Treatment of Infections in Immunocompromised Children with Cancer, Hematopoietic Stem Cell Transplantation, and other ImmunodeficienciesInfectious diseases are a major cause of morbidity and mortality in immunocompromised patients with cancer, hematopoietic stem cell transplantation (HSCT), and other immunodeficiencies. Our Section is dedicated to the mission of relieving the suffering and improving the outcome of these patients though advances in translational research of infectious diseases supportive care. Our studies of infections complicating children with neoplastic disease, HSCT, and other immunodeficiencies focus on development of new approaches to treatment and prevention of life-threatening infections, rapid molecular detection, and augmentation of innate host defenses against emerging pathogens. Our strategies reflect those used to manage such infections: pharmacologic intervention; detection and therapeutic monitoring; and immune augmentation. Using a translational research approach, we advance findings made in vitro to a series of unique animal model systems in vivo that reflect the microbiological, immunological, and histologic characteristics of these emerging infectious diseases. These studies establish a scientific rationale for conducting clinical trials that provide our patients with key advances from bench to bedside. These advances are improving patient outcome, increasing survival, and reducing suffering from the infectious complications of cancer, HSCT, and other immunodeficiencies. Among the emerging infectious diseases afflicting our immunocompromised patients, the invasive mycoses have emerged as important causes of morbidity and mortality, particularly in patients with hematological malignancies, HSCT recipients, and children with inherited immunodeficiencies. The Section has achieved significant advances in the areas of augmentation of host defense, molecular detection and pharmacology of these life-threatening infections. Augmentation of Host Defenses. Immunopharmaocological interactions between innate host defenses and antimicrobial agents are a key component of developing new strategies for augmenting host response against emerging or resistant pathogens. We have extensively characterized the immunopharmacological interactions between phagocytic effector cells (pulmonary alveolar macrophages, monocytes, and neutrophils) of the innate host defense and antifungal agents (polyenes, echinocandins, and triazoles) with and without immunomdoulators (IFN-g, GCSF, GMCSF) against several of the key pathogens infecting oncology patients: Aspergillus fumigatus, Fusarium solani, Scedosporium spp., and Zygomycetes. We have further extended our work in Th1/Th2 dysimmunoregulation of invasive candidiasis to the filamentous fungi (Aspergillus spp. , Fusarium spp., Scedosproium spp., and Zygomycetes) with particualr focus on IL-15, IL-4, and TGF-beta. Reveresal of the Th2 immunophenotyoic expression augments host response against these organisms. We are continuing are studies of augmentation of lucosal host defenses with selected antimcirbial peptides, including adrenomedullin and histatins, in order to develop new protective approaches for patients recieving myeloablative chemotherpay or radiation.We have completed the first known kineitc studies of the functional genomic repsonse of innate host defenses of human monocytes to two Candida albicans and to Aspergillus funigatus. These studies will provide fundmental guidance to investigators worldwide in understanding the coordinated transcriptional repsonses of their selected genes of interest for further exploraiton. Understanding the normal host functional genomic repsonse will guide new strategies for immune reconsitution and immunoaugmentation against these pathogens.
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