The role of KIR genes and NK alloreactivity on allogeneic haematopoietic stem cell transplantation

[Truncated abstract] NK cell cytotoxicity is regulated by a balance of inhibitory and activating signals from receptors expressed on the cell surface. NK cell cytotoxicity is inhibited when inhibitory receptors such as Killer immunoglobulin-like receptors (KIR) interact with self class I MHC molecules on potential targets. Class I HLA incompatibility in haematopoietic stem transplantation (HSCT) may therefore result in the potential for NK alloreactivity. The interaction of KIR and class I MHC molecules, and the role they play in NK alloreactivity in HSCT is investigated in this thesis. In related haploidentical transplants, donor and recipient pairs are mismatched for one haplotype, while in matched unrelated donor (MUD) transplants traditionally typed for HLA-A, -B and –DRB1 only, HLA-C is often mismatched. In both these transplant settings, there is potential for NK alloreactivity. Ruggeri et al (Ruggeri et al. 1999 and 2002) demonstrated in AML patients receiving haploidentical HSCT, NK alloreactivity in the graft-versus-host (GVH) direction resulted in less relapse, rejection and aGVHD. Based on these results I investigated whether these benefits could be observed in other allo-transplant protocols. I also investigated the interaction of KIR receptors with their ligands in a more systematic way than previously published. I firstly developed a robust PCR-SSP KIR genotyping method which incorporated, (i) an internal PCR control (amplification of human growth hormone) to allow detection of false negatives and (ii) new primers to amplify KIR alleles not amplified by the primers described by Uhrberg et al (Uhrberg et al. 1997). This method was then validated in a multi-laboratory evaluation. Using this KIR genotyping method, I retrospectively KIR genotyped donors of haploidentical HSCT and HLA-C mismatched MUD transplants performed in Israel.