A Biophysical approach towards exploiting the clinical potential of Alloreactive T-cell recognition

Lead Research Organisation: University of Birmingham
Department Name: Clinical and Experimental Medicine

Abstract

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Title Protein Structures 
Description Protein structure files submitted to the Protein Data Bank for key T cell receptors and peptide-MHC complexes relating to specific tumour antigen targeting strategies 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2009 
Provided To Others? Yes  
Impact Citation of results/structures in other papers 
 
Title T cell receptor transfectants 
Description Novel T-cell receptors that can be transferred to T cells to confer new and improved specificities for tumour antigen targets. 
Type Of Material Cell line 
Year Produced 2007 
Provided To Others? Yes  
Impact A publication in the journal Gene Therapy, with the group of Professor Hans Stauss. 
 
Description Collaboration with Dr Peter van Endert 
Organisation University of Paris - Descartes
Country France 
Sector Academic/University 
PI Contribution Dr Willcox funded the experiments carried out by Dr van Endert, and incorporated them into an extensive study of HA-1 presentation and recognition, involving a wide range of biophysical and structural techniques carried out in Dr Willcox' laboratory.
Collaborator Contribution Dr van Endert carried out critical transporter assoiated with antigen processing (TAP) binding assays for the HA-1 minor histocompatibility antigen.
Impact The most notable output was a publication in Proceedings of the National Academy of Sciences, details of which are provided below. Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition Nicholls-S, Piper-KP, Mohammed-F, Dafforn-TR, Salim-M, Tenzer-S, van Endert-P, Schild-H, Cobbold-M, Engelhard-VH, Moss-PAH and Willcox-BE. Proc Natl Acad Sci 106(10):3889-94 (2009)
Start Year 2007
 
Description Collaboration with Professor G.S.Besra 
Organisation University of Birmingham
Department College of Life and Environmental Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Dr Willcox' research team initiated a collaboration with Professor Besra, based at the College of Life and Environmental Sciences at the University of Birmingham, to carry out initial studies to define CD1-restricted responses to lipid antigen during tuberculosis
Collaborator Contribution Professor has provided a variety of lipid antigen samples for this research, and expertise in the field of Mycobacterium tuberculosis cell wall biochemistry
Impact A Wellcome Trust-funded project grant (PI, Dr Willcox) resulted from the collaboration, and a manuscript based on work carried out on the grant is currently submitted to Nature Medicine. Details of the grant and publication are outlined below. Wellcome Trust Project Grant "Characterising immune recognition of microbial lipid antigens during human Mycobacterium tuberculosis infection". 2007-2010. Principal applicant: Willcox-BE. Co-applicants: Professor Gurdyal Besra, Professor Ajit Lalvani. Wellcome Trust contribution: £302,391. Grant reference number 080988/Z/06/Z. Publication T cell responses to mycolic acid during tuberculosis are prevalent, dynamic and exhibit memory expansion after curative treatment Montamat-Sicotte-DJ, Millington-K, Willcox-CR, Hingley-Wilson-S, Hackforth-S, Innes-J, Kon-OM, Minnikin-DE, Besra-GS, Willcox-BE and Lalvani-A.
 
Description Collaboration with Professor Hansjorg Schild 
Organisation Johannes Gutenberg University of Mainz
Country Germany 
Sector Academic/University 
PI Contribution Dr Willcox provided funding for the experiments carried out by Professor Schild's laboratory, and incorporated these into an ongoing study on the HA-1 minor antigen, which involved carrying out a range of other biophysical and structural experiments in Dr Willcox' laboratory.
Collaborator Contribution Professor Schild's laboratory carried out mass spectroscopic analysis of extended peptides for a study in Dr Willcox' group on a human minor histocompatibility antigen linked closely to Graft-versus-Leukaemia responses after transplantation.
Impact The most obvious output was a publication in Proceedings of the National Academy of Sciences, which outlined the effects of polymorphism in HA-1 on immunogenicity and T cell recognition. The publication details are outlined below. Publication Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition Nicholls-S, Piper-KP, Mohammed-F, Dafforn-TR, Salim-M, Tenzer-S, van Endert-P, Schild-H, Cobbold-M, Engelhard-VH, Moss-PAH and Willcox-BE. Proc Natl Acad Sci 106(10):3889-94 (2009)
Start Year 2007
 
Description Collaboration with Professor Victor Engelhard and Professor Donald Hunt 
Organisation University of Virginia (UVa)
Country United States 
Sector Academic/University 
PI Contribution Dr Willcox' group carried out a series of structure determinations of phosphopeptide-MHC structures, that helped to explain how peptide phosphorylation may create neoantigens in cancer. These findings were published in Nature Immunology, and provide a basis for targeting of phosphopeptide antigens in cancer immunotherapy.
Collaborator Contribution The group of Professor Hunt provided unpublished sequences of human tumour-associated phosphopeptides presented by class I MHC molecules, and that of Professor Engelhard provided peptide-MHC binding data, as well as intellectual input into the project.
Impact The most notable output is a publication in Nature Immunology, in which Dr Willcox was senior author and his post-doctoral assistant Dr Fiyaz Mohammed, was first author. A second output is a New Investigator Research Grant application by Dr Mohammed, which is to be submitted in January 2010. Details of both the publication and this research grant application are provided below. Grant application Medical Research Council New Investigator Research Grant (To be resubmitted Jan 2010) "Investigating phosphopeptide display by MHC class I - understanding presentation and recognition of transformed self". Projected cost: £541,512. Proposed dates: 2010-2013. Principal applicant: Dr Fiyaz Mohammed. Publication Phosphorylation-dependent interaction of antigenic peptides with the MHC class I: a molecular basis for presentation of transformed self Mohammed-F, Cobbold-M, Zarling-AL, Salim-M, Barret-Wilt-GA, Shabanowitz-J, Hunt-DF, Engelhard-VH and Willcox-BE. Nature Immunology 9(11): 1236-43 (2008)
Start Year 2007