Marc Adrian Williams

Assistant Professor of Medicine (Pulmonary and Critical Care),

Assistant Professor of Environmental Medicine

B.Sc. - Applied (Molecular) Biology 1989 (University of Coventry, UK)

Ph.D. - Experimental Hematology 2000 (University of London, UK)

Research Interests

Role of dendritic cells in innate immunity and pattern-recognition receptor signaling in pulmonary immunity. Mechanisms of monocyte immune-paralysis in septic shock. Adverse effects of environmental atmospheric pollutants upon hematopoietic stem cell development and differentiation of myeloid progenitors.

Research Projects

i) Identify mechanisms responsible for Th2-type immune responses in asthma and allergic sensitization

ii) To understand the role played by lung dendritic cells and pattern-recognition receptor signaling in the microbiological-mediated exacerbations of asthma on exposure to environmental particulate pollutants

iii) Identify the mechanisms responsible for the immuno-paralysis of blood monocytes in septic shock and potential for immune-therapy using biological response modifiers such as rHuGM-CSF or IFN-gamma

Biographical Overview

I obtained my undergraduate education in the historic city of Coventry, England (B.Sc. with honors in Applied Biology/Molecular Cell Biology, University of Coventry, UK) and my post-graduate education in the capital city of London (Ph.D. in Experimental Hematology, University of London, UK). In the interim three years between completing my baccalaureate and commencing my Ph.D., I conducted basic immunological research in the laboratory of renowned immunologist Dr Kingston H Mills at the MRC/WHO collaborating center of The National Institute of Biological Standards and Control (NIBSC), UK. My thesis contributed several seminal papers to our understanding of the immunological effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) in modulating functions of the monocyte important in anti-tumor and anti-microbial immune defense. My research also focused on the importance of reactive oxygen and nitrogen species and their contributions to the tumoricidal properties of monocytes against hematological malignancies. I was also interested in cellular and molecular pathways of monocyte dysfunction in human disease. I identified an immune paralysis of the monocyte system in septic shock – a potentially fatal condition. Monocyte immuno-paralysis was characterized by suppressed expression of MHC class II (HLA-DR), the transferrin receptor (CD71) and certain beta-2 integrin receptors. Monocyte immuno-paralysis was also associated with a dysregulated pattern of inflammatory cytokine production. The objective of my post-graduate work was to identify how the functions of the monocyte could be therapeutically activated or even restored by rHuGM-CSF to target minimal residual disease in hematological malignancy or to restore functional responsiveness of immune-paralyzed monocytes in septic shock. At the same time, I developed protocols that enabled marked expansion and propagation of DC sub-populations from human peripheral blood hematopoietic progenitors and development of DC from non-proliferating peripheral blood monocytes. We were among the first groups in Europe and the UK to successfully use adoptively transferred autologous tumor-peptide loaded DC for the immune-therapy of primary refractory B-cell lymphoma in conjunction with administration of biological response modifiers such as rHuGM-CSF and IL-2. My interest in the functional properties and mechanisms employed by DC took my post-doctoral training to the shores of the Pacific Ocean at The University of California, San Diego at La Jolla where I took an interest in the role played by DC in the pathogenesis of HIV infection and AIDS.

I continued exploring the role played by DC in pathways of disease in the neuromuscular autoimmunity laboratoryof Dr Daniel Drachman, a world renowned authority in autoimmune neurological diseases (particularly Myasthenia gravis) at Johns Hopkins University School of Medicine, Baltimore. I helped develop a technology for targeting autoreactive antigen-specific T cells by The Guided Missile Strategy. This was a novel strategy for specific immunotherapy of Myasthenia gravis (MG), involving adenoviral (ADV) gene transfer to convert dendritic cells to "guided missiles" that would target AChR-specific T cells, and would also induce apoptosis and elimination of those antigen-specific autoreactive T cells. This strategy uses the ability of DC from a given individual to present the entire spectrum of AChR epitopes unique for that individual, and thereby to target the entire repertoire of antigen-specific T cells of the same individual. Using ADV vectors, we genetically engineered DC to process and present the most important domain of the AChR molecule (the payload), and to express a "warhead" of Fas ligand (FasL) to eliminate the activated AChR-specific T cells with which they interact. In the same lab I created novel ADV expression vectors that would promote expression and secretion of the extracellular soluble TNF binding domain of the dimeric TNF receptor (p75TNFR). The objective here was to prevent the neurotoxicity and death of human fetal cerebral neurons that were exposed in vitro to toxic agents known to be implicated in human neurological disorders, including TNF-alpha and the HIV proteins Tat and gp120 – strategies that could be therapeutically useful in the treatment of many human neurodegenerative diseases.

