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Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis.

Maiga M, Ahidjo BA, Maiga MC, Cheung L, Pelly S, Lun S, Bougoudogo F, Bishai WR - EBioMedicine (2015)

Bottom Line: BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks.C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib.Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals.

View Article: PubMed Central - PubMed

Affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Bamako, Mali.

ABSTRACT
The global tuberculosis (TB) epidemic and the spread of multi- and extensively-drug resistant strains of Mycobacterium tuberculosis (M.tb) have been fueled by low adherence to following lengthy treatment protocols, and the rapid spread of HIV (Human Immunodeficiency Virus). Persistence of the infection in immunocompetent individuals follows from the ability of M.tb to subvert host immune responses in favor of survival within macrophages. Alternative host-directed strategies are therefore being currently sought to improve treatment efficacy and duration. In this study, we evaluated tofacitinib, a new oral Janus kinase (JAK) blocker with anti-inflammatory properties, in shortening tuberculosis treatment. BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks. True sterilization with tofacitinib was not achieved until five months. C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib. Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals.

No MeSH data available.


Related in: MedlinePlus

A: Growth of M.tb in BALB/c mouse lungs during treatment.BALB/c mouse mean lung log10 CFU counts for the dosing regimens shown in the inset. Mice infected by the aerosol route achieved a day-1 lung implantation of 2.40 (standard deviation [SD] 0.08) log10 CFUs, and 8 weeks after infection at the initiation of treatment the bacterial lung burden was at 6.43 (SD 0.31) log10 CFUs. No differences across the groups were seen during the first 8 weeks. However, mice treated with 2HRZT/4HRT had lower lung bacterial burden than mice treated with the Std-Rx of 2HRZ/4HR at week 16 (P = 0.013). The group receiving 2HRT/4HR showed lower but not statistically significant CFU counts at 16 weeks (P = 0.0937).B: Cytokine levels from BALB/c and C3HeB/FeJ bone marrow-derived macrophages (BMDMs) following infection with M.tb and tofacitinib treatment.Differences in cytokine levels of infected BALB/c and C3HeB/FeJ bone marrow-derived macrophages (BMDMs) upon infection with M.tb. The BMDMs of BALB/c and C3HeB/FeJ BMDMs were infected with H37Rv for 2 h at a multiplicity of infection (MOI) of 1:10. TNF-α and IL-1β levels were measured by ELISA 24, 48 and 96 h later. Data shown here, which represents three biological and technical replicates, were analyzed by two-way ANOVA with the Bonferroni's test applied to correct for multiple comparisons. Despite similar baseline values (i.e. undetectable TNFα levels and approximately 250 pg/ml IL-1β levels), infected BALB/c mice showed consistent and significantly higher levels of both cytokine secretions when compared to C3HeB/FeJ mice. Addition of tofacitinib (300 nM) to uninfected or infected cells did not alter the cytokine levels (not shown). An asterisk (*) indicates p < 0.005.
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f0015: A: Growth of M.tb in BALB/c mouse lungs during treatment.BALB/c mouse mean lung log10 CFU counts for the dosing regimens shown in the inset. Mice infected by the aerosol route achieved a day-1 lung implantation of 2.40 (standard deviation [SD] 0.08) log10 CFUs, and 8 weeks after infection at the initiation of treatment the bacterial lung burden was at 6.43 (SD 0.31) log10 CFUs. No differences across the groups were seen during the first 8 weeks. However, mice treated with 2HRZT/4HRT had lower lung bacterial burden than mice treated with the Std-Rx of 2HRZ/4HR at week 16 (P = 0.013). The group receiving 2HRT/4HR showed lower but not statistically significant CFU counts at 16 weeks (P = 0.0937).B: Cytokine levels from BALB/c and C3HeB/FeJ bone marrow-derived macrophages (BMDMs) following infection with M.tb and tofacitinib treatment.Differences in cytokine levels of infected BALB/c and C3HeB/FeJ bone marrow-derived macrophages (BMDMs) upon infection with M.tb. The BMDMs of BALB/c and C3HeB/FeJ BMDMs were infected with H37Rv for 2 h at a multiplicity of infection (MOI) of 1:10. TNF-α and IL-1β levels were measured by ELISA 24, 48 and 96 h later. Data shown here, which represents three biological and technical replicates, were analyzed by two-way ANOVA with the Bonferroni's test applied to correct for multiple comparisons. Despite similar baseline values (i.e. undetectable TNFα levels and approximately 250 pg/ml IL-1β levels), infected BALB/c mice showed consistent and significantly higher levels of both cytokine secretions when compared to C3HeB/FeJ mice. Addition of tofacitinib (300 nM) to uninfected or infected cells did not alter the cytokine levels (not shown). An asterisk (*) indicates p < 0.005.

