Genetic polymorphisms for NK cells and acute rejection in human renal transplantation

• Main Author: Windmill, Donna Carol
• Published: University of Leicester 2006
• Subjects: 617.4
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.697329

In the studies described in this thesis I have used Sequence Specific Polymerase Chain Reaction (PCR-SSP) to identify specific Killer Immunoglobulin-like Receptor (KIR) genes and documented single nucleotide polymorphisms in certain chemokines, chemokine receptors, cytokines and adhesion molecules known to be important in leukocyte recruitment. With this information I have analysed whether there is an association between these KIR genes and the stated polymorphisms and acute allograft rejection (AAR) in human renal transplantation. A KIR-ligand effect on AAR following human renal transplantation was demonstrated. An association was seen with particular combinations of donor KIRs with recipient ligand. which implies that a KIR associated predisposition to rejection or protection would be mediated by donor-derived cells targeting recipient ligands. The data indicated that potential recipient alloreactivity was not a factor in acute rejection in our cohorts. On the contrary, it is the circumstances where the effector carrying the receptor is in combination with a ligand positive target that an association is seen, and for KIR2DL2/C1 this appears to be protective. Polymorphisms in the fractalkine receptor/CX3CR 1 impacted upon AAR following human renal transplantation. A significant increase in the frequency of both CX3CR1 249A and 280T alleles in the donors to the AAR+ recipients was seen, which translated to an association between CX3CR1 249AA homozygote donors and CX3CR1 249GA or GG recipients and AAR. These studies indicate the potential need for the development of (i) therapies to target the activity of NK cells and (ii) donor selection based upon genetic characteristics. I performed all the experimental work undertaken in this thesis. I played a central role in the design of these studies and was responsible for their statistical analysis and interpretation.