Following hematopoietic stem cell transplantation (HSCT), there are twopathways forI lymphocyte reconstitution. Transplantation of pre-formed T lymphocytes can result in adoptive transfer of competent donor-derived T lymphocytes, albeit with a restricted repertoire and the potential for alloreactivity and the risk of graft-versus-host disease (GVHD). Transplantation of hematopoietic stem cells (HSC) or committed lymphoid progenitors can result in generation of donor-derived T lymphocytes, which have a broad repertoire and were selected by the host thymus, resulting in host tolerance. When the donor graft has been highly enriched for HSC by CD34 selection and/or T cell depletion, post-HSCT immune reconstitution is dependent on the latter thymus-dependent pathway for T lymphocyte development. Post-HSCT T cell development is inherently delayed because of normally slow ontogeny and microenvironmental damage caused by pre- HSCT chemoradiotherapy, aging, and GVHD, Strategies to overcome these problems include transplantation of committed lymphoid progenitors as well as HSC, replacement of microenvironmental signals, or prevention of microenvironmental damage. Common lymphoid progenitors (CLP) are a phenotypically defined population of marrow cells capable of giving rise to T, NK, and B lymphocytes, but not myeloid 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. Studies performed in the last funding period have shown that transplantation of CLP in addition to HSC results in greater resistance to peri-transplant murine cytomegalovirus (MCMV) infection. Previous work has shown that administration of IL-7 to murine HSCT recipients results in rapid reconstitution of the thymus as well as increased mature B cells. The goal of this grant is to understand the cytokine signals that regulate the development of lymphoid progenitors in order to develop a strategy for enhancement of post-HSCT immune reconstitution by combining transplantation of CLP and therapeutic use of cytokines to enhance the development of lymphocytes from the transplanted CLP. The studies will test the hypothesis 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 be characterized to better understand whether and how expansion of transplanted CLP occurs after transplantation. 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 CLP and lead to clinical studies to induce the rapid development of a broad immunological repertoire after HSCT.
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