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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA111412-04
Application #
7669389
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$371,664
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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
Oh, Felix; Todhunter, Deborah; Taras, Elizabeth et al. (2018) Targeting EGFR and uPAR on human rhabdomyosarcoma, osteosarcoma, and ovarian adenocarcinoma with a bispecific ligand-directed toxin. Clin Pharmacol 10:113-121
Rashidi, Armin; Ebadi, Maryam; Said, Bassil et al. (2018) Absence of early HHV-6 reactivation after cord blood allograft predicts powerful graft-versus-tumor effect. Am J Hematol :
Bachanova, Veronika; Sarhan, Dhifaf; DeFor, Todd E et al. (2018) Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer Immunol Immunother 67:483-494

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