Profile: Dr Ken Smith
Title: University Lecturer
Contact: Tel: 01223 762 645; Secretary: Denise Schofield Tel:
01223 762 812 E-mail: email@example.com
Home department: Medicine
Negative regulation of the immune response in health and disease
The immune response is controlled by cell surface molecules which act as negative
regulators or brakes, preventing or turning off cellular activation. Knockout
mice with defects in these negative regulatory systems develop immune hyperactivity
and autoimmunity. Our group aims to understand how these molecules regulate
the normal immune response, and how defects in their action cause autoimmune
- Negative regulation and the normal immune response.
We have shown that interleukin-4 reduces expression of negative regulators
on B cells, suggesting that IL-4 may enhance the B cell immune response by
releasing the B cell from inhibition, rather than by directly activating it.
We are investigating the functional consequences of this reduced expression,
and whether IL-4 has a similar effect in other cell types. In addition, we
are studying the role played by the inhibitory Fc receptor FcγRII in
feedback control of the B cell response and on affinity maturation.
- Defective negative regulation and autoimmune disease.
Systemic lupus erythematosus (SLE) is an autoimmune disease arising from
the combined effects of multiple susceptibility genes. Fcg
RIIb inhibits activation of cells including B cells and macrophages. We have
identified reduced expression and function of Fcg
RII in all major SLE-prone mouse strains. The resulting immune hyperactivity
is likely to make a fundamental contribution to disease. We are examining
how reduced Fcg RII causes autoimmunity, and
how such genetic "defects" have evolved in the wild mouse population.
- The B cell immune response and viral immune modulators.
We are analysing how murine γ-herpesvirus 68 (related to human Epstein
Barr virus) influences B cell gene expression using microarray technology and
viruses deficient in potential immmunomodulatory genes [with Dr Paul Lyons (profile),
DIL, and Dr Stacey Efstathiou, Virology].This should provide insight not only
into mechanisms of viral pathogenesis, but may also identify novel B cell signalling
- The Wellcome Trust
- Medical Research Council
- Menna Clatworthy
- Tony Cutler
- Gisela Gamba Fernandez
- Andres Floto
- Jim Hair
- Karen Heilbronn
- Nick Pritchard
- Liz Rudge
- Rudge E.R., Cutler A.J., Pritchard N.R. & Smith K.G.C.
(2002) "Interleukin -4 reduces expression of inhibitory receptors
on B cells and abolishes CD22 and FcgRII-mediated B cell suppression"
Journal of Experimental Medicine. 195, 1079-1085.
- Pritchard, N.R., Cutler, A.J., Uribe, S., Chadban, S.J., Morley, B.J.
& Smith, K.G.C.(2000). "Autoimmune-prone mice share an Fcgr2
promoter haplotype associated with reduced expression and function of the
negative regulatory Fc receptor FcγRII." Current Biology
- Smith, K.G.C., Light, A., O’Reilly, L.A., Ang, S.M., Strasser, A.
& Tarlinton, D.M. (2000). "bcl-2 transgene expression
inhibits apoptosis in the germinal center and reveals differences in the selection
of memory B cells and bone marrow antibody forming cells." Journal
of Experimental Medicine 191, 475-484.
- Tarlinton, D.M. & Smith, K.G.C. (2000). "Dissecting affinity
maturation — a model explaining selection of antibody forming cells and
memory B cells in the germinal centre." Immunology Today 21,
- Smith, K.G.C., Tarlinton, D.M., Doody, G.M., Hibbs, M.L. & Fearon,
D.T (1998). "Inhibition of the B cell by CD22: a requirement for
Lyn" Journal of Experimental Medicine. 187,
- Pritchard NR, Cutler AJ, Uribe S, Chadban SJ, Morley BJ and Smith KGC. "Autoimmune-prone
mice share an Fcgr2 promoter haplotype associated with reduced expression
and function of the negative regulatory Fc receptor FcRII." Current
- Smith KGC, Light A, O’Reilly LA, Ang SM, Strasser A and Tarlinton DM
"bcl-2 transgene expression inhibits apoptosis in the germinal
center and reveals differences in the selection of memory B cells and bone
marrow antibody forming cells." Journal of Experimental Medicine 2000;
- Calne RY, Moffatt SD, Friend PJ, Jamieson NV, Bradley JA, Hale G, Firth
JD, Bradley JR, Smith KGC and Waldmann H. "Prope tolerance with induction
using campath 1H and low-dose cyclosporin monotherapy in 31 cadaveric renal
allograft recipients." Nippon Geka Gakkai Zasshi 2000; 101: 301-306.
- Cozzi E, Bhatti FNK, Schmoeckel M, Chavez G, Smith KGC, Zaidi A, Bradley
JR, Thiru S, Goddard M, Vial C, Morgan P, White DJG and Friend PJ. "Long-term
survival of non-human primates receiving life-supporting transgenic porcine
kidney xenografts." Transplantation 2000;70:15-21.
- Tarlinton DM and Smith KGC. "Dissecting affinity maturation —
a model explaining selection of antibody forming cells and memory B cells
in the germinal centre." Immunology Today 2000; 21: 436-441.
- Masroor S, Cozzi E, Soin B, Vial C, Chavez G, Smith KGC, Bradley JR, White
DJ and Friend PJ "Absence of hyperacute rejection and preservation of
function in HDAF transgenic pig kidneys exposed to prolonged cold ischaemia."
Transplantation Proceedings 2000;32:965-966.
- Chadban SJ, Bradley JR and Smith KGC. "Clinical Immunosuppression in
Renal Transplantation" in Thiru S and Waldmann H (editors) "Pathology
and Immunology of Transplantation" Blackwell Science, London 2000;180-215.
- Soin B, Cozzi E, Ostlie D, Smith KGC, Bradley JR, White DJG and Friend PJ
"Growth of porcine kidneys in the normal and xenotransplant environment"
- Tarlinton DM, Light A, Smith KGC and Nossal GJV "Affinity maturation
in the B cell response to antigen". The Immunologist 2001; 8:9-11
- Reed MJ, Alexander GJM, Thiru S and Smith KGC. "Hepatitis C-associated
glomerulonephritis: a novel therapeutic approach." Nephrology Dialysis
- Soin B, Smith KGC, Zaidi A, Cozzi E, Bradley JR, Ostlie D, Lockhart A, White
DJG and Friend PJ "Physiological aspects of pig-to-primate renal xenotransplantation"
Kidney International 2001;60:1592-1597.
- Clatworthy MR and Smith KGC "B cells and autoimmune disease" in
Lightstone EB and Friedland JS (eds) Postgraduate Medical Sciences Series
"Infection and Immunity", Harwood Academic 2001: in press.
- Rudge ER, Cutler AJ, Pritchard NR and Smith KGC. "Interleukin -4 reduces
expression of inhibitory receptors on B cells and abolishes CD22 and FcgRII-mediated
B cell suppression" Journal of Experimental Medicine 2002:195;1079-1085.
- Pritchard NR and Smith KGC "B cell inhibitory receptors and autoimmunity"
- Floto RA and Smith KGC "The vagus, macrophages and nicotine".
The Lancet 2003:361;1069-1070
- Willcocks L and Smith KGC "Renal Transplantation". Medicine, 2003:
- Marques S, Efstathiou S, Smith KGC, Haury M and Simas JP. "Selective
Gene Expression of Latent Murine Gammaherpesvirus 68 in B Lymphocytes."
2003: Journal of Virology 2003: in press
Last updated: 8 May 2003