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Efficacy of Anti-PD-1 in Immune Reconstitution and Adjunct Immunotherapy Against M. Tuberculosis
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A7751 - Efficacy of Anti-PD-1 in Immune Reconstitution and Adjunct Immunotherapy Against M. Tuberculosis
Author Block: D. Kamboj1, D. Mitra2; 1TRANSPLANT IMMUNOLOGY AND IMMUNOGENETICS, ALL INDIA INSTITUTE OF MEDICAL SCIENCES, New Delhi, India, 2TRANSPLANT IMMUNOLOGY AND IMMUNOGENETICS, ALL INDIA INSTITUTE OF MEDICAL SCIENCES, NEW DELHI, India.
Abstract
Introduction: Inhibiting PD-1 pathway boosts poly-functional T cells, which are more protective in tuberculosis than IFN-γ alone, as evident our by human in vitro human PD-1 blocking experiments and reduced bacillary load in our in vitro Monocyte Derived Macrophages (MDMs) model experiment. The role of the PD-1/PD-L pathway in murine tuberculosis so far remains unclear. So, we wanted to study the impact of inhibiting PD-1 in boosting poly-functional T cells and reduction of bacterial growth in vivo. We also propose that poly-functional CD4+ T cells are relevant as an immune biomarker for active tuberculosis and α PD-1 may act as a novel mechanism in boosting it. Here we investigated the impact of PD-1 blockade on the rescue poly-functional T cells and bacterial burden in vivo M. tuberculosis infection (mice) model.
Materials and methods: BALB/c mice were challenged with a low dose of aerosol virulent M. tuberculosis (H37Rv strain). We evaluated the impact of blocking PD-1 in a therapeutic mice model, by combinatorial intervention (ATT and α PD-1) relative to the control groups (M. tuberculosis infected mice treated with either ATT or α PD-1 alone).The number of colony forming units (CFU) and PFT (IFN-γ+TNF-α+ Poly-functional T cells) response was enumerated in lungs and spleen of infected mice.
Results: We observed significant reduction in bacterial burden in both ATT and α PD-1 treated groups relative to isotype control. The bacterial burden was corroborated with histopathological findings, which showed fewer or absent diffused granuloma–like structures in mice treated with combination therapy as compared to isotype controls and mice treated with either ATT or α PD1 alone. This was further supported by higher number of M. tuberculosis specific infiltrating poly-functional T cells in both lungs and spleen of infected mice.
Conclusions: Our results suggest crucial role of PD-1 pathway in rescuing PFTs (IFN-γ+TNF-α+) thus resulting in improved containment of M. tuberculosis. Our findings strongly suggest that rescuing poly-functional immune response by PD-1 inhibition works synergistically with anti-tuberculosis chemotherapy to confer improved control over bacillary growth and dissemination.
Author Block: D. Kamboj1, D. Mitra2; 1TRANSPLANT IMMUNOLOGY AND IMMUNOGENETICS, ALL INDIA INSTITUTE OF MEDICAL SCIENCES, New Delhi, India, 2TRANSPLANT IMMUNOLOGY AND IMMUNOGENETICS, ALL INDIA INSTITUTE OF MEDICAL SCIENCES, NEW DELHI, India.
Abstract
Introduction: Inhibiting PD-1 pathway boosts poly-functional T cells, which are more protective in tuberculosis than IFN-γ alone, as evident our by human in vitro human PD-1 blocking experiments and reduced bacillary load in our in vitro Monocyte Derived Macrophages (MDMs) model experiment. The role of the PD-1/PD-L pathway in murine tuberculosis so far remains unclear. So, we wanted to study the impact of inhibiting PD-1 in boosting poly-functional T cells and reduction of bacterial growth in vivo. We also propose that poly-functional CD4+ T cells are relevant as an immune biomarker for active tuberculosis and α PD-1 may act as a novel mechanism in boosting it. Here we investigated the impact of PD-1 blockade on the rescue poly-functional T cells and bacterial burden in vivo M. tuberculosis infection (mice) model.
Materials and methods: BALB/c mice were challenged with a low dose of aerosol virulent M. tuberculosis (H37Rv strain). We evaluated the impact of blocking PD-1 in a therapeutic mice model, by combinatorial intervention (ATT and α PD-1) relative to the control groups (M. tuberculosis infected mice treated with either ATT or α PD-1 alone).The number of colony forming units (CFU) and PFT (IFN-γ+TNF-α+ Poly-functional T cells) response was enumerated in lungs and spleen of infected mice.
Results: We observed significant reduction in bacterial burden in both ATT and α PD-1 treated groups relative to isotype control. The bacterial burden was corroborated with histopathological findings, which showed fewer or absent diffused granuloma–like structures in mice treated with combination therapy as compared to isotype controls and mice treated with either ATT or α PD1 alone. This was further supported by higher number of M. tuberculosis specific infiltrating poly-functional T cells in both lungs and spleen of infected mice.
Conclusions: Our results suggest crucial role of PD-1 pathway in rescuing PFTs (IFN-γ+TNF-α+) thus resulting in improved containment of M. tuberculosis. Our findings strongly suggest that rescuing poly-functional immune response by PD-1 inhibition works synergistically with anti-tuberculosis chemotherapy to confer improved control over bacillary growth and dissemination.
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