Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice.

Indirect evidence suggests that type-I interferons (IFN-alpha/beta) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the alpha-chain of IFN-alpha/betaR, the common receptor for the multiple IFN-alpha/beta species. Compared with littermate controls, homozygous IFN-alpha/betaR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-alpha/betaR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.

Neutralizing interferon alpha as a therapeutic approach to autoimmune diseases.

Therapeutic antibodies directed against tumor necrosis factor alpha (TNF-alpha) for the treatment of rheumatoid arthritis, and against the human EGF receptor-2 (HER2) receptor for the treatment of breast cancer have provided significant clinical benefit for the patients. The success of these antibodies has also provided strong support for the possibility that increased activity of cytokines or growth factors is causally implicated in a variety of human diseases. Interferon alpha (IFN-alpha) is induced by viruses (linked by epidemiological studies to autoimmune diseases), has significant direct effects on both epithelial cells and the immune system, and then can be further induced by the autoantibodies and apoptotic cells generated by the actions of IFN-alpha. The direct and deleterious impact on target tissues, the ability to induce an autoimmune response, and the potential for a self-sustaining cycle of induction and damage suggests that IFN-alpha could be a pivotal factor in the development of autoimmune diseases. This review will evaluate the rationale for, possible approaches to, and safety concerns associated with, targeting interferon alpha (IFN-alpha) as a therapeutic strategy for the treatment of autoimmune diseases. While the approach may be applicable to several autoimmune diseases, there will be an emphasis on systemic lupus erythematosus and insulin dependent diabetes mellitus.

Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity.

The fibroblast growth factors (FGFs), and the corresponding receptors, are implicated in more than just the regulation of epithelial cell proliferation and differentiation. Specifically, FGF23 is a regulator of serum inorganic phosphate levels, and mice deficient in FGF receptor-4 have altered cholesterol metabolism. The recently described FGF19 is unusual in that it is nonmitogenic and appears to interact only with FGF receptor-4. Here, we report that FGF19 transgenic mice had a significant and specific reduction in fat mass that resulted from an increase in energy expenditure. Further, the FGF19 transgenic mice did not become obese or diabetic on a high fat diet. The FGF19 transgenic mice had increased brown adipose tissue mass and decreased liver expression of acetyl coenzyme A carboxylase 2, providing two mechanisms by which FGF19 may increase energy expenditure. Consistent with the reduction in expression of acetyl CoA carboxylase 2, liver triglyceride levels were reduced.

Fibroblast growth factor 19 increases metabolic rate and reverses dietary and leptin-deficient diabetes.

Hormonal control of metabolic rate can be important in regulating the imbalance between energy intake and expenditure that underlies the development of obesity. In mice fed a high-fat diet, human fibroblast growth factor 19 (FGF19) increased metabolic rate [1.53 +/- 0.06 liters O(2)/h.kg(0.75) (vehicle) vs. 1.93 +/- 0.05 liters O(2)/h.kg(0.75) (FGF19); P < 0.001] and decreased respiratory quotient [0.82 +/- 0.01 (vehicle) vs. 0.80 +/- 0.01 (FGF19); P < 0.05]. In contrast to the vehicle-treated mice that gained weight (0.14 +/- 0.05 g/mouse.d), FGF19-treated mice lost weight (-0.13 +/- 0.03 g/mouse.d; P < 0.001) without a significant change in food intake. Furthermore, in addition to a reduction in weight gain, treatment with FGF19 prevented or reversed the diabetes that develops in mice made obese by genetic ablation of brown adipose tissue or genetic absence of leptin. To explore the mechanisms underlying the FGF19-mediated increase in metabolic rate, we profiled the FGF19-induced gene expression changes in the liver and brown fat. In brown adipose tissue, chronic exposure to FGF19 led to a gene expression profile that is consistent with activation of this tissue. We also found that FGF19 acutely increased liver expression of the leptin receptor (1.8-fold; P < 0.05) and decreased the expression of acetyl coenzyme A carboxylase 2 (0.6-fold; P < 0.05). The gene expression changes were consistent with the experimentally determined increase in fat oxidation and decrease in liver triglycerides. Thus, FGF19 is able to increase metabolic rate concurrently with an increase in fatty acid oxidation.

Targeted antiviral prophylaxis with oseltamivir in a summer camp setting.

OBJECTIVE: To describe the effectiveness of containment of novel influenza A(H1N1) infection at a summer camp. DESIGN: Targeted use of oseltamivir phosphate by individuals in close contact with influenza-confirmed cases. SETTING: Boys' camp in Alabama in July 2009. PARTICIPANTS: A total of 171 campers, 48 camp counselors, and 27 camp staff. INTERVENTIONS: Campers with confirmed influenza received oseltamivir and were immediately isolated and sent home. All boys and counselors in the infected child's adjoining cabins received prophylactic oseltamivir for 10 days, including 8 campers at higher risk for influenza infection (eg, those with asthma, seizure disorder, or diabetes). Alcohol-based hand sanitizer was provided at each of the daily activities, in the boys' cabins, and in the dining hall, and counselors were educated by the medical staff on the spread of influenza and its prevention through good hand hygiene. All cabins, bathrooms, and community sports equipment were sprayed or wiped down with disinfectant each day. Main Outcome Measure Virologic confirmation of influenza. RESULTS: Three of the 171 campers tested positive for influenza A during the course of the 2-week fourth session, for an attack rate of 1.8%. The probability of observing 3 or fewer infected campers if the attack rate was 12% is less than 1 in 10,000,000 (P < .0000001). An exact 95% confidence interval based on 3 events among 171 individuals estimates the attack rate to be between 0.3% and 5.0%. While 31% to 57% of campers, counselors, or staff experienced nausea with the treatment, this did not result in discontinuation of therapy. No campers tested positive for influenza A after returning home at the end of the camp session. CONCLUSION: In conjunction with comprehensive hand sanitization and surface decontamination, a targeted approach to antiviral prophylaxis contained the spread of influenza in a summer camp setting.