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 #
5P01CA111412-09
Application #
8533759
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$275,915
Indirect Cost
$50,311
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Pugh, Jason L; Nemat-Gorgani, Neda; Norman, Paul J et al. (2018) Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage. J Immunol 200:1146-1158
Cichocki, Frank; Wu, Cheng-Ying; Zhang, Bin et al. (2018) ARID5B regulates metabolic programming in human adaptive NK cells. J Exp Med 215:2379-2395
Grzywacz, Bartosz; Moench, Laura; McKenna Jr, David et al. (2018) Natural Killer Cell Homing and Persistence in the Bone Marrow After Adoptive Immunotherapy Correlates With Better Leukemia Control. J Immunother :
Sarhan, Dhifaf; Hippen, Keli L; Lemire, Amanda et al. (2018) Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37. Cancer Immunol Res 6:766-775
Williams, Robin L; Cooley, Sarah; Bachanova, Veronika et al. (2018) Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells. Biol Blood Marrow Transplant 24:618-622
Don Yun, Hyun; Felices, Martin; Vallera, Daniel A et al. (2018) Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity against neoplastic mast cells. Blood Adv 2:1580-1584
Cooley, Sarah; Parham, Peter; Miller, Jeffrey S (2018) Strategies to activate NK cells to prevent relapse and induce remission following hematopoietic stem cell transplantation. Blood 131:1053-1062
Williams, Shelly M; Sumstad, Darin; Kadidlo, Diane et al. (2018) Clinical-scale production of cGMP compliant CD3/CD19 cell-depleted NK cells in the evolution of NK cell immunotherapy at a single institution. Transfusion 58:1458-1467
Romee, Rizwan; Cooley, Sarah; Berrien-Elliott, Melissa M et al. (2018) First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood 131:2515-2527

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