National Jewish Health

About: National Jewish Health is a healthcare organization based out in Denver, Colorado, United States. It is known for research contribution in the topics: Asthma & T cell. The organization has 883 authors who have published 833 publications receiving 79201 citations. The organization is also known as: National Jewish Medical and Research Center.

Interferon- γ for delayed pulmonary toxicity syndrome resistant to steroids

Abstract: Delayed pulmonary toxicity syndrome, characterized by interstitial pneumonia and pulmonary fibrosis, is common following high-dose bischloroethylnitrosourea (BCNU) (carmustine, [1,3-bis (2-chloroethyl)-1-nitrosourea]) containing chemotherapeutic regimens. Depending upon the treatment protocol, it may develop in over 70% of patients. Early and aggressive corticosteroid treatment leads to improvement in the majority of patients. However, up to 8% of affected patients may fail to respond to corticosteroids and develop progressive respiratory failure leading to death. No alternatives to corticosteroids have thus far been shown useful. We report the symptomatic and physiological improvement of a patient with severe steroid-resistant delayed pulmonary toxicity syndrome, following treatment with interferon-γ.

Allelic differences in TCR gamma-chains alter gamma delta T cell antigen reactivity.

Abstract: Mouse gamma delta T cell hybridomas from various strains that express a TCR-V gamma 1/V delta 6 respond weakly to an autologous Ag and more strongly to a short segment of the mycobacterial heat shock protein-60 (HSP-60). However, V gamma 1/V delta 6 hybridomas derived from AKR mice show greatly reduced or absent responses to these stimuli. To determine whether the lack of response in these AKR hybridomas is caused by polymorphisms found in the expressed AKR gamma and TCR-delta genes or, instead, stems from other genes in AKR, we crossed an AKR mouse with a responder mouse, C57BL/10 (B10), and prepared hybridomas from F1 progeny. Expression of an AKR V gamma 1-J gamma 4-C gamma 4 gene correlated with nonresponsiveness, whereas expression of a B10 V gamma 1-J gamma 4-C gamma 4 gene in most hybridomas ensured responses to both self Ag and the HSP-60 peptide. An allelic difference in the expressed V gamma 6 gene was irrelevant to these responses. Moreover, transfection of a functional B10 V gamma 1-J gamma 4-C gamma 4 gene into an F1 hybridoma variant that had lost the AKR version of this gene restored responses. The allelic gamma gene products differ at nine amino acids in the V region, and three amino acids in the C region. In addition, the AKR C gamma 4 region contains a 16-amino acid insertion. We propose that amino acid differences among those encoded by the AKR V gamma 1-J gamma 4-C gamma 4 gene are responsible for the lack of response, and reduce the ability of the TCR-gamma delta to bind the relevant Ag.

Role of protein kinase C in interleukin 1, anti-T3, and mitogenic lectin-induced interleukin 2 secretion.

Abstract: Activation of T-lymphocytes by antigen, mitogenic lectins, or antibodies against the T-cell receptor complex, particularly in the presence of IL1, induces the secretion of the T-cell growth factor IL2. IL2 then has a major role in regulating the duration and magnitude of the immune response. Interaction of antigen, antibodies against the T-cell receptor complex, or mitogenic lectins with T-lymphocytes also induces hydrolysis of membrane phospholipids, leading to the production of diacylglycerol, an activator of the Ca2+- and phospholipid-dependent phosphotransferase, protein kinase C (PKC). Phorbol esters, potent activators of PKC, augment secretion of the T-cell growth factor, interleukin 2 (IL2). Activation of PKC may therefore serve as an important early event in the production and secretion of IL2. We have determined whether IL2 secretion can be induced in the murine cell T-lymphocyte line LBRM 331A5, where PKC is inhibited by staurosporine or sphingosine or in cells where PKC is depleted by prolonged incubation with high concentrations of phorbol esters. In cells in which PKC was either inhibited or depleted, antibodies against the T3 portion of the T-cell receptor complex and the mitogenic lectin phytohemagglutinin (PHA) still triggered IL2 secretion. In addition, the monokine IL1 augmented this IL2 secretion irrespective of whether PKC was inhibited or depleted. These data indicate that activation of PKC is not an obligatory step for IL2 secretion in LBRM 331A5 murine T-lymphocytes.

Activation of group IVC phospholipase A2 by polycyclic aromatic hydrocarbons induces apoptosis of human coronary artery endothelial cells

Abstract: Exposure to environmental pollutants, such as polycyclic aromatic hydrocarbons (PAHs) found in coal tar mixtures and tobacco sources, is considered a significant risk factor for the development of heart disease in humans. The goal of this study was to determine the influence of PAHs present at a Superfund site on human coronary artery endothelial cell (HCAEC) phospholipase A2 (PLA2) activity and apoptosis. Extremely high levels of 12 out of 15 EPA high-priority PAHs were present in both the streambed and floodplain sediments at a site where an urban creek and its adjacent floodplain were extensively contaminated by PAHs and other coal tar compounds. Nine of the 12 compounds and a coal tar mixture (SRM 1597A) activated group IVC PLA2 in HCAECs, and activation of this enzyme was associated with histone fragmentation and poly (ADP) ribose polymerase (PARP) cleavage. Genetic silencing of group IVC PLA2 inhibited both 3H-fatty acid release and histone fragmentation by PAHs and SRM 1597A, indicating that individual PAHs and a coal tar mixture induce apoptosis of HCAECs via a mechanism that involves group IVC PLA2. Western blot analysis of aortas isolated from feral mice (Peromyscus leucopus) inhabiting the Superfund site showed increased PARP and caspase-3 cleavage when compared to reference mice. These data suggest that PAHs induce apoptosis of HCAECs via activation of group IVC PLA2.

Methylation Analysis Reveals Fundamental Differences Between Ethnicity and Genetic Ancestry

Abstract: In clinical practice and biomedical research populations are often divided categorically into distinct racial and ethnic groups. In reality, these categories comprise diverse groups with highly heterogeneous histories, cultures, traditions, religions, as well as social and environmental exposures. While the factors captured by these categories contribute to clinical practice and biomedical research, the use of race/ethnicity is widely debated. As a response to this debate, genetic ancestry has been suggested as a complement or alternative to this categorization. However, few studies have examined the effect of genetic ancestry, racial/ethnic identity, and environmental exposures on biological processes. Herein, we examine the contribution of self-identification within ethnicity, genetic ancestry, and environmental exposures on epigenetic modification of DNA methylation, a phenomenon affected by both genetic and environmental factors. We typed over 450,000 variably methylated CpG sites in primary whole blood of 573 individuals of Mexican and Puerto Rican descent who also had high-density genotype data. We found that methylation levels at a large number of CpG sites were significantly associated with ethnicity even when adjusting for genetic ancestry. In addition, we found an enrichment of ethnicity-associated sites amongst loci previously associated with environmental and social exposures. Interestingly, one of the strongest associated sites is driven by the Duffy Null blood type variant, demonstrating a new function of the locus in lymphocytes. Overall, the methylation changes associated with race/ethnicity, driven by both genes and environment, highlight the importance of measuring and accounting for both self-identified race/ethnicity and genetic ancestry in clinical and biomedical studies and the benefits of studying diverse populations.