David B. Lewis

Clinical Focus

• Infectious Diseases, Pediatric
• Pediatric Infectious Disease

Administrative Appointments

• Director of the Jeffrey Modell Primary Immunodeficiency Center at Stanford, Supported by the Jeffrey Modell Foundation and the Lucile Packard Fund of Children's Health , (2002– present )

Honors and Awards

• Henry J. Kaiser Award for Excellence in Preclinical Teaching (Immunology), Kaiser Foundation (2005)
• Henry J. Kaiser Award for Excellence in Preclinical Teaching (Immunology), Kaiser Foundation (2001)

Professional Education

• Board Certification: Pediatric Infectious Disease, American Board of Pediatrics (1994)
• Children's Hospital and Regional Medical Center (1988) WA
• Board Certification: General Pediatrics, American Board of Pediatrics (1986)
• UCSF Medical Center (1984) CA
• Children's Hospital and Regional Medical Center (1982) WA
• UCSF Medical Center (1981) CA USA
• B.S., Yale University Biology (1976)
• M.D., Univ.Calif at San Francisco Medicine (1981)

Postdoctoral Advisees

• Crystal Botham, Minna Koskenvuo

Graduate & Fellowship Program Affiliations

• Immunology
• Infectious Diseases
• Pediatrics
• Neonatology and Developmental Biology

Web Site Links

• Lewis Lab Website

Industry Relationships

Stanford is committed to ethical and transparent interactions with our industry partners. It is our policy to disclose payments of $5,000 or more, equity valued at $5,000 or more in a publicly traded company, or any equity in a privately held company, to physicians and scientists employed by Stanford University from companies or other commercial entities with which they interact as part of their professional activities. 

• Equity: Juvaris Biotherapeutics, Inc.

Research Interests

A long-standing interest is to understand the cellular and molecular basis for this vulnerability of the human neonate to infection with intracellular pathogens that require T helper 1 (Th1) cells [CD4 T cell producing interferon-gamma (IFN-gamma)] for effective immune control. We have previously shown that CD4 T cells of the newborn have a unique limitation in the ability to produce certain effector molecules, such as CD40-ligand (CD154) and IFN-gamma compared to these cells in adults due to both reduced gene transcriptional and impaired signals that lead to gene transcription. Recently, we have shown that these limitations apply to physiological T-cell activation, e.g., using allogeneic dendritic cells. Defining the molecular mechanisms for decreased IFN-gamma production by neonatal CD4 T cells is a current focus.
We have also found that recent thymic emigrants, which predominate in the newborn and young infant, are less able to differentiate into T helper 1 cells, which produce IFN-gamma. These studies required the development of a novel marker for recent thymic emigrants (RTEs) of the CD4 T-cell lineage in humans. Using a combination of approaches, we have identified protein tyrosine kinase 7 (PTK7) as such a marker. In progress are to studies to define the role of PTK7, an orphan member (no known ligand) of the receptor tyrosine kinase family, in T-cell development and immunity, and to determine how this marker can be used to follow the output of recent thymic emigrants in health and disease. We are also interesed in determining the molecular mechanisms for the reduced RTE function and to what extent these mechanisms are shared by neonatal CD4 T cells and CD4+CD8-CD3+ thymocytes, the immediate precursors of antigenically naive CD4 T cells.
We have also found that limitations in T-cell immunogenicity to viruses and viral vaccines extend beyond the neonatal period to childhood. These studies highlight a need to develop more potent vaccines to overcome developmental and other factors, such as genetic inheritance, in mounting adaptive immunity. With this as an ultimate goal, we are examining the ability of a novel adjuvant, cationic liposome DNA complexes (CLDC)(Juvaris Biotherapeutics), to induce durable CD4 and CD8 T-cell immunity and humoral immunity to influenza A. The molecular and cellular components of the innate immune system that are required for immunogenicity are of particular interest. Our preliminary results in mice suggest that the CLDC adjuvant will be substantially more robust than any adjuvants currently approved for clinical use or in clinical trials.

