Academic Staff

Professor Neil A. Williams

B.Sc. (1985) University of Birmingham
PhD: (1989) University of Bristol

Professor of Immunology

Contact Details
Dept. of Cellular & Molecular Medicine, University of Bristol,
School of Medical Sciences, Bristol, BS8 1TD
Tel: +44 (0)117 33 12064 (internal 12064)
Fax: +44 (0)117 33 12091
Email: neil.a.williams@bristol.ac.uk

Overview

Professor Neil Williams graduated from the University of Birmingham and obtained a PhD in Immunology in 1989. He was appointed as a Lecturer in Immunology at Bristol in 1991 and has since been promoted through to being Professor of Immunology and Head of the Department of Cellular and Molecular Medicine. His research interests in the modulation of immune responses in autoimmune and allergic disease have led to substantial funding, a large number of publications and international recognition. This work has also led to the granting of 5 international patents and the formation of two spin-out companies. Aegis Pharmaceuticals Ltd was acquired in 2001 by Hunter-Fleming Ltd, and then led to the formation of Trident Inc. in 2006 with whom Neil still works closely as a member of the Scientific Board. KWS BioTest Ltd was launched in 2003 with Neil remaining as Director of Science. Neil is also currently a member of the Meningitis Research Foundation's Scientific Advisory Group, and an Honorary Vice President of the London International Youth Science Forum.

Research Interests

Research ongoing within the Williams laboratory focuses on basic and applied aspects of immunity at mucosal surfaces. Current research within the laboratory is focussed into two main areas:

Studies of the unique immunological properties of the cholera-like enterotoxins. Cholera toxin (Ctx) and its relative, Escherichia coli heat-labile enterotoxin (Etx), are highly effective mucosal adjuvants triggering strong protective immunity to unrelated antigens, and their B-subunits (CtxB and EtxB respectively) can be used to prevent or treat inflammatory diseases. We are investigating these molecules as adjuvants (for herpes simplex virus and influenza virus vaccination), immunotherapeutics (for treating autoimmunity and allergy) and as delivery vehicles for the generation of cytotoxic T cell responses to tumours and viruses. In addition, we are currently defining at the cellular and cell signaling level the precise processes by which these molecules modulate cells of the immune system.

Our work with EtxB has established that this remarkable protein is able to inhibit or treat disease in models of rheumatoid arthritis, type I diabetes, Crohn's disease, asthma and autoimmune uveitis. This ability stems from the fact that EtxB generates an environment in tissue sites local to its delivery in which T cell diffierentiation is altered in favour of the generation of T regulatory cells. These cells then circulate through the body and control inflammation at distant sites. We continue to try to uncover the mechanisms involved, and in collaboration with Trident Inc. we are now preparing for clinical trials with EtxB as a treatment for inflammatory disease.

Other work has shown that when antigens are conjugated to EtxB, this facilitates their delivery into class I MHC processing pathways and that this can be used as an effective means of stimulating anti-viral and anti-tumour cytotoxic T cell responses. We are working with CRUK in order to develop this approach as a means of generating novel vaccination and immunotherapy approaches against human cancers.
Studies of mucosal immunity to nasopharyngeal pathogens. We have established a strong interest in understanding the basis of immunity to Neisseria meningitidis group B (NmB) and are extending the approaches that we have developed in this area to understand important issues for vaccine design and also the similarities and differences that there are to the immune response to a related commensal, Neisseria lactamica, and another pathogen of the same site, the pneumococcus. This work is a close collaboration between the Williams group and that of Professor Robert Heyderman. We have developed novel ways of investigating the nature of mucosal T cell immunity in humans through the use of tonsillectomy samples and have established the basis of naturally acquired immunity to NmB. As part of this work, we have shown that the immune response to NmB is at least initially characterised by high levels of T regulatory activity balancing a pro-inflammatory phenotype. We are continuing to define the mechanisms involved in the induction of this response through studies of the interaction between NmB and dendritic cells and the nature of the T regulatory responses. In addition, we are using vaccination in humans as a means of probing the nature of immunity to these important organisms.

