Professor Andrew George

Molecular Immunotherapy Laboratory

Our work focuses on understanding the molecular process involved in immunological responses, and harnessing them for the treatment of disease.

Within this broad remit the laboratory has particular interests in corneal transplantation, in dendritic and endothelial cells, in using antibodies to target gene therapy vectors and contrast agents for imaging, induction of tolerance (including during xenotransplantation) and using mathematical and computer models to help understand the specificity of the immune system.

Corneal transplantation

The cornea is the most commonly transplanted organ, with around 40 000 grafts performed every year in the USA alone. It is commonly thought that corneal grafts are not rejected, as the eye is an immune privileged site. However, this is not the case, and around a quarter of all grafts are lost within 4-5 years, in most cases due to immunological rejection of the cornea. In this laboratory, in work that is led by Andrew George and Frank Larkin, we are investigating the mechansisms by which the grafts are rejected, as well as devising methods to prevent or reduce rejection. This includes the administration of recombinant immunomodulatory proteins as well as gene therapy.

Antibody targeting

We have developed methods of using antibodies to target gene therapy vectors, including liposomes and dendrimers, to particular tissues. We have concentrated on vascular and corneal endothelium, and have shown specific delivery using antibodies directed against adhesion molecules. This allows specific delivery of the gene construct to activated endothelium. This work is carried out in collaboration with Martin Weber (Qiagen), Lance Twyman (Sheffield) as well as Dorian Haskard from NHLI.

Magnetic resonance imaging (MRI) provides extremely detailed anatomical information. However, the amount of functional data that can be obtained is limited. Together with David Edwards (CSC), Dorian Haskard (NHLI), David Larkman (CSC) and Jo Hajnal (CSC) we have developed methods of attaching paramagnetic particules onto antibodies which can act as contrast agents for MRI. This allows us to use MRI to detect inflammatory disease.

Induction of tolerance

Allied to both the above areas is the use of genetic modification to induce tolerance, including during xenotransplantation. This offers the attractive prospect of being able to downregulate the immune response specifically to the graft, without causing generalised immunusuppression. We have developed methods to genetically modify dendritic cells (the cells responsible for initial activation of T cells) so that rather than activating T cells they render them tolerant. We are also developing methods to genetically modify other cells, such as endothelial cells, so that they no longer express adhesion molecules. These strategies, which can be achieved either using gene therapy (for example for allografts) or by trangenesis (in the case of xenotransplantation), are being developed in collaboration with Giovanna Lombardi and Robert Lechler in the Department of Immunology.

Mathematical immunology

In order to understand complex systems, such as the immune system, it is increasingly necessary to use mathematical or computational tools. In collaboration with Jaroslav Stark (Department of Mathematics) we have used a variety of models to explore how the specificity of the immune system. We have concentrated on using these tools to understand how the T cell can be specific for antigen, looking at the level of the T cell receptor for antigen, the cell, and the clone of T cells. In addition we have suggested that the need for tolerance to self antigens may be one of the forces that limits the number of genes in the human genome.

Funding

Work in our laboratory is currently funded by

• BBSRC
• MRC
• Action Reseach
• British Heart Foundation
• Arthritis and Rheumatism Council
• Wellcome Trust

For publications from our laboratory please see Andrew George's personal web page . For details of positions available etc. please email Andrew directly.

Recent publications:

Beutelspacher SC, Tan PH, McClure MO, Larkin DFP, Lechler RI and George AJT (2006) Expression of indoleamine 2,3-dioxygenase (IDO) by endothelial cells: implications for the control of allosponses. Am J of Transplant 6: 1320-1330

Tan PH, Yates J, Xue SA, Jordan WR, Dong R, Ritter MA, Lechler RI, Lombardi G and George AJT (2005) Creation of tolerogenic antigen presenting cells via intracellular CTLA4: a novel strategy with potential clinical utility. Blood 106:2936-2943

Tan PH, Sagoo P, Chan C, Yates JB, Campbell J, Beutelspacher SC, Foxwell BMJ, Lombardi G and George AJT (2005) J Immunol 174:7633-7644

Tan PH, Beutelspacher SC, Xue S-A, Wang Y-H, Mitchell P, McAlister JC, Lar
kin DFP, McClure MO, Stauss HJ, Ritter MA, Lombardi G and George AJT (2005) Blood 105:3824-3832