We propose an integrated, multidisciplinary program of basic and clinical research addressing a central theme: The characterization and therapeutic modulation of the genetic, molecular and cellular attributes of an allogeneic hematopoietic stem cell graft (HSCT) and transplanted host which contribute to the early establishment of innate and adaptive immunity and provide the patient with effective resistance to infections, and the patient's underlying malignancy. The Program Project includes 6 research projects and 5 cores. Project 1 is focused on the early development of NK cells, their acquisition of self tolerance and their recognition of allogeneic normal and malignant hematopoietic cells through activating and unengaged inhibitory KIR receptors. Project 2 will examine the functional characteristics and cytokine modulated activation of recently identified subsets of monocytes, specifically focusing on the attributes of specific types of monocytes that contribute to resistance to invasive Aspergillus infection in immuno-ablated hosts early after transplantation and the capacity of cytokines to selectively stimulate monocytes providing resistance. Project 3 will examine the relative capacities of different types of dendritic cells developing early post transplant to: a) stimulate T cell responses specific for minor alloantigens (GVH) or antigens differentially expressed by leukemic cells (GVL), and b) influence the reconstitution of NK cell populations and, (with Project 1), the repertoire of KIR receptor reactivity in histocompatible hosts. Project 4 proposes the development and evaluation of novel, broadly applicable strategies for rapidly generating donor-derived leukemia-reactive WT1-specific CD8 and CD4 T cells for adoptive cell therapy to treat or prevent relapse. The T cells generated by these strategies will be compared for their activity against leukemic and normal cells both in vitro and in immunodeficient mice bearing leukemic xenografts in vivo. Project 5 proposes the development and evaluation of synthetic heteroclytic analog peptides of predicted and newly identified epitopes of WT1 and JAK2 kinase for use as vaccines to induce or augment leukemia reactive T cell responses in leukemic patients and transplant recipients at responsive stages of immune reconstitution post transplant. Project 6 presents a program of clinical trials evaluating strategies for enhancing early recovery of innate and adaptive immunity post transplant, particularly in older, and HLA disparate recipients of T cell depleted grafts who do not require or receive immunosuppressive agents post transplant to prevent acute or chronic GVHD. These include trials of KGF to promote reconstitution of thymopoiesis and trials of adoptive therapy with donor NK cells or T cells specific for WT1 to treat leukemic relapse or CMV-pp65 specific T cells for persistent CMV infection. We will also evaluate double cord blood grafts in patients lacking 8-10/10 allele matched HSCT donors, focusing on prospective analyses to identify genetic and cellular attributes of the grafts and host that determine the sustained engraftment and establishment of normal hematopoiesis by one of the two grafts. 5 Cores provide: A) HLA and NK receptor genotyping of research specimens; B) evaluation of cells generated for adoptive immunotherapy; C) monitoring of reconstitution post transplant; D) Biostatistics;and E) administrative support and oversight. Relevance to Public Health: This integrated program of research and therapeutics should improve in transplants for hematologic malignancies and elucidate genetic and cellular interactions that contribute to the re-establishment of resistance to infection and disease recurrence.
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