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Cellular and genetic factors involved in the difference among rat strains to develop procainamide - induced Autoimmunity

ABSTRACT: To examine the influence cellular and genetics on the procainamide-induced autoimmune response in spleens we compared rats that are genetically Th2-predisposed (Brown Norway), Th1-predisposed (Lewis) or not genetically predisposed (Sprague Dawley). Rats were treated with procainamide three times per week. From the second week, blood samples were taken once a week for antinuclear antibody (ANA) detection. At 56d after treatment, rats were sacrificed and spleens samples were collected for microarray test and histopathology examination. Frequencies of T cell subsets and B cells in rat spleen were measured to assess the effects on splenocyte. Also, 12 serum cytokines/chemokines were determined to explored the Th1/Th2 cytokine pattern after treatment. We found that ANA were makedly elevated in BN and SD rats, while the elevated appeared earlier in BN rats, and the magnitude of its increase were much higher than that of SD rats. There was no marked change in serum ANA in Lewis rats. Histopathological analysis indicated that spleen weight increased significantly both in BN and SD rats after stimulated with procainamide. No significant changes in spleen weight and lesions were observed in Lewis rats. We also found the percentage of CD86 positive cells in spleen of BN rats was significantly increased, while the percentage of CD4+CD25+ cells was decreased in BN rats. In addition, percentage of CD11b/c positive cells were decreased, and the levels of Th-2 (IL-10), Th-1 type cytokine (IFN-γ) and chemokine (IL-1β) in serum were markedly elevated both in BN and SD rats after treatment. Th-2 type cytokine (IL-4, IL-6) in serum were markedly increased only in BN rats. Furthermore, similar immune mechanisms were found in BN and SD rat, and the altered genes were mainly associated in immune response, and inflammatory response. However, the number of differentially expressed genes (DEGs) in BN rats was higher than that in SD rats. Overall, we revealed significant differences in response to autoimmunity induced by procainamide among three strains rats, the BN rats was the most sensitive one, SD rats exhibited less sensitive while Lewis resistance to procainamide. Much more pronounced of Th2-type responses and more complex DEGs involved in immune regulation and response in BN rats might contribute to its susceptible to drug-induced lupus erythematosus. Moreover, similar immune mechanisms were found between BN and SD rat, which suggesting that these changes would served as the potential bridge biomarkers to predict drug-induced autoimmune reactions among species. The results may also provide a scientic basis for the high sensitivity of BN rats in prediction immunotoxicity in preclinical studies.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE92500 | GEO | 2018/11/28

REPOSITORIES: GEO

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Project description:Chronic obstructive pulmonary disease (COPD) is diagnosed by airway obstruction and underlies a group of ailments such as bronchitis, emphysema and often asthma; however, rodent models do not resemble human pathology. Because genetically predisposed spontaneously hypertensive (SH) rats display phenotypes such as systemic inflammation, thrombosis, oxidative stress, and suppressed immune function, that are also apparent in COPD patients, we exposed SH and commonly used male Sprague Dawley (SD) to 0, 250, or 350 ppm sulfur dioxide (SO2), 5h/d for 4 consecutive days. Airways disease was characterized by pulmonary functional, pathological and molecular analysis. SO2 caused dose-dependent changes in breathing parameters in both strains with SH rats being slightly more affected than SD. Bronchoalveolar lavage fluid (BALF) total cells and neutrophilic inflammation were dose-dependent and significantly greater in SH than in SD rats. The recovery was incomplete 4-day following SO2 exposure in SH rats. Pulmonary protein leakage did not occur in either strain but lactate dehydrogenase and n-acetyl glucosaminidase activity was increased in BALF of SH rats. Lung pathology and morphometric evaluation of mucin production in the airways demonstrated significantly greater impact of SO2 in SH than in SD rats. Baseline differences in lung gene expression pattern suggested marked immune dysregulation, oxidative stress, and impairment cell signaling and fatty acid metabolism in SH rats. Gene expression pattern of SD and SH rats following SO2 exposure demonstrated greater effect on inflammation/immune markers, and oxidative stress. Thus, the SH rat may serve as a better and more susceptible rat strain to be used for experimental model of bronchitis which is relevant to human disease. Experiment Overall Design: Spontaneously hypertensive and Sprague Dawley rats were used in this experiment. Each strain of rat was treated with either SO2 or AIR (control). There were 4 biological replicates for each strain/treatment.

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Cellular and genetic factors involved in the difference among rat strains to develop procainamide - induced Autoimmunity

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