This Program Project Grant (PPG) seeks continued support for basic and translational clinical studies in the setting of hematopoietic cell transplantation (HCT). These studies serve as a paradigm for cellular therapeutics and the exploration of immune function for the treatment of cancer. The PPG is composed of five interactive Projects and four Cores focused on the themes of graft vs host disease biology and prevention, disease relapse treatment and prevention and immune reconstitution. The Program utilizes innovative animal modeling, imaging, molecular biological assessment of immunoglobulin and T cell receptor sequencing and novel clinical trial interventional studies with highly purified cell populations to explore the fundamental aspects of transplantation biology and improve outcomes for patients undergoing both autologous and allogeneic HCT. The Projects focus on different aspects of immune effector (conventional and memory CD4+ and CD8+ T cells, cytokine induced killer cells) and regulatory (Treg, NK-T) cell biology, vaccination strategies (CpG stimulated cancer cells), common lymphoid progenitor cell biology and immune recovery in a highly interactive and complementary fashion. In each of the Projects both fundamental biological explorations in animal models and clinical translation in phase 1/11 trials are proposed aimed at enhancing the clinical efficacy of HCT. The Projects and Project leaders are highly interactive using similar animal models, imaging strategies, novel approaches to analysis of T cell receptor sequencing to analyze distinct yet iterative approaches to answer fundamental biological questions and explore translation to the clinic. The four Cores provide administrative, clinical trial, molecular, sample distribution and cellular manufacture support. Ou hypothesis is that through the study of the cellular components of hematopoietic and immunological progenitor, regulatory and effector cells will result in novel insights into improvin immune function resulting in more effective therapy for patients with serious hematological malignancies.

Public Health Relevance

This PPG focuses on the immune basis of hematopoietic cell transplantation and the treatment of patients with severe hematological malignancies. The fundamental and clinical insights gained also have major implications for induction of tolerance in solid organ transplantation and for the treatment of patients with autoimmune disorders.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-J (J1))
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Merritt, William D
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Sega, Emanuela I; Leveson-Gower, Dennis B; Florek, Mareike et al. (2014) Role of lymphocyte activation gene-3 (Lag-3) in conventional and regulatory T cell function in allogeneic transplantation. PLoS One 9:e86551
Hongo, D; Tang, X; Baker, J et al. (2014) Requirement for interactions of natural killer T cells and myeloid-derived suppressor cells for transplantation tolerance. Am J Transplant 14:2467-77
Florek, Mareike; Sega, Emanuela I; Leveson-Gower, Dennis B et al. (2014) Autologous apoptotic cells preceding transplantation enhance survival in lethal murine graft-versus-host models. Blood 124:1832-42
Benjamin, Jonathan; Chhabra, Saurabh; Kohrt, Holbrook E et al. (2014) Total lymphoid irradiation-antithymocyte globulin conditioning and allogeneic transplantation for patients with myelodysplastic syndromes and myeloproliferative neoplasms. Biol Blood Marrow Transplant 20:837-43
Medeiros, B C; Tian, L; Robenson, S et al. (2014) European LeukemiaNet classification intermediate risk-1 cohort is associated with poor outcomes in adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation. Blood Cancer J 4:e216
Popli, Rakesh; Sahaf, Bita; Nakasone, Hideki et al. (2014) Clinical impact of H-Y alloimmunity. Immunol Res 58:249-58
Logan, Aaron C; Vashi, Nikita; Faham, Malek et al. (2014) Immunoglobulin and T cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant 20:1307-13
Logan, A C; Zhang, B; Narasimhan, B et al. (2013) Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia. Leukemia 27:1659-65
Colonna, Lucrezia; Florek, Mareike; Leveson-Gower, Dennis B et al. (2013) IL-17 gene ablation does not impact Treg-mediated suppression of graft-versus-host disease after bone marrow transplantation. Biol Blood Marrow Transplant 19:1557-65
Shamloo, Amir; Manchandia, Milan; Ferreira, Meghaan et al. (2013) Complex chemoattractive and chemorepellent Kit signals revealed by direct imaging of murine mast cells in microfluidic gradient chambers. Integr Biol (Camb) 5:1076-85

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