In collaboration with Dr. Neal Boerkoel, University of British Columbia, we are defining the mechanism of T-cell lymphopenia in genetic deficiency of SMARCAL1, a protein that may play a novel role in PolII gene transcription using T cells from patients with SMARCAL1 deficiency (Schimke immuno-osseous dysplasia) as well as SMARCAL1 knockout mice. We hypothesize that the peripheral T-cell lymphopenia is due to attenuation of transcriptional efficiency for multiple genes required for T-cell development and peripheral homeostasis, e.g., cytokines and cytokine receptors.

Publications

• Cationic lipid/DNA complexes (JVRS-100) combined with influenza vaccine (Fluzone) increases antibody response, cellular immunity, and antigenically drifted protection. Lay M,  Callejo B, Chang S, Hong DK, Lewis DB, Carroll TD, Matzinger S, Fritts L, Miller CJ, Warner JF, Liang L, Fairman J.  Vaccine.  2009; 27 (29): 3811-20
• Human CD4+ T cell recent thymic emigrants are identified by protein tyrosine kinase 7 and have reduced immune function. Haines CJ,  Giffon TD, Lu LS, Lu X, Tessier-Lavigne M, Ross DT, Lewis DB.  J Exp Med.  2009; 206 (2): 275-85
• Focus on FOCIS: the continuing diagnostic challenge of autosomal recessive chronic granulomatous disease. Yu G,  Hong DK, Dionis KY, Rae J, Heyworth PG, Curnutte JT, Lewis DB.  Clin Immunol.  2008; 128 (2): 117-26
• Maternal T-cell engraftment associated with severe hemophagocytosis of the bone marrow in untreated X-linked severe combined immunodeficiency. Dvorak CC,  Sandford A, Fong A, Cowan MJ, George TI, Lewis DB.  J Pediatr Hematol Oncol.  2008; 30 (5): 396-400
• Asymmetric dimethylarginine and cardiac allograft vasculopathy progression: modulation by sirolimus. Potena L,  Fearon WF, Sydow K, Holweg C, Luikart H, Chin C, Weisshaar D, Mocarski ES, Lewis DB, Valantine HA, Cooke JP.  Transplantation.  2008; 85 (6): 827-33
• Influenza A virus elevates active cathepsin B in primary murine DC. Burster T,  Giffon T, Dahl ME, Björck P, Bogyo M, Weber E, Mahmood K, Lewis DB, Mellins ED.  Int Immunol.  2007; 19 (5): 645-55
• Humoral and cellular immune responses in children given annual immunization with trivalent inactivated influenza vaccine. Zeman AM,  Holmes TH, Stamatis S, Tu W, He XS, Bouvier N, Kemble G, Greenberg HB, Lewis DB, Arvin AM, Dekker CL.  Pediatr Infect Dis J.  2007; 26 (2): 107-15
• Newborn immunology: relevance to the clinician. Lewis DB,  Gern JE, Hill HR, Friedlander SL, La Pine TR, Lemanske RF, Stiehm ER.  Curr Probl Pediatr Adolesc Health Care.  2006 May-Jun; 36 (5): 189-204
• T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease. Tu W,  Potena L, Stepick-Biek P, Liu L, Dionis KY, Luikart H, Fearon WF, Holmes TH, Chin C, Cooke JP, Valantine HA, Mocarski ES, Lewis DB.  Circulation.  2006; 114 (15): 1608-15
• Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines. He XS,  Holmes TH, Zhang C, Mahmood K, Kemble GW, Lewis DB, Dekker CL, Greenberg HB, Arvin AM.  J Virol.  2006; 80 (23): 11756-66
• Cutting edge: Decreased accumulation and regulatory function of CD4+ CD25(high) T cells in human STAT5b deficiency. Cohen AC,  Nadeau KC, Tu W, Hwa V, Dionis K, Bezrodnik L, Teper A, Gaillard M, Heinrich J, Krensky AM, Rosenfeld RG, Lewis DB.  J Immunol.  2006; 177 (5): 2770-4
• Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection. Potena L,  Holweg CT, Chin C, Luikart H, Weisshaar D, Narasimhan B, Fearon WF, Lewis DB, Cooke JP, Mocarski ES, Valantine HA.  Transplantation.  2006; 82 (3): 398-405
