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The majority of the population living near the tropics carries a varying degree of tolerance against BCG due to the widespread prevalence of non-tuberculous mycobacteria (NTM). Interestingly, \u224890% of the <jats:italic>Mycobacterium tuberculosis (Mtb)<\/jats:italic> infected population restrain the bacilli on its own, which strengthens the notion of empowering the host immune system to advance the protective efficacy of existing mycobacterial vaccines. In general, <jats:italic>Mtb<\/jats:italic> modulates IL-10\/STAT3 signaling to skew host mononuclear phagocytes toward an alternatively activated, anti-inflammatory state that helps it thrive against hostile immune advances. We hypothesized that modulating the IL-10\/STAT3 driven anti-inflammatory effects in mononuclear cells may improve the prophylactic ability of TB vaccines. This study investigated the immunotherapeutic ability of a porphyrin based small molecule inhibitor of IL-10\/STAT3 axis, 5, 15-diphenyl porphyrin (DPP), in improving anti-TB immunity offered by second generation recombinant BCG30 (rBCG30-ARMF-II<jats:sup>\u00ae<\/jats:sup>) vaccine in mice. The DPP therapy potentiated vaccine induced anti-TB immunity by down-modulating anti-inflammatory responses, while simultaneously up-regulating pro-inflammatory immune effector responses in the immunized host. The employed DPP based immunotherapy led to the predominant activation\/proliferation of pro-inflammatory monocytes\/macrophages\/DCs, the concerted expansion of CD4+\/CD8+ effector and central memory T cells, alongside balanced Th17 and Treg cell amplification, and conferred augmented resistance to aerosol <jats:italic>Mtb<\/jats:italic> challenge in rBCG30 immunized BALB\/c mice.<\/jats:p>","DOI":"10.3389\/fimmu.2021.706727","type":"journal-article","created":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T06:37:28Z","timestamp":1635489448000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Immunotherapy With 5, 15-DPP Mediates Macrophage M1 Polarization and Modulates Subsequent Mycobacterium tuberculosis Infectivity in rBCG30 Immunized Mice"],"prefix":"10.3389","volume":"12","author":[{"given":"Faraz","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd. 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