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Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances Bacillus Calmette-Guerin vaccine efficacy against tuberculosis.
Bhattacharya D, Dwivedi VP, Kumar S, Reddy MC, Van Kaer L, Moodley P, Das G
(2014) J Biol Chem 289: 33404-11
MeSH Terms: Animals, Anti-Allergic Agents, Arylsulfonates, Benzamides, Cell Differentiation, Imidazoles, Mice, Mice, Inbred BALB C, Mycobacterium bovis, Mycobacterium tuberculosis, Sulfonium Compounds, T-Lymphocytes, Regulatory, Th2 Cells, Tuberculosis Vaccines, Tuberculosis, Pulmonary
Show Abstract · Added January 20, 2015
Tuberculosis affects nine million individuals and kills almost two million people every year. The only vaccine available, Bacillus Calmette-Guerin (BCG), has been used since its inception in 1921. Although BCG induces host-protective T helper 1 (Th1) cell immune responses, which play a central role in host protection, its efficacy is unsatisfactory, suggesting that additional methods to enhance protective immune responses are needed. Recently we have shown that simultaneous inhibition of Th2 cells and Tregs by using the pharmacological inhibitors suplatast tosylate and D4476, respectively, dramatically enhances Mycobacterium tuberculosis clearance and induces superior Th1 responses. Here we show that treatment with these two drugs during BCG vaccination dramatically improves vaccine efficacy. Furthermore, we demonstrate that these drugs induce a shift in the development of T cell memory, favoring central memory T (Tcm) cell responses over effector memory T (Tem) cell responses. Collectively, our findings provide evidence that simultaneous inhibition of Th2 cells and Tregs during BCG vaccination promotes vaccine efficacy.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Are herbal products dietary supplements or drugs? An important question for public safety.
Stein CM
(2002) Clin Pharmacol Ther 71: 411-3
MeSH Terms: Anti-Allergic Agents, Cardiovascular System, Ephedra, Histamine H1 Antagonists, Humans, Hypericum, Pharmacokinetics, Plant Extracts, Terfenadine, United States, United States Food and Drug Administration
Added December 10, 2013
0 Communities
1 Members
0 Resources
11 MeSH Terms
Identification of functionally variant MDR1 alleles among European Americans and African Americans.
Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG, Wilkinson GR
(2001) Clin Pharmacol Ther 70: 189-99
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 1, Africa, African Continental Ancestry Group, Alleles, Anti-Allergic Agents, Area Under Curve, Cloning, Molecular, DNA Primers, Digoxin, Enzyme Inhibitors, Europe, European Continental Ancestry Group, Genes, MDR, Genetic Variation, Genotype, Haplotypes, Humans, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Terfenadine, Time Factors
Show Abstract · Added March 27, 2014
MDR1 (P-glycoprotein) is an important factor in the disposition of many drugs, and the involved processes often exhibit considerable interindividual variability that may be genetically determined. Single-strand conformational polymorphism analysis and direct sequencing of exonic MDR1 deoxyribonucleic acid from 37 healthy European American and 23 healthy African American subjects identified 10 single nucleotide polymorphisms (SNPs), including 6 nonsynonymous variants, occurring in various allelic combinations. Population frequencies of the 15 identified alleles varied according to racial background. Two synonymous SNPs (C1236T in exon 12 and C3435T in exon 26) and a nonsynonymous SNP (G2677T, Ala893Ser) in exon 21 were found to be linked (MDR1*2 ) and occurred in 62% of European Americans and 13% of African Americans. In vitro expression of MDR1 encoding Ala893 (MDR1*1 ) or a site-directed Ser893 mutation (MDR1*2 ) indicated enhanced efflux of digoxin by cells expressing the MDR1-Ser893 variant. In vivo functional relevance of this SNP was assessed with the known P-glycoprotein drug substrate fexofenadine as a probe of the transporter's activity. In humans, MDR1*1 and MDR1*2 variants were associated with differences in fexofenadine levels, consistent with the in vitro data, with the area under the plasma level-time curve being almost 40% greater in the *1/*1 genotype compared with the *2/*2 and the *1/*2 heterozygotes having an intermediate value, suggesting enhanced in vivo P-glycoprotein activity among subjects with the MDR1*2 allele. Thus allelic variation in MDR1 is more common than previously recognized and involves multiple SNPs whose allelic frequencies vary between populations, and some of these SNPs are associated with altered P-glycoprotein function.
1 Communities
1 Members
2 Resources
22 MeSH Terms