• Transient deficiencies of T-cell-mediated immunity in the neonate. Randolph DA,  Lewis DB.  Adv Exp Med Biol.  2006; 582 55-69
• Impaired allogeneic activation and T-helper 1 differentiation of human cord blood naive CD4 T cells. Chen L,  Cohen AC, Lewis DB.  Biol Blood Marrow Transplant.  2006; 12 (2): 160-71
• Avian flu to human influenza. Lewis DB,  Annu Rev Med.  2006; 57 139-54
• Chemotactic responses of IL-4-, IL-10-, and IFN-gamma-producing CD4+ T cells depend on tissue origin and microbial stimulus. Debes GF,  Dahl ME, Mahiny AJ, Bonhagen K, Campbell DJ, Siegmund K, Erb KJ, Lewis DB, Kamradt T, Hamann A.  J Immunol.  2006; 176 (1): 557-66
• Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Zhou B,  Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB, Gyarmati D, Aye T, Campbell DJ, Ziegler SF.  Nat Immunol.  2005; 6 (10): 1047-53
• Antiviral CD8 T cells in the control of primary human cytomegalovirus infection in early childhood. Chen SF,  Tu WW, Sharp MA, Tongson EC, He XS, Greenberg HB, Holmes TH, Wang Z, Kemble G, Manganello AM, Adler SP, Dekker CL, Lewis DB, Arvin AM.  J Infect Dis.  2004; 189 (9): 1619-27
• Persistent and selective deficiency of CD4+ T cell immunity to cytomegalovirus in immunocompetent young children. Tu W,  Chen S, Sharp M, Dekker C, Manganello AM, Tongson EC, Maecker HT, Holmes TH, Wang Z, Kemble G, Adler S, Arvin A, Lewis DB.  J Immunol.  2004; 172 (5): 3260-7
• Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells. Dahl ME,  Dabbagh K, Liggitt D, Kim S, Lewis DB.  Nat Immunol.  2004; 5 (3): 337-43
• Toll-like receptors and T-helper-1/T-helper-2 responses. Dabbagh K,  Lewis DB.  Curr Opin Infect Dis.  2003; 16 (3): 199-204
• Impaired accumulation and function of memory CD4 T cells in human IL-12 receptor beta 1 deficiency. Cleary AM,  Tu W, Enright A, Giffon T, Dewaal-Malefyt R, Gutierrez K, Lewis DB.  J Immunol.  2003; 170 (1): 597-603
• Decreased CD154 expression by neonatal CD4+ T cells is due to limitations in both proximal and distal events of T cell activation. Jullien P,  Cron RQ, Dabbagh K, Cleary A, Chen L, Tran P, Stepick-Biek P, Lewis DB.  Int Immunol.  2003; 15 (12): 1461-72
• Toll-like receptor 4 is required for optimal development of Th2 immune responses: role of dendritic cells. Dabbagh K,  Dahl ME, Stepick-Biek P, Lewis DB.  J Immunol.  2002; 168 (9): 4524-30
• Allergy immunotherapy and inhibition of Th2 immune responses: a sufficient strategy? Lewis DB,  Curr Opin Immunol.  2002; 14 (5): 644-51
• Dynamics of CD4 and CD8 T cell responses to cytomegalovirus in healthy human donors. Dunn HS,  Haney DJ, Ghanekar SA, Stepick-Biek P, Lewis DB, Maecker HT.  J Infect Dis.  2002; 186 (1): 15-22
• Simple febrile seizures: do polymorphisms of the interleukin 1 gene cluster simplify our understanding? Lewis DB,  Arch Pediatr Adolesc Med.  2002; 156 (6): 529-30
• A T cell-specific enhancer of the human CD40 ligand gene. Schubert LA,  Cron RQ, Cleary AM, Brunner M, Song A, Lu LS, Jullien P, Krensky AM, Lewis DB.  J Biol Chem.  2002; 277 (9): 7386-95
• Octamer proteins inhibit IL-4 gene transcription in normal human CD4 T cells. Cron RQ,  Zhou B, Brunvand MW, Lewis DB.  Genes Immun.  2001; 2 (8): 464-8
• Group A streptococcal meningitis: report of a case and review of literature since 1976. Shetty AK,  Frankel LR, Maldonado Y, Falco DA, Lewis DB.  Pediatr Emerg Care.  2001; 17 (6): 430-4
