Childhood sickle cell disease (SCD), especially in the homozygous state is characterized by significant morbidity and early mortality. Individuals affected by this hemoglobinopathy exhibit many of the manifestations associated with immunodeficiency disorders. However, the overwhelming majority of the research in SCD concerns erythrocyte rheological phenomena and anti-sickling agents. Except for polysaccharide vaccines and daily penicillin prophylaxis, there have been no major advances in the prevention of infections in SCD. Clearly, these interventions have not significantly decreased the incidence of pneumonia, which is the most common infection seen in children with SCD. The current proposal represents the next phase in the comprehensive evaluation of SCD as a model for immunosuppression, separate and distinct from the hematological disorder. Recent studies have shown that impaired gamma interferon (IFN) production in vitro during the SCD steady (healthy) state is a reliable functional immunologic marker for susceptibility to frequent pulmonary infections. The current proposal has two principal objectives. The first objective is to ascertain the role of type 1 and type 2 cytokine responses in the pathogenesis of increased susceptibility to infection in patients with SCD. The second is for this work to serve as a preamble for clinical trials with gamma IFN in selected SCD patients with proven impaired production in vitro during the steady state. All assessments will be done in SCD patients during their steady and infection associated crisis states of disease. Comparable age and gender matched normal healthy and infected controls will have similar evaluations. The major cellular elements to be enumerated by flow cytometry include three helper T cell subsets (Th0, Th1 and Th2), cytotoxic/suppressor T cells, monocytes/macrophages, B lymphocytes and natural killer (NK) cells. Type 1 cytokine (IL-1, IL-2, IL-12 and gamma IFN), type cytokine (IL-4, IL-5, IL-6 and IL-10) and tumor necrosis factor (TNF) production in vivo (circulating serum levels) and in vitro (cell culture supernatants) will be quantitated by ELISA methods in both groups. Serums from healthy SCD patients and any comparable controls showing high levels of type 1 or type 2 cytokines will be utilized to delineate their effects in vitro on cell mediated immune (CMI) and humoral responses. CMI responses will include antigenic and mitogenic responses, as well as cytokine production. Humoral immunity will entail in vitro pokeweed stimulation and measurement of in vitro antibody production. In addition in vitro co-cultivation experiments utilizing SCD Th1 cells and macrophages, along with comparable normal control cells, will be done to determine the principal cellular defect in SCD patients with impaired gamma IFN production. The final in vitro tests will attempt to correct diminished NK lytic activity in SCD patients with gamma IFN deficiency.
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