Hematopoietic stem-cell transplantation (HSCT) cures many malignant and non-malignant diseases. However, the transplant recipient incurs significant infectious morbidity and mortality during periods of profound cytopenia and immunodeficiency caused by transplantation itself and its associated complications, such as graft-versus-host-disease (GVHD). Infection risk dramatically declines as donor hematopoiesis is functionally reconstituted in the transplant recipient. Unlike adaptive immune reconstitution, innate cellular mediated immune (iCMI) recovery is largely undefined despite its having well-characterized anti-infective properties. The research proposal hypothesizes that reconstituted iCMI following HSCT serves to protect the host against infection and that cytokine therapy using FIt3L (fms-like tyrosine kinase 3 ligand) can augment its anti-microbial properties. In support of this hypothesis, preliminary data using an established murine model of autologous bone marrow transplantation defines biphasic functional iCMI reconstitution. In addition, FIt3L accelerates dendritic and natural killer (NK) cell reconstitution, leading to enhanced interleukin 12 (IL-12) and earlier IL-12-induced interferon-gamma (IFN-gamma) production. The proposal will further characterize phasic iCMI reconstitution in the established murine model using standard techniques of immunology research, such as cytokine augmentation, monoclonal antibody depletion and ex vivo cell-culture stimulation. Specifically, the proposal will define relationships between distinct cell populations and cytokine responses and the role of reconstituted Toll-like receptors in transplant host defense. Once defined, anti-infective properties of iCMI will be tested using systemic Candida albicans and Staphylococcus aureus challenge in the presence and absence of FIt3L. Future directions include defining iCMI reconstitution in the presence of immunosuppressive therapy and GVHD using murine models incorporating cyclosporine administration and allogeneic transplantation, respectively. This research focus complements the applicant's dual training in hematology/oncology and infectious diseases and serves as a catalyst for his career as a physician scientist exploring host defense defects in immunocompromised hosts. Sound mentorship and established infrastructure will combine with the applicant's personal commitment in fostering his development into a fully funded independent investigator.
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