol. 9:355-364 (1997).
Altmann DM, Lider O, Douek DC, Cohen IR. Activation of specific T cell lines by the antigens avidin and myelin basic protein in the absence of antigen-presenting cells. Eur J Immunol. 17:1635-1640 (1987).
If you are interested in a Research Fellowship, please send your CV to:
Daniel Douek, M.D., MRCP, Ph.D.
Vaccine Research Center
Building 40, Room 3504
40 Convent Drive
Bethesda, MD 20892-3022
Phone: 301-594-8484
Fax: 301-480-2779
ddouek@mail.nih.gov
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