Present co-workers

EtxB group

Dr Claire Richards (post-doctoral researcher)
Dr David Donaldson (post-doctoral researcher)
Dr Lee Faulkner (post-doctoral researcher)
Dr Beatrice Ondondo (post-doctoral researcher)

Meningitis group

Dr Sarah Glennie (post-doctoral researcher)
Dr Jeffrey Pido (Research Associate)
Dr Louise Brackenbury (Research Assistant)
Miss Claire Willer (PhD student)
Mr Andrew Vaughan (PhD student)
Dr Ed Clarke (clinical PhD student)
Miss Begonia Morales-Aza (Research technician)

Recent Publications

Davenport, V., Groves, E., Hobbs, C.G., Williams, N.A. and Heyderman, R.S. (2007) Regulation of Th-1 T cell-dominated immunity to Neisseria meningitidis within the human mucosa. Cell. Microbiol. 9, 1050-1061.

Milling, S.W.F., Yrlid, U., Jenkins, C., Richards, C.M., Williams, N.A. and MacPherson, G. (2007) Regulation of intestinal immunity: Effects of the oral adjuvant Escherichia coli heat-labile enterotoxin on migrating dendritic cells. Eur. J. Immunol. 37, 87-99.

Heyderman, R.S., Davenport, V. and Williams, N.A. (2006) Mucosal immunity and optimizing protection with meninglococcal serogroup B vaccines. Trends Microbiol. 14, 120-124.

Ola, T.O. and Williams, N.A. (2006) Protection of non-obese diabetic mice from autoimmune diabetes by Escherichia coli heat-labile enterotoxin B subunit. Immunol. 117, 262-270.

Horton, R.E., Stuart, J., Christensen, H., Borrow, R., Guthrie, T., Davenport, V., Finn, A., Williams, N.A., Heyderman, R.S. and the ALSPAC Study Team (2005) Influence of age and carriage status on salivary IgA to Neisseria meningitides. Epidemiol. & Infect. 133, 883-889.

Jenkinson, S.R., Williams, N.A. and Morgan, D.J. (2005) The role of intercellular adhesion molecule-1/LFA-1 interactions in the generation of tumor-specific CD8⁺ T cell responses. J. Immunol. 174, 3401-3407.

Guthrie, T., Hobbs, C.G.L., Davenport, V., Horton, R.E., Heyderman, R.S. and Williams, N.A. (2004) Parenteral influenza vaccination influences mucosal and systemic T cell-mediated immunity in healthy adults. J. Infect. Dis. 190, 1927-1935.

Plant, A. & Williams, N.A. (2004) Modulation of the immune response by the cholera-like enterotoxins. Curr. Topics Med. Chem. 5, 509-519.

Apostolaki, M. & Williams, N.A. (2004) Nasal delivery of antigen with the B-subunit of Escherichia coli heat-labile enterotoxin augments antigen-specific T cell clonal expansion and differentiation. Infect. Imm. 72, 4072-4080.

Plant, A., Williams, R.M., Jackson, M.E. & Williams, N.A. (2003) The B-subunit of Escherichia coli heat labile enterotoxin abrogates oral tolerance, promoting predominantly Th2 type responses. Eur. J. Immunol. 33, 3186-3195.

Davenport, V., Guthrie, T., Finlow, J., Borrow, R., Williams, N.A. & Heyderman, R.S. (2003) Evidence for naturally acquired T cell mediated mucosal immunity to Neisseria meningitidis. J. Immunol. 171, 4263-4270.

Smartt, H.J.M., Elder, D.J.E., Hicks, D.J., Williams, N.A. & Paraskeva, C. (2003) Increased NF-κB DNA binding but not transcriptional activity during apoptosis induced by the COX-2-selective inhibitor NS-398 in colorectal carcinoma cells. Brit. J. Cancer 89, 1358-1365.

