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Research Laboratories
Human Immunology Laboratory
Daniel Douek, M.D., MRCP, Ph.D.

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 NIH. 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:

1. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M and Roederer M. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 434:1093-1097(2005).

2. Wooldridge L, van den Berg HA, Glick M, Gostick E, Laugel B, Hutchinson SL, Milicic A, Brenchley JM, Douek DC, Price DA and Sewell AK. Interaction between the CD8 coreceptor and MHC class I stabilizes TCR-antigen complexes at the cell surface. JBiolChem (2005).

3. Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani-Ingoni R, Campbell C, Memon S, Nagle JW, Hakim FT, Gress RE, McFarland HF, Burt RK and Martin R. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. JExpMed 201:805-816(2005).

4. Laugel B, Boulter JM, Lissin N, Vuidepot A, Li Y, Gostick E, Crotty LE, Douek DC, Hemelaar J, Price DA, Jakobsen BK and Sewell AK. Design of soluble recombinant T cell receptors for antigen targeting and T cell inhibition. JBiolChem 280:1882-1892(2005).

5. Casazza JP, Betts MR, Hill BJ, Brenchley JM, Price DA, Douek DC and Koup RA. Immunologic pressure within class I-restricted cognate human immunodeficiency virus epitopes during highly active antiretroviral therapy. JVirol 79:3653-3663(2005).

6. 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 and Douek DC. T Cell receptor recognition motifs govern immune escape patterns in acute SIVInfection. Immunity 21:793-803(2004).

7. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT and Douek DC. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. JExpMed 200:749-759(2004).

8. Lee JK, Stewart-Jones G, Dong T, Harlos K, Di Gleria K, Dorrell L, Douek DC, van der Merwe PA, Jones EY and McMichael AJ. T cell cross-reactivity and conformational changes during TCR engagement. JExpMed 200:1455-1466(2004).

9. Douek DC. Thymic output and HIV infection: on the rightTREC. Immunity 21:744-745(2004).

10. Stebbing J, Gazzard B and Douek DC. Where does HIV live. NEnglJMed 350:1872-1880(2004).

11. Betts MR, Price DA, Brenchley JM, Lore K, Guenaga FJ, Smed-Sorensen A, Ambrozak DR, Migueles SA, Connors M, Roederer M, Douek DC and Koup RA. The functional profile of primary human antiviral CD8+ T cell effector activity is dictated by cognate peptide concentration. JImmunol172:6407-6417(2004).

12. Crawford MP, Yan SX, Ortega SB, Mehta RS, Hewitt RE, Price DA, Stastny P, Douek DC, Koup RA, Racke MK and Karandikar NJ. High prevalence of autoreactive, neuroantigen-specific CD8+ T cells in multiple sclerosis revealed by novel flow cytometricassay. Blood 103:4222-4231(2004).

13. Brenchley JM, Hill BJ, Ambrozak DR, Price DA, Guenaga FJ, Casazza JP, Kuruppu J, Yazdani J, Migueles SA, Connors M, Roederer M, Douek DC and Koup RA. T-cell subsets that harbor human immunodeficiency virus (HIV) in vivo: implications for HIV pathogenesis. JVirol 78:1160-1168(2004).

14. Fujiwara H, El Ouriaghli F, Grube M, Price DA, Rezvani K, Gostick E, Sconocchia G, Melenhorst J, Hensel N, Douek DC and Barrett AJ. Identification and in vitro expansion of CD4+ and CD8+ T cells specific for human neutrophilelastase. Blood 103:3076-3083(2004).

15. Rezvani K, Grube M, Brenchley JM, Sconocchia G, Fujiwara H, Price DA, Gostick E, Yamada K, Melenhorst J, Childs R, Hensel N, Douek DC and Barrett AJ. Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem celltransplantation. Blood 102:2892-2900(2003).

16. Douek DC, Picker LJ and Koup RA. T cell dynamics in HIV-1 infection. AnnuRevImmunol 21:265-304(2003).

17. Lederman MM and Douek DC. Sometimes help may not be enough. AIDS 17:1249-1251(2003).

18. Michalek J, Collins RH, Durrani HP, Vaclavkova P, Ruff LE, Douek DC and Vitetta ES. Definitive separation of graft-versus-leukemia- and graft-versus-host-specific CD4+ T cells by virtue of their receptor beta loci sequences. Proc Natl AcadSciUSA 100:1180-1184(2003).

19. Michalek J, Collins RH, Hill BJ, Brenchley JM and Douek DC. Identification and monitoring of graft-versus-host specific T-cell clone in stem cell transplantation. Lancet 361:1183-1185(2003).

20. Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, Casazza JP, Kuruppu J, Migueles SA, Connors M, Roederer M, Douek DC and Koup RA. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ Tcells. Blood 101:2711-2720(2003).

