Following hematopoietic stem cell transplantation (HSCT), there are twopathways forI lymphocytereconstitution. Transplantation of pre-formed T lymphocytes can result in adoptive transfer of competentdonor-derived T lymphocytes, albeit with a restricted repertoire and the potential for alloreactivity and the riskof graft-versus-host disease (GVHD). Transplantation of hematopoietic stem cells (HSC) or committedlymphoid progenitors can result in generation of donor-derived T lymphocytes, which have a broad repertoireand were selected by the host thymus, resulting in host tolerance. When the donor graft has been highlyenriched for HSC by CD34 selection and/or T cell depletion, post-HSCT immune reconstitution is dependenton the latter thymus-dependent pathway for T lymphocyte development. Post-HSCT T cell development isinherently delayed because of normally slow ontogeny and microenvironmental damage caused by pre-HSCT chemoradiotherapy, aging, and GVHD, Strategies to overcome these problems includetransplantation of committed lymphoid progenitors as well as HSC, replacement of microenvironmentalsignals, or prevention of microenvironmental damage. Common lymphoid progenitors (CLP) are aphenotypically defined population of marrow cells capable of giving rise to T, NK, and B lymphocytes, but notmyeloid lineages. CLP express receptors for interleukin-7 (IL-7), Kit ligand (KL, aka stem cell factor [SCF]),and FltS ligand (FLT3L). In vivo, CLP are highly proliferative, which is in distinct contrast to HSC. Studiesperformed in the last funding period have shown that transplantation of CLP in addition to HSC results ingreater resistance to peri-transplant murine cytomegalovirus (MCMV) infection. Previous work has shownthat administration of IL-7 to murine HSCT recipients results in rapid reconstitution of the thymus as well asincreased mature B cells. The goal of this grant is to understand the cytokine signals that regulate thedevelopment of lymphoid progenitors in order to develop a strategy for enhancement of post-HSCTimmune reconstitution by combining transplantation of CLP and therapeutic use of cytokines toenhance the development of lymphocytes from the transplanted CLP. The studies will test thehypothesis that IL-7, KL, and FltSL are the complementary cytokines which regulate the proliferation,survival and differentiation of CLP in vivo. The effects of IL-7, KL, and FltSL on transplanted CLP will becharacterized to better understand whether and how expansion of transplanted CLP occurs aftertransplantation. The effects of IL-7, KL, and/or FltSL on immune reconstitution from CLP will be tested,including the evaluation of functional immunity to MCMV. Gene expression by CLP stimulated with IL-7, KL,and FltSL will be characterized and compared. Together, the studies will advance the understanding of CLPand lead to clinical studies to induce the rapid development of a broad immunological repertoire after HSCT.
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