Current Research Overview

The major focus of current research in my laboratory is to understand the cellular and molecular mechanisms involved in the innate immune response to inhaled particulate pollutants including diesel exhaust particles, atmospheric allergens. In particular, my laboratory studies the mechanisms responsible for the altered functional behavior of DC on activation by atmospheric pollutants such as ambient environmental particulate matter and diesel exhaust particulates. These particulate pollutants have been shown by us to dramatically alter the state of differentiation and maturation of both human and murine myeloid DC. We have recently reported the functional consequences and mechanisms involved during the interaction of particulate matter and human DC and identified dramatic effects of particulate pollution on the Toll-Like and Nod-Like family of microbial pattern-recognition receptors such as TLR2, TLR4 and NOD-1/2 (see Porter M et al, 2007; Williams MA and Porter M et al, 2007; Williams MA and Cheadle C et al, 2007). We have identified the importance of the p38 MAP kinase and ERK1/2 pathways of signal transduction and suspect the involvement of PI3 kinase and JNK1/2 pathways of cellular activation as well in the transcriptional mobilization of NF-kappa B and AP-1. Two lines of investigation form the theme of my research program in this context:

i) To identify mechanisms responsible for Th2-type immune responses in asthma and allergic sensitization;

ii) To understand the role played by lung DC and pattern-recognition receptor signaling in the microbiological-mediated exacerbations of asthma on exposure to environmental pollutants.

In a separate focus of research, I am exploring the cellular and molecular mechanisms that lead to innate immune dysregulation and immuno-paralysis of the monocyte and neutrophil populations in the peripheral blood of septic shock subjects. The hope is that biological response modifiers such as rHuGM-CSF or rHuIFN-gamma could be used to therapeutically target the monocyte and restore host immunity and inflammatory responses in septic shock. This work is an exciting and new initiative in the Division of Pulmonary and Critical Care Medicine and benefits from the close collaboration of Dr Tony Pietropaoli and the GCRC.

Currently, Dr Williams is an Associate Editor (and former Co-Editor) of Stem Cells and Development, serves on the editorial board of Biomarker Insights (an open access journal) and is an Active Member of The American Thoracic Society (Program Committee Member of the ATS Assembly of Allergy, Immunology and Inflammation).

Recent Publications. (Since 1998 Only)

Porter M, Karp M, Killedar S, Bauer S, Guo J, Williams D, Breysse P, Georas SN, Williams MA. Diesel exhaust particles induce a novel pattern of pro-allergic dendritic cell activation. American Journal of Respiratory Cell and Molecular Biology E-pub Ahead of Print, July 13^th 2007.

Cheadle C, Watkins T, Fan J, Williams MA, Georas SN, Hall J, Rosen A, Barnes KC. GSMA: Gene set matrix analysis, an automated method for rapid hypothesis testing of gene expression data. Bioinformatics and Biology Insights 1:49-62, 2007.

Williams MA, Cheadle C, Watkins T, Tailor A, Killedar SY, Breysse P, Barnes K, Georas SN. TLR2 and TLR4 as Potential Biomarkers of Environmental Particulate Matter Exposed Human Myeloid Dendritic Cells. Biomarker Insights 2: 225-239, 2007.

Williams MA, Porter M, Roman J, Breysse P, Williams D, Georas SN. Ambient Baltimore Particulate Matter Directs Non-Classical Immune Activation of Human Myeloid Dendritic Cells. Journal of Allergy and Clinical Immunology 119:488-497, 2007.

Tsai YJ, Gao P, Williams MA, Grigoryev G, Stockton M, Watkins T, Cheadle C, Georas S, Liu M, Breslin L, Barnes KC. The interleukin 1-beta gene (IL1B) is upregulated in CD14+monocytes but not alveolar macrophages after lipopolysaccharide (LPS) stimulation by genomic expression profiling. Journal of Allergy and Clinical Immunology 119:S175-76, 2007.