• NFAT1 enhances HIV-1 gene expression in primary human CD4 T cells. Cron RQ,  Bartz SR, Clausell A, Bort SJ, Klebanoff SJ, Lewis DB.  Clin Immunol.  2000; 94 (3): 179-91
• Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Alizadeh AA,  Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM.  Nature.  2000; 403 (6769): 503-11
• An immunosuppressive and anti-inflammatory HLA class I-derived peptide binds vascular cell adhesion molecule-1. Ling X,  Tamaki T, Xiao Y, Kamangar S, Clayberger C, Lewis DB, Krensky AM.  Transplantation.  2000; 70 (4): 662-7
• Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI. Dabbagh K,  Xiao Y, Smith C, Stepick-Biek P, Kim SG, Lamm WJ, Liggitt DH, Lewis DB.  J Immunol.  2000; 165 (6): 3418-22
• Respiratory infection with influenza A virus interferes with the induction of tolerance to aeroallergens. Tsitoura DC,  Kim S, Dabbagh K, Berry G, Lewis DB, Umetsu DT.  J Immunol.  2000; 165 (6): 3484-91
• Bone marrow NK1.1(-) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease. Zeng D,  Lewis D, Dejbakhsh-Jones S, Lan F, García-Ojeda M, Sibley R, Strober S.  J Exp Med.  1999; 189 (7): 1073-81
• T cell priming enhances IL-4 gene expression by increasing nuclear factor of activated T cells. Cron RQ,  Bort SJ, Wang Y, Brunvand MW, Lewis DB.  J Immunol.  1999; 162 (2): 860-70
• Consistent transient transfection of DNA into non-transformed human and murine T-lymphocytes. Cron RQ,  Schubert LA, Lewis DB, Hughes CC.  J Immunol Methods.  1997; 205 (2): 145-50
• Influence of the route of allergen administration and genetic background on the murine allergic pulmonary response. Zhang Y,  Lamm WJ, Albert RK, Chi EY, Henderson WR, Lewis DB.  Am J Respir Crit Care Med.  1997; 155 (2): 661-9
• Beta 2-microglobulin-dependent T cells are dispensable for allergen-induced T helper 2 responses. Zhang Y,  Rogers KH, Lewis DB.  J Exp Med.  1996; 184 (4): 1507-12
• The importance of leukotrienes in airway inflammation in a mouse model of asthma. Henderson WR,  Lewis DB, Albert RK, Zhang Y, Lamm WJ, Chiang GK, Jones F, Eriksen P, Tien YT, Jonas M, Chi EY.  J Exp Med.  1996; 184 (4): 1483-94
• Coexpression of the interleukin-13 and interleukin-4 genes correlates with their physical linkage in the cytokine gene cluster on human chromosome 5q23-31. Dolganov G,  Bort S, Lovett M, Burr J, Schubert L, Short D, McGurn M, Gibson C, Lewis DB.  Blood.  1996; 87 (8): 3316-26
• The human gp39 promoter. Two distinct nuclear factors of activated T cell protein-binding elements contribute independently to transcriptional activation. Schubert LA,  King G, Cron RQ, Lewis DB, Aruffo A, Hollenbaugh D.  J Biol Chem.  1995; 270 (50): 29624-7
• Diminished expression of CD40 ligand by activated neonatal T cells. Nonoyama S,  Penix LA, Edwards CP, Lewis DB, Ito S, Aruffo A, Wilson CB, Ochs HD.  J Clin Invest.  1995; 95 (1): 66-75
• Hypomethylation of the interferon-gamma gene correlates with its expression by primary T-lineage cells. Melvin AJ,  McGurn ME, Bort SJ, Gibson C, Lewis DB.  Eur J Immunol.  1995; 25 (2): 426-30
• Lymphokine regulation and the role of abnormal regulation in immunodeficiency. Wilson CB,  Penix L, Melvin A, Lewis DB.  Clin Immunol Immunopathol.  1993; 67 (3 Pt 2): S25-32
• Osteoporosis induced in mice by overproduction of interleukin 4. Lewis DB,  Liggitt HD, Effmann EL, Motley ST, Teitelbaum SL, Jepsen KJ, Goldstein SA, Bonadio J, Carpenter J, Perlmutter RM.  Proc Natl Acad Sci U S A.  1993; 90 (24): 11618-22
