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.
Highlights
Immunological parameters induced by Bacillus Calmette-Guerin (BCG) and the requirement of immunologic responses for optimal vaccine efficacy is incompletely understood
Our results showed that simultaneous inhibition of Th2 and T regulatory (Treg) cell differentiation enhances the efficacy of BCG vaccination, which was associated with enhanced T helper 1 (Th1) responses
Simultaneous Treatment with Th2 and Treg Cell Inhibitors Increases BCG Vaccine Efficacy—To examine the effect of Th2 and Treg cell inhibitors on BCG-vaccinated mice, we immunized BALB/c mice with BCG and treated the animals with D4476 and suplatast tosylate, inhibitors of TGFRI signaling and Th2 cell differentiation, respectively, for 10 days. These animals were subsequently rested for another 20 days and reinfected with M. tuberculosis strain H37Rv through the aerosol route
Summary
Immunological parameters induced by BCG and the requirement of immunologic responses for optimal vaccine efficacy is incompletely understood. This was associated with increased Th1 cell responses, as shown by a dramatic increase in IFN-␥-producing cells with a moderate increase in IL-17-producing cells and by the finding that this therapeutic regimen was not effective in T-bet-deficient animals that are unable to produce Th1 type immune responses (15) These observations suggested that combined inhibition of Th2 and Treg cell differentiation promotes protective immune responses in the host, which is in agreement with the concept that Th1 cells are necessary and sufficient for resistance against TB (16). As these compounds enhance hostprotective immune responses, which successfully eliminate the harbored M. tuberculosis organisms, it is likely that this therapeutic modality induces long-lasting protective memory responses in the host These findings suggested that mounting Th1 responses while inhibiting Th2 and Treg responses should be beneficial in developing TB vaccines. This strategy holds promise for developing improved TB vaccines in humans
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