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Steven D. Douglas, MD
Professor of Pediatrics
Children's Hospitalof Philadelphia

Office Phone: 215 590-1978
Office Fax: 215 590-3044
Email: douglas@email.chop.edu
Website(s):

Education: MD 1963, Cornell University Medical College

Keywords: Substance P, HIV Cellular Immunology in Adolescents and Children

Research and/or Clinical Interests:
To study the interaction between the immune system and the nervous system by examining the role of the neuropeptide SP, and its receptor (NK-1R), in the immunopathogenesis of HIV infection and AIDS, in order to determine how the SP-NK-1R pathway operates as a central mediator in these pathways.

To study the virologic and immunologic effects of HAART , interleukin-1, immune reconstitution in adolescents, novel antiretroviral combinations in infants, children and adolescents, and to develop preventive and therapeutic HIV vaccines.

Summary:
The neuropeptide substance P (SP), the most abundant neurokinin in the CNS, is an important modulator of neuroimmunoregulation. We have demonstrated that HIV-infected subjects, both men and women, have increased levels of circulating SP in comparison to uninfected subjects. A possible cellular source of the increased circulating plasma SP is HIV-infected immune cells, including monocytes, macrophages and lymphocytes. SP enhances HIV replication in human blood isolated mononuclear phagocytes. HIV reciprocally enhances SP expression in human immune cells eliciting a "feed forward cycle". This effect is in part mediated by down-regulation of the CCR5 chemokine receptor. The SP receptor (NK-1R) facilitates HIV entry into macrophages. The nonpeptide SP antagonist (CP-96,345) blocked HIV infection of macrophages in vitro by antagonizing SP receptors and SP interactions with the chemokine receptor CCR5. Thus, the effects of SP on HIV infection are mediated through several inter-related pathways: by enhancing HIV entry into immune cells; by facilitating HIV replication directly within the immune cell; and/or by indirectly affecting virus proliferation through replication of HIV co-receptors. SP modulates beta-chemokine expression both in immune cells and in the neuronal cell line (NT2-N). SP mRNA expression, and synthesis are enhanced by HIV infection and gp 120 treatment of human immune cells, further indicating a reciprocal relationship between SP and HIV in the infected immune cells. Since macrophages and CD4+ T cells are important immune cells in inflammatory reactions and primary target cells for HIV infection, the data from our studies imply that the interaction between SP and HIV in these immune cells are involved in the immunopathogenesis of HIV infection and AIDS. Since SP is a stress-released neuropeptide, our current ex vivo and in vivo studies are investigating the relationships between SP, SP receptor, depression/anxiety and HIV infection, taking advantage of well-characterized subjects participation in ongoing cross-sectional and longitudinal epidemiological studies of HIV infection, psychosocial and behavioral factors and immune measures.

Dr. Douglas is the Principal Investigator of the Philadelphia Pediatric AIDS Clinical Trials Unit (PPACTU), a consortium consisting of The Children's Hospital of Philadelphia as the main unit, St. Christopher's Hospital for Children as a pediatric subunit, and four perinatal subunits, the Hospital of the University of Pennsylvania, Temple University School of Medicine, Thomas Jefferson University Hospital, and Drexel University College of Medicine. The Philadelphia PACTU has been highly effective in enrolling subjects into perinatal, primary therapy, adolescent, complications of therapy, and immunology/immune-based therapy/vaccine protocols. Several members of the Philadelphia PACTU hold leadership positions in the PACTG. The Philadelphia PACTU enrolls adolescents and children into protocols, complies with regulatory and data management procedures, contributes to the scientific agenda of the PACTG. Members of the Philadelphia PACTU are involved in the following studies: virologic and immunologic effects of long-term effective combination therapy (PACTG 382), safety and immunologic effects of interleukin-2 (PACTG 299), immune reconstitution in adolescents receiving HAART (PACTG 381), novel antiretroviral combinations in infants, children and adolescents (PACTG 1020), and both preventive and therapeutic HIV vaccines.

HIV/AIDS Related Publications:
Pham, T., Belzer, M., Church, J.A., Kitchen, C., Wilson , C.M., Douglas , S.D. , Geng, Y, Silva, M., Mitchell, R.M. and Paul Krogstad. Assessment of thymic activity in human immunodeficiency virus-negative and -positive adolescents by real-time PCR quantitation of T-cell receptor rearrangement excision circles. Clin. Diagn. Lab. Immunol. 10 :323-328, 2003.