21. Wu CY, Kirman JR, Rotte MJ, Davey DF, Perfetto SP, Rhee EG, Freidag BL, Hill BJ, Douek DC and Seder RA. Distinct lineages of T(H)1 cells have differential capacities for memory cell generation in vivo. NatImmunol 3:852-858(2002).

22. 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 and Koup RA. HIV preferentially infects HIV-specific CD4+ Tcells. Nature 417:95-98(2002).

23. Douek DC, Betts MR, Brenchley JM, Hill BJ, Ambrozak DR, Ngai KL, Karandikar NJ, Casazza JP and Koup RA. A novel approach to the analysis of specificity, clonality, and frequency of HIV-specific T cell responses reveals a potential mechanism for control of viral escape. JImmunol 168:3099-3104(2002).

24. Brenchley JM, Douek DC, Ambrozak DR, Chatterji M, Betts MR, Davis LS and Koup RA. Expansion of activated human naive T-cells precedes effector function. ClinExpImmunol 130:432-440(2002).

25. Bitmansour AD, Douek DC, Maino VC and Picker LJ. Direct ex vivo analysis of human CD4(+) memory T cell activation requirements at the single clonotype level. JImmunol 169:1207-1218(2002).

26. Okamoto Y, Douek DC, McFarland RD and Koup RA. Effects of exogenous interleukin-7 on human thymusfunction. Blood 99:2851-2858(2002).

27. Weinberg K, Blazar BR, Wagner JE, Agura E, Hill BJ, Smogorzewska M, Koup RA, Betts MR, Collins RH and Douek DC. Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 97:1458-1466(2001).

28. Douek DC, Betts MR, Hill BJ, Little SJ, Lempicki R, Metcalf JA, Casazza J, Yoder C, Adelsberger JW, Stevens RA, Baseler MW, Keiser P, Richman DD, Davey RT and Koup RA. Evidence for increased T cell turnover and decreased thymic output in HIV infection. JImmunol 167:6663-6668(2001).

29. Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, Berenson JR, Collins RH and Koup RA. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355:1875-1881(2000).

30. Douek DC and Altmann DM. T-cell apoptosis and differential human leucocyte antigen class II expression in human thymus. Immunology 99:249-256(2000).

31. McFarland RD, Douek DC, Koup RA and Picker LJ. Identification of a human recent thymic emigrant phenotype. Proc Natl AcadSciUSA 97:4215-4220(2000).

32. Douek DC, Koup RA, McFarland RD, Sullivan JL and Luzuriaga K. Effect of HIV on thymic function before and after antiretroviral therapy in children. JInfectDis 181:1479-1482(2000).

33. Markert ML, Boeck A, Hale LP, Kloster AL, McLaughlin TM, Batchvarova MN, Douek DC, Koup RA, Kostyu DD, Ward FE, Rice HE, Mahaffey SM, Schiff SE, Buckley RH and Haynes BF. Transplantation of thymus tissue in complete DiGeorge syndrome. NEnglJMed 341:1180-1189(1999).

34. Jamieson BD, Douek DC, Killian S, Hultin LE, Scripture-Adams DD, Giorgi JV, Marelli D, Koup RA and Zack JA. Generation of functional thymocytes in the human adult. Immunity 10:569-575(1999).

35. Nixon DF, Douek DC, Kuebler PJ, Jin X, Vesanen M, Bonhoeffer S, Cao Y, Koup RA, Ho DD and Markowitz M. Molecular tracking of an Human Immunodeficiency Virus nef specific cytotoxic T-cell clone shows persistence of clone-specific T-cell receptor DNA but not mRNA following early combination antiretroviral therapy. ImmunolLett 66:219-228(1999).

36. 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 and Koup RA. Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690-695(1998).

37. Douek DC and Altmann DM. HLA-DO is an intracellular class II molecule with distinctive thymic expression. IntImmunol 9:355-364(1997).

38. Douek DC, Corley KT, Zal T, Mellor A, Dyson PJ and Altmann DM. Negative selection by endogenous antigen and superantigen occurs at multiple thymic sites. IntImmunol 8:1413-1420(1996).

39. Birk OS, Douek DC, Elias D, Takacs K, Dewchand H, Gur SL, Walker MD, van der Zee R, Cohen IR and Altmann DM. A role of Hsp60 in autoimmune diabetes: analysis in a transgenic model. Proc Natl AcadSciUSA 93:1032-1037(1996).

40. Altmann DM, Douek DC, Frater AJ, Hetherington CM, Inoko H and Elliott JI. The T cell response of HLA-DR transgenic mice to human myelin basic protein and other antigens in the presence and absence of human CD4. JExpMed 181:867-875(1995).

41. Altmann DM, Lider O, Douek DC and 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).