Killer cell Immunoglobulin-like Receptor (KIR) polymorphism : functional implications and clinical relevance
NK cell function is regulated by Killer-cell Immunoglobulin-like Receptors (KIR) some of which recognise class I Major Histocompatibility Complex molecules. KIRs have been shown to exhibit a high degree of functional diversity which is generated at several levels. However, the functional relevance of this diversity remains largely unknown. This thesis describes our approach towards elucidating the functional relevance of KIR diversity. To study this we first compiled all known KIR sequences into a database. We developed bioinformatics tools to facilitate the study of these sequences and have made both the tools and database publicly accessible online. Subsequent efforts were directed towards investigating the structural impact of KIR polymorphism by means of molecular modelling software. The results that were generated by this approach have provided information with regards to the ligand binding properties of most activating KIR proteins. In addition, we have also developed a KIR gene typing system capable of detecting all known KIR genes as well as the alleles of five of the KIR proteins for which a ligand has been described. We have implemented this KIR typing system to three different sample panels: a reference panel of more than 100 B-lymphoblastoid cell lines (BLCL), a family based KIR haplotype segregation study and a cohort of 141 unrelated donor (UD) haematopoietic stem cell transplant pairs. Our investigations have allowed us to generate the largest KIR typing reference panel, to characterise the KIR profile of a Mexican Mestizo population and to investigate the clinical relevance of KIRs in UD-Haematopoietic Stem Cell Transplantation (HSCT). Our results demonstrate that the beneficial effect of NK alloreactivity in the Graft-versus-Host direction as predicted by Ruggeri's algorithm cannot be applied to the UD-HSCT setting. In addition, I describe our findings relating to the clinical role of KIR genes and alleles in the UD-HSCT cohort.