Georas SN, Berdyshev E, Hubbard W, Gorshkova I, Usatyuk P, Saatian B, Myers A, Williams MA, Xiao H, Liu M, Natarajan V. Lysophosphatidic acid is increased in bronchoalveolar lavage fluids during allergic inflammation. Clinical and Experimental Allergy 37:311-322, 2006.

Chen R, Roman, J, Guo J, West E, McDyer J, Williams MA, Georas SN. Lysophosphatidic acid modulates the activation of human monocytes-derived dendritic cells. Stem Cells and Development 15: 797-804, 2006.

Williams MA, Georas SN. Gene expression patterns and susceptibility to allergic responses. Expert Review of Clinical Immunology 2: 59-73, 2006.

Parker GC, Anastassova-Kristeva M, Dajani N, Eisenberg L, Rao MS, Williams MA, Sanberg PR, English D. Stem Cells: From Shibboleths Toward Functional Definition. Stem Cells and Development 14:463-468, 2005.

. Williams MA, Turchen J, Lu Y, Nath A, Drachman DB. Protection of human cerebral neurons from neurodegenerative insults by gene delivery of soluble tumor necrosis factor p75 receptor. Experimental Brain Research, E-pub Ahead of Print, April 13th, 2005.

. Drachman DB, Wu J-M, Miagkov A, Williams MA, Adams RN, Wu B. Specific immunotherapy of experimental myasthenia by genetically engineered APCs: The "guided missile" strategy. Annals of the New York Academy of Sciences 998, 520-532, 2003.

English D, Williams MA*. The therapeutic promise of non-embryonic stem cells, where’s the beef? Journal of Hematotherapy and Stem Cell Research 12(5): 465-466, 2003.

Williams MA*. Neural Stem Cells: One of the Keys to Everything. Journal of Hematotherapy and Stem Cell Research 12(6): 591-594, 2003.

Williams MA*. Could the functional expression of HLA-G be exploited for successful stem cell transplantation and engraftment? Journal of Hematotherapy and Stem Cell Research 12(6): 757-758, 2003.

Williams MA*, Trout R, Spector SA. HIV-1 gp120 modulates the immunological function and expression of accessory and co-stimulatory molecules of monocyte-derived dendritic cells. Journal of Hematotherapy and Stem Cell Research 11:829-847, 2002.

Gilston V, Williams MA, Newland AC, Winyard PG. Hydrogen peroxide and tumor necrosis factor-alpha induce NF-kappa B-DNA binding in primary human T lymphocytes in addition to T cell lines. Free Radical Research 35:681-691, 2001.

Rhoades CJ, Williams MA*, Kelsey SM, Newland AC. Monocyte-macrophage system as targets for immunomodulation by intravenous immunoglobulin. Blood Reviews 14:14-30, 2000.

Williams MA*, Newland AC, Kelsey SM. Cytokine modulated transmembrane tumor necrosis factor expression is associated with enhanced monocyte-mediated killing of human leukemic targets. Leukemia Res 24: 317-330, 2000.

Mainwaring CJ, Williams MA, Springer CRJ, Lush RJ, Smith JG, Haynes CL, Kelsey SM. Monocyte dysfunction in patients with multiple myeloma and lymphoplasmacytic disorders is related to serum paraprotein levels. British Journal of Haematology 105: 948-954, 1999.

James SY, Williams MA, Newland AC, Colston KW. Leukemia cell differentiation: cellular and molecular interactions of retinoids and vitamin D. General Pharmacology 32: 143-154, 1999.

Taussig D, Williams MA*, Wiggins C, Feakins RM, Newland AC and Kelsey SM. Clinical regression and remission of primary refractory lymphoma following tumour peptide antigen-charged dendritic cells after high-dose chemotherapy and autologous stem cell rescue. Hematology 3: 277-289, 1998.

Williams MA*, White SA, Miller JJ, Toner C, Withington S, Newland AC, Kelsey SM. Granulocyte-macrophage colony-stimulating factor induces activation and restores respiratory burst activity in monocytes from septic patients. Journal of Infectious Diseases 177: 107-115, 1998.

Williams MA*, Withington S, Newland AC, Kelsey SM. Monocyte anergy in septic shock is associated with a predilection to apoptosis and is reversed by granulocyte-macrophage colony-stimulating factor ex vivo. Journal of Infectious Diseases 178: 1921-1933, 1998.