Exploring the Links Between Regulatory T cell Populations and Development of HLA Antibodies in Renal Patients Awaiting Transplantation.

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Kidney transplantation is the gold-standard treatment for patients with kidney failure. It offers a better quality and longer life than the alternative, which is dialysis. However, half of all patients on the waiting list are disadvantaged because of previous exposure to human tissues, either through receiving a blood transfusion, being pregnant, or having a failed kidney transplant, which results in some of them becoming 'sensitised' to tissue proteins called human leukocyte antigens (HLA). This is detected by the appearance of antibodies (Ab) against HLA in the circulation. HLA sensitisation significantly increases the time a patient spends waiting for a suitable kidney, increases the chance of a patient dying whilst awaiting a suitable kidney, and also causes a shortened life-span of a kidney once transplanted. The latter problem arises because the patients' immune system is 'boosted' by the sensitisation to cause more aggressive rejection, similar to the boost the immune system gets from a vaccine to protect against infection. Surprisingly little is known about the biological mechanisms that result in some patients becoming sensitised whilst others remain unsensitised, and less is known about why different routes of sensitisation (i.e. pregnancy vs. previous transplant, for instance), appear to promote different problems. Not surprisingly, there is no reliable way to prevent sensitisation.This project will attempt to understand the biological mechanisms that promote or prevent sensitisation. I hope my findings will provide the foundation for novel strategies to prevent sensitisation in all. My hypothesis is that differences in patients' natural immune regulatory mechanisms, primarily those mediated by a specific type of cell called 'Regulatory T cells' or Tregs, are what differentiates those who become sensitised from those who do not, and that these cells underpin the differences seen when patients become sensitised by pregnancy or a previous transplant. Tregs exist in nature as a defence mechanism to suppress inflammatory responses and prevent autoimmune diseases, but are made up of various different types, varying in potency, stability and ability to move between certain tissues. I will study the numbers of Tregs and the mix of the different subtypes in patients with a failing transplant who are transitioning onto dialysis, as well as renal patients who become pregnant (who will be in the main non-transplant patients). In addition, I will perform analyses of the functional capacity of patient Tregs to suppress other T cells, and using a recently described assay, to suppress B cell manufacture of Ab. I expect to show differences in Tregs between those who develop HLA Ab and those who do not, and to show that Tregs in pregnancy differ in phenotype and functional ability from those suffering a transplant failure. The final part of my project is more exploratory and looks towards a potential strategy of enhancing the ability of all Tregs to suppress sensitisation. It builds upon preliminary data I generated during my ACF research project. Tregs can be influenced by multiple different signals, including inflammatory signals that act through a variety of different receptors. Following on from unpublished work of my supervisors, I showed that human Tregs express a family of receptors called protease activated receptors (PAR), one member of which (PAR-4) appears to be basally stimulated to reduce Treg suppressive capacity. I will attempt to identify the enzyme responsible for the basal stimulation, with a view to showing that inhibiting it, or inhibiting PAR-4 signalling, can enhance the suppressive capacity of Tregs. This strategy may prove a valuable adjunct in any future intervention based upon enhancing the suppressive ability of Tregs to prevent HLA sensitisation.