Defining the Genomic Organisation of the Killer Cell Inhibitory Receptor (KIR) Locus Human Chromosome 19 - Key for a KIR DNA - Typing System

Natural killer cells (NK) cells play an important role in the early human immune response. on major task for these NK cells is the identification of "self, e.g. healthy tissue, or "non self", e.g. cancer tissue. Activation of NK cells (attacking anon self), is likely to be induced by soluble factors e.g. interferons, cytokines and chemokines and certain membrane bound molecules on surrounding tissue. Opposite regulation is mediated by inhibitory receptors and cytokines that Jim and potentially terminate the response. The inhibition of NK cell-mediated activation (e.g. cytotoxicity) is regulated by two types of certain membrane receptors that recognize "self presenting" HLA class I molecules on target cells receptors of the immunoglobulin superfamily, called Killer Cell Inhibitory Receptors (KIR) are specific for determinants shared by subsets of Human Leucocyte Antigen (HLA)-A, -B, or -C types, whereas the other (activation-) inhibiting receptor: ("CD94:NKG2A), is specific for a determinant shared by most HLA-A, -B and -C types. Recent studies demonstrate a huge variety among the killer cell inhibitory receptors. The evident, individually different genetic combination of the KIR multigene locus suggests an immunological relevance of the polymorphism itself, probably comparable to that of HLA. Since knowledge is incomplete, it is the major intent of this project to understand and elucidate the genomic organisation of the KIR genes. Although genomic analyses of the KIR genes and a preliminary map of the KIR complex have been reported, the number and organisation of the KIR genes on human chromosome 19 have yet to be defined. Preliminary mapping indicated that the region of human chromosome 19q13.4, containing the KIR genes is greater than 100 kbp long. Definition of this genomic region is an absolutely mandatory step towards understanding the KIR function and their importance in transplantation (as receptors for blocking allorecognition or inducing anergy) and tumor immunity.