Repetto, M.J., Evans, D.L., Cruess, D.G., Gettes, D., Douglas, S.D. and Petitto, J.M. Neuropsychopharmacological treatment of depression and other neuropsychiatric disorders in HIV-infected individuals. CNS Spectr. 8 :59-63, 2003.

Cruess, D.G., Petitto, J.M., Leserman, J., Douglas, S.D., Gettes, D.R., Ten Have, T.R., Evans, D.L. Depression and HIV infection: Prevalence and impact on immune function and disease progression. CNS Spectr. 8 :52-58, 2003.

Douglas , S.D. , Camarca, M., Xu, J-H, Durako, S., Murphy, D., Moscicki, B. and Wilson, C., for the Reaching for Excellence in Adolescent Care and Health Project of the Adolescent Medicine HIV/AIDS Research Network. The relationships between substance abuse, psychosocial variables and natural killer cell enumeration and function in HIV-infected and high-risk uninfected adolescents. AIDS Research Human Retroviruses 19 :399-408, 2003.

Douglas , S.D. , Durako, S.J., Sullivan, K.E., Camarca, M., Moscicki, A.B. and Wilson , C.M. for the Adolescent Medicine HIV/AIDS Research Network. TH1 and TH2 cytokine mRNA and protein levels in human immunodeficiency virus (HIV)-seropositive and HIV-seronegative youths. Clin. Diagn. Lab. Immunol. 10 : 2003.

Zhang, T., Li, Y., Lai, J-P, Douglas , S.D. , Metzger, D.S., O'Brien, C.P. and Ho, W-P. Alcohol potentiates Hepatitis C virus replicon expression. Hepatology, 38 :57-65, 2003.

Pahwa, S., Chitnis, V., Mitchell, R.M., Fernandez, S., Chandrasekharan, A., Wilson , C.M. and Douglas , S.D. CD4+ and CD8+ T cell receptor repertoire perturbations with normal levels of T cell receptor excision circles in HIV-infected, therapy naive adolescents. AIDS Res. Human Retroviruses 19 :487-496, 2003.

Cruess, D.G., Evans, D.L., Repetto, M.J., Gettes, D., Douglas , S.D. and Petitto, J.M. Prevalence, diagnosis, and pharmacological treatment of mood disorders in HIV. Biol. Psychiatry 54 :307-316, 2003.

SP Related Publications:
Lai, J-P, Ho, W-Z, Zhan, G-X, Yi, Y-J, Collman, R.G. and Douglas , S.D. : Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes. Proc. Nat. Acad. Sci. ( USA ) 98 :3970-3975, 2001.

Douglas , S.D. , Gettes, D.R., Ho, W-Z, Cnaan, A, Zhao, H. and Evans, D.L. Elevated Substance P levels in HIV-infected men. AIDS 15 :2043-2045, 2001.

Li, Y., Douglas , S.D. , Song, L., Sun, S. and Ho, W-Z. Substance P enhances HIV-1 replication in latently infected human immune cells. J. Neuroimmunology 121 :67-75, 2001.

Li, Y., Wang, X., Tian, S., Guo, C-J, Douglas , S.D. and Ho, Wen-Zhe. Methadone enhances human immunodeficiency virus infection of human immune cells. J. Infect. Dis. 185 :118-122, 2002.

Lai, J-P, Douglas , S.D. , Shareen, F., Pleasure, D.D. and Ho, W-Z. Quantification of SP mRNA in human Immune cells by real time RT-PCR assay. Clin. Diagn. Lab. Immunol. 9 :138-143, 2002.

Ho, W-Z, Lai, J-P, Li, Y. and Douglas , S.D. HIV enhances Substance P in human immune cells. FASAB J 10.1096/fj 01-0655/fje (February 12, 2002) and 16:616-618, 2002.

Lai, J-P, Ho, W-Z, Yang, J-H, Wang, X, Song, L. and Douglas , S.D. A non-peptide Substance P antagonist down-regulates SP mRNA expression in human mononuclear phagocytes. J. Neuroimmunol. 128 :101-108, 2002.

Morrison, M.F., Petitto, J.M., Ten Have, T., Gettes, D.R., Chiappini, M.S., Weber, A.L., Brinker-Spence, P., Bauer, R., Douglas , S.D. and Evans, D.L. Depressive and anxiety disorders in women with HIV infection, Am. J. Psychiatry 159 :789-796, 2002.

