Killer-cell immunoglobulin-like receptors (KIR) are encoded by a diverse, polymorphic gene family in the leukocyte receptor complex on human chromosome 19. KIR are expressed in combinationswhich distinguish clones of natural killer (NK) cells, also subpopulations of yS and memory-type upT cells. Interactions between inhibitory KIR and MLA class I ligands determine the specificity of alloreactive NK cells, which reject tone marrow allografts in animal models and are implicated in beneficial grafl-versus-leukcmia effects in patients receiving HLA haploidentical hematopoietic cell transplants (HCT). KIR genotype diversity in human populations is so extensive that almost every HLA-matched HCT between an unrelated donor and recipient involves some form of KIR mismatch. Preliminary studies from several groups point to KIR genotype and KIR mismatch having influences on the clinical outcome of HLA-matched allogeneic HCT. Limiting these studies has been the small numbers of transplants studied and poor resolution in the methods used for KIR detection and analysis. These factors in combination with differences in study population and transplant protocols likely contribute to apparent inconsistencies in the findings. The proposed project aims to address these limitationsby performing a larger and more sensitive study of the effect of KIR variation on the outcome of allogeneic HCT. Retrospective analysis will be performed on the unrelated donor-recipient pairs from 600 HCT in which HLA-matched unrelated donors were selected through the auspices of the National Marrow Donor Program (NMDP).
In Aim 1 KIR genotype will be defined at high resolution and KIR phenotypes will be determined using flow cytomctry and anli-KIR antibodies. Both genotyping and phenotyping methods have the potential to identify new variant KIR, which in Aim 2 will be characterised and their nucleotide sequences used to refine the system of genotyping.
Aim 3 will, rigorously test a set of hypotheses to correlate genotyptc and phenotypic aspects of KIR variation and mismatch with the clinical outcome of transplantation.
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