Mentions: We infected BALB/c mice by the aerosol route with a day-1 lung implantation of 2.40 (standard deviation [SD] 0.08) log10 CFUs. Drug treatments commenced 8 weeks after infection, when the bacterial lung burden was at 6.43 (SD 0.31) log10 CFUs. No significant differences in the different treatment groups were seen during the first eight weeks. However, at week 16 of treatment, mice treated with 2HRZT/4HRT showed significantly lower CFU counts compared to Std-Rx of 2HRZ/4HR, with p values of 0.013 (Fig. 2A and Supplementary Table 2). Mice receiving 2HRZT/4HRT had no detectable bacteria in the lungs after 16 weeks of treatment, whereas the 2HRT/4HR and Std-Rx groups required 24 weeks, to reach the same endpoint. Replacement of pyrazinamide with tofacitinib (2HRT/4HR versus 2HRZ/4HR) improved bacterial killing between 12 to 16 weeks of treatment (Fig. 2A). Although pyrazinamide is known to be effective against poorly replicating or semi-dormant bacilli, this suggests that reactivation mediated by tofacitinib may be most active when administered together with pyrazinamide during the bactericidal phase of treatment (Fig. 2A between the t = 0 and 4 weeks).


Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis.

Maiga M, Ahidjo BA, Maiga MC, Cheung L, Pelly S, Lun S, Bougoudogo F, Bishai WR - EBioMedicine (2015)

