P r o j e c t 1 Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative option for patients with certain hematologic malignancies, including acute myelogenous leukemia (AML), Despite precise matching between stem cell donor and recipient for HI_A genes, outcomes for more than half of patients remain disappointing due to post-transplant complications, such as leukemic relapse and viral reactivation. Activation of donor natural killer (NK) cells, key components ofthe innate immune system, can significantly prevent these complications and Improve HCT outcomes. NK response is dictated by interactions between the NK KIR receptors and their HLA ligands. Determining which KIR/HLA interactions most potently impact NK function and understanding how these Interactions take place is vital to the ultimate objective of selecting donors based on KIR and HLA to favor NK activation and improve HCT outcomes.
The first aim ofthe proposal uses a unique transgenic mouse system and FRET technology to demonstrate that inhibitory KIR molecules interacting with HLA presented by adjacent cells (trans) as well as by the NK cell itself (cis) can both shape NK function. These results are directly relevant to predicting NK response in HLA-matched and mismatched HCT.
The second aim i s to show that the activating KIR2DS1 and KIR3DS1 contribute in an HLA-dependent manner to the functional capacity of the cell, explaining findings that KIR2DS1 in patients with the KIR ligand HLA-C1 is associated with lower relapse following HCT and that KIR3DS1 is associated with lower CMV reactivation. Findings from Alms 1 and 2 will support the concept that to capture NK activation In HCT, one must minimize NK inhibition. A novel donor selection algorithm based on KIR/HLA genotypes to maximize NK activity and improve HCT outcomes Is presented.
The third aim seeks to apply this algorithm to donor selection, comparing outcomes post-selection with historic outcomes of HCT patients. Successful demonstration ofthe algorithm's feasibility and clinical impact will potentially change donor selection from an HIA-based strategy to a KIR/HLA-based strategy that will take advantage of innate immune effects against infection and relapse without increasing the risk of T-cell alloreactivity and graft-versus-host disease.
Natural killer (NK) cells are a vital component ofthe body's immune system, protecting the individual from viral infections and from developing cancer. This proposal is designed to help bone marrow transplant doctors understand what controls NK cells so that they can use NK cells and the immune system to fight viral infections and leukemia. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Proiect/Perfonnance Site Fomiat Page) Project/
|Tarek, N; Gallagher, M M; Chou, J F et al. (2015) KIR and HLA genotypes have no identifiable role in single-unit dominance following double-unit umbilical cord blood transplantation. Bone Marrow Transplant 50:150-2|
|Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie et al. (2014) Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41:579-91|
|Dubrovsky, Leonid; Pankov, Dmitry; Brea, Elliott Joseph et al. (2014) A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR-ABL+ leukemias. Blood 123:3296-304|
|Maguire, William F; McDevitt, Michael R; Smith-Jones, Peter M et al. (2014) Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for ?-particle radioimmunotherapy of cancer. J Nucl Med 55:1492-8|
|Olson, Amanda L; Dahi, Parastoo B; Zheng, Junting et al. (2014) Frequent human herpesvirus-6 viremia but low incidence of encephalitis in double-unit cord blood recipients transplanted without antithymocyte globulin. Biol Blood Marrow Transplant 20:787-93|
|Curran, Shane A; Romano, Emanuela; Kennedy, Michael G et al. (2014) Phenotypic and functional activation of hyporesponsive KIRnegNKG2Aneg human NK-cell precursors requires IL12p70 provided by Poly(I:C)-matured monocyte-derived dendritic cells. Cancer Immunol Res 2:1000-10|
|Dahi, P B; Ponce, D M; Devlin, S et al. (2014) Donor-recipient allele-level HLA matching of unrelated cord blood units reveals high degrees of mismatch and alters graft selection. Bone Marrow Transplant 49:1184-6|
|Dahi, Parastoo B; Ponce, Doris M; Devlin, Sean et al. (2014) "No wash" albumin-dextran dilution for double-unit cord blood transplantation is safe with high rates of sustained donor engraftment. Biol Blood Marrow Transplant 20:490-4|
|Tyler, Eleanor M; Jungbluth, Achim A; Gnjatic, Sacha et al. (2014) Cancer-testis antigen 7 expression and immune responses following allogeneic stem cell transplantation for multiple myeloma. Cancer Immunol Res 2:547-58|
|Pai, Sung-Yun; Logan, Brent R; Griffith, Linda M et al. (2014) Transplantation outcomes for severe combined immunodeficiency, 2000-2009. N Engl J Med 371:434-46|
Showing the most recent 10 out of 304 publications