The Role Of Cytokines In The Developing Immune System

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We hypothesized that specific events in the developing immune system are altered by environmental exposures. Insults such as upper respiratory tract infections could make neonates more susceptible to the effects of later infections. In collaboration with Dr. Jane Blood-Siegfried at Duke University, we have designed a dual infection model of upper respiratory tract infection and bacterial sepsis to induce a SIDS-like pathology in an inbred rat strain. Using this model, we have established a critical window of dual infectious insults, which result in a SIDS-like death. Neonatal rat pups given influenza and endotoxin two days post influenza had a 73% mortality rate within 7-23 hours post endotoxin for doses of 2 mg/kg, 0.5 mg/kg and 0.2 mg/kg. There were no deaths with 0.05 mg/kg endotoxin and no mortality in the influenza or endotoxin only control groups. Evaluation by Dr. Abraham Nyska, LEP indicates that there were no gross pathology findings in the control pups. In animals challenged with both agents, specific gross and microscopic changes on necropsy were similar to those found on autopsy of SIDS infants. Pups dosed with 0.2 mg/kg endotoxin had petechiae and hemorrhage in the lungs, mild congestion of the spleen and other degenerative lesions consistent with the pathological findings in human SIDS deaths. Dr. Nyskas evaluation suggests that mortality in this model is related to a systemic event rather than specific lung damage. Significant differences were observed in serum interferon gamma levels and splenic leukocyte populations in dual-infected rat pups as compared to endotoxin-only or RAIV-only controls. Increased macrophage activation and increased numbers of natural killer cells in the spleen during the critical period for increased mortality suggest an exaggerated TH-1 type immune response. A manuscript detailing the baseline immune parameters and pathology of the lesion has been submitted for publication. It is well documented that autoimmune disease susceptibility is largely dependent upon the presence of particular major histocompatibility complex (MHC) genotypes, however, development of disease symptoms also appears to require critical environmental factors, such as bacterial or viral infections or chemical exposure. We are examining the role of prenatal and adult exposures to environmental agents in the development of autoimmunity. Although the effects of developmental exposure may be of critical importance, these effects have not been comprehensively studied in appropriate rodent models predisposed to autoimmune dysfunction. We have begun to examine postnatal immune consequences of prenatal exposure to endocrine disrupting chemical in autoimmune-prone rodents. We have examined the potential for increased incidence and/or exacerbation of autoimmune disease in MRL/lpr autoimmune-prone mice exposed during gestation to TCDD. MRL/lpr mice exhibit severe renal necrosis (glomerulonephritis) similar to that observed in human patients with systemic lupus erythematosus, with females normally presenting circulating autoantibodies against nucleoprotein particles and subsequent renal complement-antibody immune complexes at approximately 14-16 weeks of age vs. males at 20-22 weeks. Severity of autoimmunity as assessed via quantitation of serum autoantibodies to ssDNA, urinary protein levels, and renal histopathology was compared in female versus male mice to determine if differential chemical-induced effects were present. Results in female mice indicated a significant, dose-dependent increase in anti-ssDNA, urinary protein, and renal abnormalities in TCDD-exposed animals as compared to controls at six, ten, and 12 weeks of age, respectively. Similar results were noted in dioxin-exposed males at eight, ten and 12 weeks of age.