Jordan, R.W., Hamilton, T.D.C., Hayes, C.M., Patel, D., Jones, P.H., Roe, J.M. & Williams, N.A. (2003) Modulation of the humoral immune response of swine and mice mediated by toxigenic Pasteurella multocida. FEMS Immunol. Microbiol. 39, 51-59.

Richards, C.M., Case, R., Hirst, T.R., Hill, T.J. & Williams, N.A. (2003) Protection against recurrent ocular HSV-1 disease following therapeutic vaccination of latently infected mice. J. Virol. 77, 6692-6699.

Salmond, R.J., Hirst, T.R. & Williams, N.A. (2003) Selective induction of CD8+CD4- thymocyte apoptosis mediated by the B-subunit of Escherichia coli heat-labile enterotoxin. Imm. Lett. 88, 43-46.

Fraser, S.A., deHaan, L., Hearn, A.R., Bone, H.K., Salmond, R.J., Rivett, A.J., Williams, N.A. & Hirst, T.R. (2003) Mutant Escherichia coli heat-labile toxin B-subunit that separates toxoid-mediated signalling and immunomodulatory action from trafficking and delivery functions. Inf. Imm. 71, 1527-1537.

Salmond, R. Luross, J.A. & Williams, N.A. (2002) Immune modulation by the cholera-like enterotoxins. Expert Reviews in Molecular Medicine. 1 October, http://www.expertreviews.org/02005057h.htm.

Turcanu, V. Hirst, T.R. & Williams, N.A. (2002) Modulation of human monocytes by Escherichia coli heat-labile enterotoxin B-subunit; altered cytokine production and its functional consequences. Immunol. 106, 316-325.

Bone, H.K., Eckholdt, S. & Williams, N.A. (2002) Modulation of B lymphocyte signalling by the B-subunit of Escherichia coli heat-labile enterotoxin. Int. Immunol. 14, 647-658.

Luross, J.A., Heaton, C.P.E., Hirst, T.R., Day, M.J. & Williams, N.A. (2002) Escherichia coli heat-labile enterotoxin B-subunit prevents autoimmune arthritis through the induction of regulatory CD4⁺ T cells. Arthritis Rheum. 46, 1671-1682.

Salmond, R., Pitman, R.S., Jimi, E., Soriani, M., Hirst, T.R., Ghosh, S., Rincon, M. & Williams, N.A. (2002) CD8⁺ T cell apoptosis induced by Escherichia coli heat-labile enterotoxin B subunit occurs via a novel pathway involving NF-κB-dependent caspase activation Eur. J. Immunol. 37, 1737-1747.

Nicholls, S.M. & Williams, N.A. (2001) MHC matching and mechanisms of alloactivation in corneal transplantation. Transplant. 72, 1491-1497.

Soriani, M., Williams, N.A. & Hirst, T.R. (2001) Escherichia coli enterotoxin B subunit triggers apoptosis of CD8⁺ T cells by activating transcription factor c-Myc. Infect. Immun. 69, 4923-4930.

Aman, A.T., Fraser, S., Merritt, E.A., Rodigherio, C, Kenny, M., Ahn, M., Hol, W.G.J., Williams, N.A., Lencer, W.I. & Hirst, T.R. (2001) A mutant cholera toxin B subunit that binds GM1-ganglioside but lacks immunomodulatory or toxic activity. Proc. Natl. Acad. Sci. USA. 98, 8536-8541.

Bone, H.K. & Williams, N.A. (2001) Antigen-receptor cross-linking and lipopolysaccharide trigger distinct phosphoinositide 3-kinase-dependent pathways to NF-κB activation in primary B cells. Int. Immunol. 13, 807-816.

Turcanu, V. & Williams, N.A.. (2001) Cell identification and isolation on the basis of cytokine secretion: a novel tool for investigating immune responses. Nature Med. 7, 373-376.

Richards, C.M., Aman, T., Hirst, T.R., Hill, T.J. & Williams, N.A. (2001) Protective mucosal immunity to ocular herpes simplex virus type-1 infection in mice using Escherichia coli heat-labile enterotoxin B-subunit as an adjuvant. J. Virol. 75, 1664-1671.