ISTM

Research alongside my clinical training began with an MRC-sponsored student project at Southampton University on interstitial collagenase: cellular origin and expression in human liver fibrosis, supervised by Prof Michael Arthur at Southampton General Hospital.

At PhD level I studied Cellular and molecular mechanisms in liver transplant tolerance, supervised by Prof David Adams at the MRC Centre for Immunoregulation, Birmingham. Initially human sinusoidal endothelial cells were assessed in vitro for their ability to present antigen and modulate an allo-immune response. Human spleen dendritic cells (DCs) were used as a positive control antigen-presenting cell in these experiments and whilst working with the cells I became increasingly interested in liver DCs and their role in initiating allo-responses. I devised a novel method of isolating these cells from human liver and went on to characterise their phenotype and function. I also carried out a study of the regulation and expression of chemokine receptors on liver infiltrating T cells during graft rejection.

Collaborators in this work included:
• Professor Jonathon Lamb, Edinburgh University, to investigate the possible role of Jagged and Notch in hepatic dendritic cell function. This work was funded by a project grant awarded to Prof Adams and myself from the Roche Organ Transplantation Research Foundation.
• Professor Neil Barclay, Oxford to investigate a novel cell surface molecule OX2 (CD200).
• Dr Chris Mueller, at the Pasteur Institute, Paris to show that a novel member of the TNF superfamily called TRANCE is expressed on hepatic DCs and that it may play a critical role with its receptor RANK in determining DC survival.
• Prof Angus Thomson, University of Pittsburgh, where I presented my work on human hepatic DCs and observed some of their studies on murine hepatic DCs.

Ongoing research in clinical immunology has been in collaboration with Prof Eamonn Maher in the Department of Medical and Molecular Genetics, Birmingham Medical School. Two paediatric samples processed in our laboratory had distinctive lymphocyte immuno-phenotyping, and this prompted me to look at them further (poster presentation ESID 2005). I established links with clinical genetics and then found that Professor Maher had special expertise in studying genetic defects in consanguineous families. I carried out some of the work to exclude candidate genes such as the CD3 subunits. We then looked at the whole genome and homozygosity mapping highlighted the area containing the TCRalpha gene. Further sequencing and cell biological studies confirmed this gene defect as the cause of the immunodeficiency.

Prof. Maher, Dr Hackett (paediatric immunologist) and I are now studying a large consanguineous family with neutropaenia, poor neutrophil migration and recurrent sepsis, and another family with a T cell defect. I am keen to continue this collaboration. I am particularly interested in partial T cell defects with the perhaps surprising combination of immunodeficiency and autoimmunity.

ISTM research theme: Infection, Inflammation and Immunity

Research interests:

• clinical immunology
• immunodeficiency

Collaborators:

• Professor Eamonn Maher, Department of Medical and Molecular Genetics, Institute of Biomedical Research, Birmingham University. 
• Dr Scott Hackett, Consultant Paediatric Immunologist, Birmingham Heartlands Hospital, Birmingham.

Peer-reviewed papers:

Morgan, NV; Goddard, S; Cardno, TS; McDonald, D; Rahman, F; Barge, D; Ciupek, A; Straatman-Iwanowska, A; Pasha, S; Guckian, M; Anderson, G; Huissoon, A; Cant, A; Tate, WP; Hambleton, S; Maher, ER (2011) Mutation in the TCR alpha subunit constant gene (TRAC) leads to a human immunodeficiency disorder characterized by a lack of TCR alpha beta(+) T cells. J Clin Invest. 2011 Feb. 121(2):695-702.   DOI: 10.1172/JCI41931   

Lai WK, Curbishley SM, Goddard S, Alabraba E, Shaw J, Youster J, McKeating J, Adams DH. Hepatitis C is associated with perturbation of intrahepatic myeloid and plasmacytoid dendritic cell function. J Hepatol. 2007 Sep;47(3):338-47.

Goddard S, Youster J, Morgan E and Adams D.H. IL-10 secretion differentiates dendritic cells from human liver and skin. Am J Pathol. 2004 Feb;164(2):511-9.

Cremer I, Dieu-Nosjean M-C, Maréchal S, Dezutter-Dambuyant C, Goddard S, Adams D, Sautès-Fridman C, Fridman W and Mueller C. Homeostasis of immature dendritic cells mediated by TRANCE-RANK interaction. Blood. 2002 Nov 15;100(10):3646-55.

Grant G, Goddard S, Hübscher S, Briskin M, Wu L & Adams D. Hepatic expression of secondary lymphoid chemokine promotes the development of portal associated lymphoid tissue in chronic inflammatory liver disease. Am J Pathol. 2002;160(4):1445-55.

Goddard S, Williams A, Morland C, Qin S, Gladue R, Hubscher SG, and Adams DH. Differential expression of chemokines and chemokine receptors in the inflammatory response in rejecting human liver transplants. Transplantation 2001 ;72(12):1957-67.

Iredale JP, Goddard S, Murphy G, Benyon RC, Arthur MJ. Tissue inhibitor of metalloproteinase-I and interstitial collagenase expression in autoimmune chronic active hepatitis and activated human hepatic lipocytes. Clin Sci (Colch). 1995 Jul;89(1):75-81.

Benyon RC, Iredale JP, Goddard S, Winwood PJ, Arthur MJ. Expression of tissue inhibitor of metalloproteinases 1 and 2 is increased in fibrotic human liver. Gastroenterology. 1996 Mar;110(3):821-31.

Review articles:

Goddard S and D Kelly. Is there any immunological advantage to live related donor liver transplantation in paediatric recipients? Pediatric Transplantation. Invited editorial 2002 Oct 6(5):364.

S Goddard and DH Adams. New approaches to immunosuppression in liver transplantation. J Gastroenterology and Hepatology. 2002 17 (2); 116-126.

S Goddard and DH Adams. Methylprednisolone therapy for acute rejection: Too much of a good thing? Liver Transpl. 2002;8(6):535-6.

Goddard S, Adams DH. Another nail in the coffin for conventional immuno-suppressive regimes with the advent of tolerising regimes. Transplantation. 2001;72(1):11-2.

S Goddard, J Pirenne, DH Adams. Immunological Tolerance and future strategies for immunosuppression in liver transplantation. In Treatment of Liver Diseases. Eds Arroyoy, Bosch, Bruguera, Rodes, Sanchez Tapias. Section 4 pages 197 – 204. Masson SA (Barcelona) 1999.