A: Growth of M.tb in BALB/c mouse lungs during treatment.BALB/c mouse mean lung log10 CFU counts for the dosing regimens shown in the inset. Mice infected by the aerosol route achieved a day-1 lung implantation of 2.40 (standard deviation [SD] 0.08) log10 CFUs, and 8 weeks after infection at the initiation of treatment the bacterial lung burden was at 6.43 (SD 0.31) log10 CFUs. No differences across the groups were seen during the first 8 weeks. However, mice treated with 2HRZT/4HRT had lower lung bacterial burden than mice treated with the Std-Rx of 2HRZ/4HR at week 16 (P = 0.013). The group receiving 2HRT/4HR showed lower but not statistically significant CFU counts at 16 weeks (P = 0.0937).B: Cytokine levels from BALB/c and C3HeB/FeJ bone marrow-derived macrophages (BMDMs) following infection with M.tb and tofacitinib treatment.Differences in cytokine levels of infected BALB/c and C3HeB/FeJ bone marrow-derived macrophages (BMDMs) upon infection with M.tb. The BMDMs of BALB/c and C3HeB/FeJ BMDMs were infected with H37Rv for 2 h at a multiplicity of infection (MOI) of 1:10. TNF-α and IL-1β levels were measured by ELISA 24, 48 and 96 h later. Data shown here, which represents three biological and technical replicates, were analyzed by two-way ANOVA with the Bonferroni's test applied to correct for multiple comparisons. Despite similar baseline values (i.e. undetectable TNFα levels and approximately 250 pg/ml IL-1β levels), infected BALB/c mice showed consistent and significantly higher levels of both cytokine secretions when compared to C3HeB/FeJ mice. Addition of tofacitinib (300 nM) to uninfected or infected cells did not alter the cytokine levels (not shown). An asterisk (*) indicates p < 0.005.
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f0015: A: Growth of M.tb in BALB/c mouse lungs during treatment.BALB/c mouse mean lung log10 CFU counts for the dosing regimens shown in the inset. Mice infected by the aerosol route achieved a day-1 lung implantation of 2.40 (standard deviation [SD] 0.08) log10 CFUs, and 8 weeks after infection at the initiation of treatment the bacterial lung burden was at 6.43 (SD 0.31) log10 CFUs. No differences across the groups were seen during the first 8 weeks. However, mice treated with 2HRZT/4HRT had lower lung bacterial burden than mice treated with the Std-Rx of 2HRZ/4HR at week 16 (P = 0.013). The group receiving 2HRT/4HR showed lower but not statistically significant CFU counts at 16 weeks (P = 0.0937).B: Cytokine levels from BALB/c and C3HeB/FeJ bone marrow-derived macrophages (BMDMs) following infection with M.tb and tofacitinib treatment.Differences in cytokine levels of infected BALB/c and C3HeB/FeJ bone marrow-derived macrophages (BMDMs) upon infection with M.tb. The BMDMs of BALB/c and C3HeB/FeJ BMDMs were infected with H37Rv for 2 h at a multiplicity of infection (MOI) of 1:10. TNF-α and IL-1β levels were measured by ELISA 24, 48 and 96 h later. Data shown here, which represents three biological and technical replicates, were analyzed by two-way ANOVA with the Bonferroni's test applied to correct for multiple comparisons. Despite similar baseline values (i.e. undetectable TNFα levels and approximately 250 pg/ml IL-1β levels), infected BALB/c mice showed consistent and significantly higher levels of both cytokine secretions when compared to C3HeB/FeJ mice. Addition of tofacitinib (300 nM) to uninfected or infected cells did not alter the cytokine levels (not shown). An asterisk (*) indicates p < 0.005.
Mentions: We infected BALB/c mice by the aerosol route with a day-1 lung implantation of 2.40 (standard deviation [SD] 0.08) log10 CFUs. Drug treatments commenced 8 weeks after infection, when the bacterial lung burden was at 6.43 (SD 0.31) log10 CFUs. No significant differences in the different treatment groups were seen during the first eight weeks. However, at week 16 of treatment, mice treated with 2HRZT/4HRT showed significantly lower CFU counts compared to Std-Rx of 2HRZ/4HR, with p values of 0.013 (Fig. 2A and Supplementary Table 2). Mice receiving 2HRZT/4HRT had no detectable bacteria in the lungs after 16 weeks of treatment, whereas the 2HRT/4HR and Std-Rx groups required 24 weeks, to reach the same endpoint. Replacement of pyrazinamide with tofacitinib (2HRT/4HR versus 2HRZ/4HR) improved bacterial killing between 12 to 16 weeks of treatment (Fig. 2A). Although pyrazinamide is known to be effective against poorly replicating or semi-dormant bacilli, this suggests that reactivation mediated by tofacitinib may be most active when administered together with pyrazinamide during the bactericidal phase of treatment (Fig. 2A between the t = 0 and 4 weeks).

Bottom Line: BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks.C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib.Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals.

View Article: PubMed Central - PubMed

Affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA ; Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Bamako, Mali.

ABSTRACT
The global tuberculosis (TB) epidemic and the spread of multi- and extensively-drug resistant strains of Mycobacterium tuberculosis (M.tb) have been fueled by low adherence to following lengthy treatment protocols, and the rapid spread of HIV (Human Immunodeficiency Virus). Persistence of the infection in immunocompetent individuals follows from the ability of M.tb to subvert host immune responses in favor of survival within macrophages. Alternative host-directed strategies are therefore being currently sought to improve treatment efficacy and duration. In this study, we evaluated tofacitinib, a new oral Janus kinase (JAK) blocker with anti-inflammatory properties, in shortening tuberculosis treatment. BALB/c mice, which are immunocompetent, showed acceleration of M.tb clearance achieving apparent sterilization after 16 weeks of adjunctive tofacitinib therapy at average exposures higher than recommended in humans, while mice receiving standard treatment alone did not achieve clearance until 24 weeks. True sterilization with tofacitinib was not achieved until five months. C3HeB/FeJ mice, which show reduced pro-inflammatory cytokines during M.tb infection, did not show improved clearance with adjunctive tofacitinib therapy, indicating that the nature of granulomatous lesions and host immunity may influence responsiveness to tofacitinib. Our findings suggest that the JAK pathway could be explored further for host-directed therapy in immunocompetent individuals.

No MeSH data available.


Related in: MedlinePlus