Diverse and polymorphic killer cell immunoglobulin-like receptors (KIR) interact with highly polymorphic HLA class I ligands to regulate the development and effector functions of natural killer (NK) cells. The KIR gene family on human chromosome 19 varies In gene content and allelic polymorphism to give two distinctive forms of haplotype: A and B, that are the fundamental basis of KIR variability. We have shown for unrelated T-cell replete hematopoietic cell transplantations for acute myelogenous leukemia (AML) that the outcome of transplantation is significantly improved if the donor carries one or two KIR B haplotypes.
Aim 1 ofthe proposed investigation will perform genetic analysis, and study of further transplant cohorts, to assess the contribution of the telomeric and centromeric halves of the B haplotype to beneficial transplant outcome, and the role of the individual B haplotype specific genes and alleles.
Aim 2 will comJDare the HLA class I specificity and avidity of the various KIR isotypes and allotypes that distinguish A and B KIR haplotypes, with emphasis on B-specific KIR. This analysis will use a recently developed binding assay that is markedly more sensitive and reliable than previously used assays, and will examine the full range of HLA class I variation. The functional effects of positive binding reactions will be tested using an in vitro assay of cellular cytotoxicity in which single defined KIR variant interacts with a single defined HLA class I variant. Defined combinations of KIR will also be examined. The results from the functional analysis will be used, to develop rnore informed and new hypotheses, that will be tested by further retrospective analysis of the cohort of >1000 AML transplants studied in Aim 1. Thus the progress of investigation will logically move from bedside to bench and then back to bedside. This project will determine functional differences between the A and B haplotype KIR and determine which of these factors contribute to life-enhancing effect ofthe B haplotype in transplantation for acute myelogenous leukemia. The results should refine the genetic assessment of potential donors for transplantation, and thus improve the outcome of life-saying therapeutic transplantation for life-threatening leukemia.

Public Health Relevance

This project will identify which NK cell receptors of donor origin are important for improving the outcome of transplantation as therapy for leukemia, and their mechanism of action. This knowledge will refine the selection of transplant donors and guide design of novel cellular therapy for leukernia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-10
Application #
8721713
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$283,825
Indirect Cost
$51,670
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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He, F; Warlick, E; Miller, J S et al. (2016) Lymphodepleting chemotherapy with donor lymphocyte infusion post-allogeneic HCT for hematological malignancies is associated with severe, but therapy-responsive aGvHD. Bone Marrow Transplant 51:1107-12
Weisdorf, Daniel (2016) The role of second transplants for leukemia. Best Pract Res Clin Haematol 29:359-364
Sarhan, Dhifaf; Cichocki, Frank; Zhang, Bin et al. (2016) Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. Cancer Res 76:5696-5706
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Holtan, Shernan G; DeFor, Todd E; Lazaryan, Aleksandr et al. (2015) Composite end point of graft-versus-host disease-free, relapse-free survival after allogeneic hematopoietic cell transplantation. Blood 125:1333-8
Schlums, Heinrich; Cichocki, Frank; Tesi, Bianca et al. (2015) Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42:443-56

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