A successful kidney transplant is the best treatment for established renal failure, yet around 300 patients per annum are denied transplants because they have antibodies, most notably directed against donor HLA or ABO in their blood, which have the potential to cause acute and chronic rejection of the transplant. Such antibodies are present in 25% (roughly 1750 of the 7000 on the kidney transplant waiting list) of the patients listed for a deceased donor transplant. Programmes to remove antibody and transplant patients across HLA antibody barriers have been developed, but are limited by a high rate of acute rejection. This thesis explores the factors which may impact upon the pathogenicity of HLA-specific antibodies and also aims to enhance the understanding of the techniques used in the laboratory to define these antibodies. A range of studies were carried out examining factors such as the IgG subclass composition of the anti-HLA response. Assay variations were designed to enable a higher definition of antibody specificity to be achieved, and for the first time in the literature the direct quantification of HLA-specific antibodies in patient sera was performed. In addition, proof of principle design and testing was carried out on a novel prototype therapeutic device for the selective depletion of HLA-specific antibodies directly from patient plasma and sera. The antibodies isolated from this approach were also used in studies to examine the factors which determine serum cytotoxicity.

Regulatory T cells (Treg) are enriched in tumour tissue relative to other compartments. Anti-tumour immunity is promoted through their depletion. It is hypothesised that Treg are recruited to human colorectal cancer (CRC) via a specific combination of chemokine receptors and integrins, blockade of which reduces tumour Treg recruitment, ameliorating the anti-tumour immune response. A systematic examination was conducted of receptors expressed by CRC-isolated Treg and the cognate ligands expressed by CRC. The effects of receptor inhibition were tested in murine models of colorectal cancer. Human CRC-infiltrating Treg exhibit a specific chemokine receptor signature, expressing significantly higher levels of CCR5 than conventional T cells. CRC expresses the ligands for CCR5 at significantly higher levels than distal tissue. Isolated Treg migrated towards CCR5 ligands in vitro and suppressed allogeneic T cell proliferation. CCR5 inhibition in murine models of CRC led to delayed tumour growth but had no effect on tumour Treg infiltration compared with vehicle control. CCR5 inhibition is unlikely to provide any significant reduction in the infiltration of Treg into human CRC. Given the effects CCR5 inhibition had on tumour growth, CCR5 antagonists command further investigation into their potential role as novel therapeutic agents in the treatment armoury against human CRC.