Investigations into the outcomes of HLA antibody incompatible renal transplantation and the influence of immune memory

• Main Author: Shaw, Olivia Jane
• Other Authors: Vaughan, Robert; Hernandez Fuentes, Maria Puerto
• Published: King's College London (University of London) 2014
• Subjects: 617.4
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.656894

Antibodies specific for donor HLA molecules are seen as a contraindication to renal transplantation. The presence of these antibodies suggests a patient has previously been exposed to non-self HLA, with resulting immune response and memory generation. Immune memory allows for a rapid response upon re-exposure, manifesting as rapid acute rejection. Antibody removal pre-transplant facilitates transplantation across HLA antibody incompatibilities, however there is no rationale as to which patients will benefit from this treatment. I have developed a testing procedure to identify which patients are suitable for antibody removal and the amount required to allow transplantation from a specified donor. I hypothesised that patients producing HLA specific antibody to previous mismatches will have both cellular and humoral memory to those antigens, and therefore be at greater risk of rejection and graft failure, compared to patients with HLA specific antibody but no memory of the mismatches with which they are presented. By observing outcomes I have investigated the effect that a repeat HLA mismatch with antibody, and therefore presumed memory, has on outcome, with patients in this category having reduced graft survival at 5 years and a shorter time to rejection. Whilst HLA specific antibody is relatively simple to define in the laboratory, donor specific memory T cells are not. I have also developed a novel assay to identify donor specific memory T cells pre transplant, through their production of IL-17 on stimulation. This predicted T cell mediated rejection with 100% accuracy in the patient group tested. However the presence of memory T cells did not correlate with repeat mismatches or the presence of HLA specific antibody. The conclusions are that repeat mismatches influence humoral memory but are not obviously indicative of T cell memory, which cannot in this assay system be predicted based on the presence of a repeat mismatch or HLA specific antibody.