title: Simultaneous inhibition of T helper 2 and T regulatory cell differentiation by small molecules enhances Bacillus Calmette-Guerin vaccine efficacy against tuberculosis.
abstract: 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.
authors.affiliation: From the Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa.
authors.forename: Debapriya
authors.initials: D
authors.lastname: Bhattacharya
authors.affiliation: From the Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa.
authors.forename: Ved Prakash
authors.initials: VP
authors.lastname: Dwivedi
authors.affiliation: From the Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Yogi Vemana University, Kadapa 516003, India.
authors.forename: Madhava C
authors.initials: MC
authors.lastname: Reddy
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, and.
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.affiliation: From the Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa.
authors.forename: Prashini
authors.initials: P
authors.lastname: Moodley
authors.affiliation: From the Laboratory Medicine and Medical Sciences, College of Health Sciences, University of Kwazulu Natal, Durban 4001, South Africa, Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India gobardhan.das07@gmail.com.
authors.forename: Gobardhan
authors.initials: G
authors.lastname: Das
mesh_terms: D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D001190:Arylsulfonates / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009163:Mycobacterium bovis; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D013452:Sulfonium Compounds / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000494:pharmacology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*
chemical_list: C493177:4-(4-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D018926:Anti-Allergic Agents; D001190:Arylsulfonates; D001549:Benzamides; D007093:Imidazoles; D013452:Sulfonium Compounds; D032581:Tuberculosis Vaccines; C073028:suplatast tosilate
keywords: Cytokine; Immunotherapy; Mycobacterium tuberculosis; T Helper Cells; Vaccine