The overall objective of this project is to investigate the role of natural killer (NK) cells in allogeneic marrow transplantation with emphasis on their influence on graft rejection, residual leukemia and leukemia relapse. The goal is to develop a DNA based typing system ofor the Killer Cell Inhibitory Receptors (KIR) expressed on NK cells and to investigate how matching donors and recipients for these receptors will affect the outcome of marrow transplantation. KIRs are ligands for HLA class I molecules and some KIRs mediate inhibitory signals for NK cells while others transduce activating signals. At present, 40 different cDNA clones encoding KIRs have been identified.
The specific aims for the projects are: (i) To determine the exon- intron organization of genomic KIR genes and develop a genomic map for the KIR genetic region. (ii) to develop a PCR-DNA based typing method for KIRs encoded by the individual KIR genes. (iii) To apply this typing method to a panel of unrelated individuals and pairs of HLA identical siblings and perform family segragation analysis for individual KIRs. New KIR genes will be identified and characterized by neucleotide sequencing of clones genes. (iv) To develop a gene specific RT-PCR method for detection of individual KIRs expressed on NK cells. (v) To determine the IKR genotype in patients and their marrow donors and determine if patients experiencing graft-rejection, poor graft function or relapse of leukemia can be distinguished from patients without these clinical events. (vi) To determine the pattern of reconstitution of the KIR repertoire as it develops in themarrow transplant recipient during the post-transplantation period. This project should determine if matching for KIR between donors and recipients of allogeneic marrow grafts will affect the risk for graft rejection and the risk for minimal residual disease and relapse of leukemia. We will simultaneously investigate the KIR repertoire development in the post- transplantation period and determine if this influences transplant outcome.
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