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.
|Boudreau, Jeanette E; Hsu, Katharine C (2018) Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned. Trends Immunol 39:222-239|
|Lin, Richard J; Ho, Caleb; Hilden, Patrick D et al. (2018) Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with TP53 alterations. Br J Haematol :|
|Malard, Florent; Labopin, Myriam; Cho, Christina et al. (2018) Ex vivo and in vivo T cell-depleted allogeneic stem cell transplantation in patients with acute myeloid leukemia in first complete remission resulted in similar overall survival: on behalf of the ALWP of the EBMT and the MSKCC. J Hematol Oncol 11:127|
|Luduec, Jean-Benoît Le; Kudva, Anupa; Boudreau, Jeanette E et al. (2018) Novel multiplex PCR-SSP method for centromeric KIR allele discrimination. Sci Rep 8:14853|
|Shah, Gunjan L; Moskowitz, Craig H (2018) Transplant strategies in relapsed/refractory Hodgkin lymphoma. Blood 131:1689-1697|
|Avanzi, Mauro P; Yeku, Oladapo; Li, Xinghuo et al. (2018) Engineered Tumor-Targeted T Cells Mediate Enhanced Anti-Tumor Efficacy Both Directly and through Activation of the Endogenous Immune System. Cell Rep 23:2130-2141|
|Staffas, Anna; Burgos da Silva, Marina; Slingerland, Ann E et al. (2018) Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone Marrow Transplantation in Mice. Cell Host Microbe 23:447-457.e4|
|Velardi, Enrico; Tsai, Jennifer J; Radtke, Stefan et al. (2018) Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24:239-246|
|Moskowitz, Craig H (2018) Should all patients with HL who relapse after ASCT be considered for allogeneic SCT? A consult, yes; a transplant, not necessarily. Blood Adv 2:821-824|
|Kim, Seong Jin; Huang, Yao-Ting; Foldi, Julia et al. (2018) Cytomegalovirus resistance in CD34+ -selected hematopoietic cell transplant recipients. Transpl Infect Dis 20:e12881|
Showing the most recent 10 out of 452 publications