Evans, D.L., Ten Have, T.R., Douglas, S.D., Gettes, D.R., Morrison, M., Chiappini, M.S., Brinker-Spence, P., Job, C., Mercer, D.E., Want, Y.L., Cruess, D., Dube, B., Dalen, E.A., Brown, T., Bauer, R. and Petitto, J.M. Association of depression with viral load, CD8 T lymphocytes, and natural killer cells in women with HIV infection. Amer. J. Psychiatry 159 : 1752-1759, 2002.

Guo, C-J, Lai, J-P, Luo, H-M, Douglas , S.D. and Ho, W.Z. Substance P up-regulates macrophage inflammatory protein-1 b expression in human T lymphocytes. J. Neuroimmunol. 131 :160-167, 2002.

Guo, C-J, Li, Y., Tian, S., Wang, X., Douglas , S.D. and Ho, W-Z. Morphine enhances HIV infection of human blood mononuclear phagocytes through modulation of b -chemokines and CCR5 receptor. J. Invest. Med. 50 :435-442, 2002.

Li, Y., Douglas , S.D. , Pleasure, D.E., Lai, J., Guo C., Bannerman, P., Williams, M. and Ho, W. Human neuronal cells (NT2-N) express functional substance P and neurokinin-1 receptor coupled to MIP-1 b expression. J. Neuroscience Research, 71 :559-566, 2003.

Guo, C-J, Douglas , S.D. , Lai, J-P, Pleasure, D.E., Li, Y., Williams, M., Bannerman, P., Song, L. and Ho, W-Z. Interleukin-1 b stimulates macrophage inflammatory protein-1 a and b expression in human neuronal cells (NT2-N). J. Neurochem. 84 :997-1005, 2003.

Macrophage-Pathogen Interactions. Marcel Dekker, Inc. (ed. by Zwilling)

Reviews and Chapters:
Ho, W-Z, Cherukuri, R. and Douglas , S.D. : The macrophage and HIV-1. In: , B.S. and Eisenstein, T.K.) pp. 569-587, 1994.

Douglas , S.D. Monocyte-macrophages in diagnosis and immunopathogenesis. Commentary, Clin. Diagn. Lab. Immunol. 6 :283-285, 1999.

Fehder, W. P., Ho, W-Z, Douglas , S.D. Macrophages. Ed., George Fink, In Encyclopedia of Stress, Vol.2, p. 663-669. Academic Press, San Diego , CA , 2000.

Fehder, W.P. and Douglas , S.D. Interactions between the nervous and immune systems. Seminars in Clinical Neuropsychiatry 6 :229-240, 2001.

Lai, J-P, Douglas , S.D. and Ho, W-Z. Mimic-based RT-PCR quantitation of substance P mRNA in human mononuclear phagocytes and lymphocytes. From Methods in Molecular Biology, Volume 193: "RT-PCR Protocols", Edited by: J. O'Connell, Chapter 10, pp. 129-147, Humana Press, Inc., Totowa, NJ, USA, 2002.

Ho, W-Z, Evans, D.L. and Douglas , S.D. Substance P and human immunodeficiency virus infection: Psychoneuroimmunology. Review in CNS Spectr. 7 :867-874, 2002.

Goode, T., Ho, W-Z, O'Connor, G.C., Busteed, S., Douglas , S.D. , Shanahan, F. and O'Connell, J. Nested RT-PCR: sensitivity controls are essential to determine the biological significance of detected mRNA. Chapter in Methods in Molecular Biology, Volume 193, "RT-PCR Protocols in Biomedicine" , edited by J. O'Connell, Humana Press, Inc. Totowa , NJ , Chapter 5, pp. 65-79, 2002.

Manuscripts in Press:
Fang, C.Y., Miller, S.M., Mills, M., Mangan, C.E., Belch, R., Campbell , D.E. and Douglas , S.D. Avoidance and immunity in women with cervical lesions. Psycho-Oncology, 11 : , 2002, in press.

Douglas , S.D. , Kapur, R., Merrill, J.D., Yoder, M.C. and Ho, W-Z. Mononuclear Phagocytes, dendritic cells, and natural killer cells. Ed. Stiehm RE, Ochs HD and Winkelstein JA, 5 th edition of Immunology Disorders in Infants and Children. Harcourt Health Sciences, W. B. Saunders, Philadelphia , PA , 2001, in press.