• Ontogeny of T lymphocyte function in the neonate. Wilson CB,  Penix L, Weaver WM, Melvin A, Lewis DB.  Am J Reprod Immunol.  1992 Oct-Dec; 28 (3-4): 132-5
• Clinical and microbiologic characteristics of cutaneous infection with Yersinia enterocolitica. Krogstad P,  Mendelman PM, Miller VL, Clausen C, Abbott S, Weagant S, Wilson CL, Lewis DB.  J Infect Dis.  1992; 165 (4): 740-3
• Decreased granulocyte-macrophage colony-stimulating factor production by human neonatal blood mononuclear cells and T cells. English BK,  Hammond WP, Lewis DB, Brown CB, Wilson CB.  Pediatr Res.  1992; 31 (3): 211-6
• Hawkinsinuria in two families. Borden M,  Holm J, Leslie J, Sweetman L, Nyhan WL, Fleisher L, Nadler H, Lewis D, Scott CR.  Am J Med Genet.  1992; 44 (1): 52-6
• T cell development in the fetus and neonate. Wilson CB,  Lewis DB, English BK.  Adv Exp Med Biol.  1991; 310 17-27
• Cellular and molecular mechanisms for reduced interleukin 4 and interferon-gamma production by neonatal T cells. Lewis DB,  Yu CC, Meyer J, English BK, Kahn SJ, Wilson CB.  J Clin Invest.  1991; 87 (1): 194-202
• Interleukin 4 expressed in situ selectively alters thymocyte development. Lewis DB,  Yu CC, Forbush KA, Carpenter J, Sato TA, Grossman A, Liggitt DH, Perlmutter RM.  J Exp Med.  1991; 173 (1): 89-100
• Developmental regulation of lck gene expression in T lymphocytes. Wildin RS,  Garvin AM, Pawar S, Lewis DB, Abraham KM, Forbush KA, Ziegler SF, Allen JM, Perlmutter RM.  J Exp Med.  1991; 173 (2): 383-93
• Basis and implications of selectively diminished cytokine production in neonatal susceptibility to infection. Wilson CB,  Lewis DB.  Rev Infect Dis.  1990 May-Jun; 12 Suppl 4 S410-20
• Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE syndrome. Vercelli D,  Jabara HH, Cunningham-Rundles C, Abrams JS, Lewis DB, Meyer J, Schneider LC, Leung DY, Geha RS.  J Clin Invest.  1990; 85 (5): 1666-71
• Gamma-interferon: an immunoregulatory lymphokine with immunotherapeutic potential. Lewis DB,  Wilson CB.  Pediatr Infect Dis J.  1990; 9 (9): 642-51
• Lymphocyte activation provokes modification of a lymphocyte-specific protein tyrosine kinase (p56lck). Marth JD,  Lewis DB, Cooke MP, Mellins ED, Gearn ME, Samelson LE, Wilson CB, Miller AD, Perlmutter RM.  J Immunol.  1989; 142 (7): 2430-7
• Restricted production of interleukin 4 by activated human T cells. Lewis DB,  Prickett KS, Larsen A, Grabstein K, Weaver M, Wilson CB.  Proc Natl Acad Sci U S A.  1988; 85 (24): 9743-7
• Structure and expression of lck transcripts in human lymphoid cells. Perlmutter RM,  Marth JD, Lewis DB, Peet R, Ziegler SF, Wilson CB.  J Cell Biochem.  1988; 38 (2): 117-26
• Regulation of pp56lck during T-cell activation: functional implications for the src-like protein tyrosine kinases. Marth JD,  Lewis DB, Wilson CB, Gearn ME, Krebs EG, Perlmutter RM.  EMBO J.  1987; 6 (9): 2727-34
• Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin. Ziegler SF,  Marth JD, Lewis DB, Perlmutter RM.  Mol Cell Biol.  1987; 7 (6): 2276-85
• Decreased production of interferon-gamma by human neonatal cells. Intrinsic and regulatory deficiencies. Wilson CB,  Westall J, Johnston L, Lewis DB, Dower SK, Alpert AR.  J Clin Invest.  1986; 77 (3): 860-7
• Reduced interferon-gamma mRNA levels in human neonates. Evidence for an intrinsic T cell deficiency independent of other genes involved in T cell activation. Lewis DB,  Larsen A, Wilson CB.  J Exp Med.  1986; 163 (4): 1018-23