Prolonged treatment of tuberculosis (TB) often leads to poor compliance, default and relapse, converting primary TB patients into category II TB (Cat IITB) cases, many of whom may convert to multi-drug resistant TB (MDR-TB). We have evaluated the immunotherapeutic potential of Mycobacterium indicus pranii (MIP) as an adjunct to Anti-Tubercular Treatment (ATT) in Cat II pulmonary TB (PTB) patients in a prospective, randomized, double blind, placebo controlled, multicentric clinical trial. 890 sputum smear positive Cat II PTB patients were randomized to receive either six intra-dermal injections (2 + 4) of heat-killed MIP at a dose of 5 × 108 bacilli or placebo once in 2 weeks for 2 months. Sputum smear and culture examinations were performed at different time points. MIP was safe with no adverse effects. While sputum smear conversion did not show any statistically significant difference, significantly higher number of patients (67.1%) in the MIP group achieved sputum culture conversion at fourth week compared to the placebo (57%) group (p = 0.0002), suggesting a role of MIP in clearance of the bacilli. Since live bacteria are the major contributors for sustained incidence of TB, the potential of MIP in clearance of the bacilli has far reaching implications in controlling the spread of the disease.
The current vaccine against tuberculosis (TB), Mycobacterium bovis BCG, fails to protect against the most prevalent disease form, pulmonary TB in adults. It is generally assumed that active TB occurs because of a weakening of the immune system, which keeps Mycobacterium tuberculosis in check as long as it is fully competent. M. tuberculosis does not induce the optimum protection because the pathogen is not eradicated, and it has now been shown that exogenous reinfection does occur, suggesting that natural immunity is insufficient (26) and fails to control the pathogen in the long run. Hence, other mycobacterial strains which share cross-reactive antigens (Ags) with M. tuberculosis have also been considered as alternatives to M. bovis for vaccine use. One strain, "Mycobacterium w," had been evaluated for its immunomodulatory properties in leprosy. M. w is a nonpathogenic, cultivable mycobacterium (18) which has been found to improve immunity to leprosy (30). A vaccine against leprosy based on M. w is approved for human use, where it has resulted in clinical improvement, accelerated bacterial clearance, and increased immune responses to Mycobacterium leprae Ags (13,21,25). M. w shares Ags not only with M. leprae but also with M. tuberculosis (29), and initial studies have shown that vaccination with killed M. w induces protection against TB in animal models (22, 23) and also resulted in early sputum conversion in TB patients (17). Recently it has been suggested that M. w be referred to as Mycobacterium indicus pranii to avoid confusion with M. tuberculosis-W (Beijing strain) (24). It is generally known that live bacteria impart greater protection than killed bacteria. It may be that persistence of live bacteria in the host for some time results in a robust memory response (12). Another important factor is that secretory proteins which are absent in the killed bacterial vaccines have been shown to play an important role in protection. In this study, we analyzed the M. tuberculosis-specific immune response induced in mice immunized with live or killed M. w and compared it with the BCG-induced immune response and also compared the protective efficacies of the two mycobacteria.As the lung is the primary target organ of this disease, immunization potential by the aerogenic route was also studied. Inhalation of aerosols provides a noninvasive delivery system that physically targets the lung as the desired site of the pharmacological effect. This route of immunization has emerged a very attractive route of vaccine delivery, inducing both local and systemic immunity (7, 10).
BackgroundRole of immune system in protecting the host from cancer is well established. Growing cancer however subverts immune response towards Th2 type and escape from antitumor mechanism of the host. Activation of both innate and Th1 type response is crucial for host antitumor activity. In our previous study it was found, that Mycobacterium indicus pranii (MIP) also known as M. w induces Th1 type response and activates macrophages in animal model of tuberculosis. Hence, we studied the immunotherapeutic potential of MIP in mouse tumor model and the underlying mechanisms for its antitumor activity.Methodology and Principal FindingsTumors were implanted by injecting B16F10 melanoma cells subcutaneously into C57BL/6 mice. Using the optimized dose and treatment regimes, anti-tumor efficacy of heat killed MIP was evaluated. In MIP treated group, tumor appeared in only 50–60% of mice, tumor growth was delayed and tumor volume was less as compared to control. MIP mediated immune activation was analysed in the tumor microenvironment, tumor draining lymph node and spleen. Induction of Th1 response and higher infiltration of immune cells in the tumor microenvironment was observed in MIP treated mice. A large fraction of these immune cells were in activated state as confirmed by phenotypic and functional analysis. Interestingly, percentage of Treg cells in the tumor milieu of treated mice was less. We also evaluated efficacy of MIP along with chemotherapy and found a better response as compared to chemotherapy alone.ConclusionMIP therapy is effective in protecting mice from tumor. It activates the immune cells, increases their infiltration in tumor, and abrogates tumor mediated immune suppression.
BackgroundThe 9-month-long chemotherapy of tuberculosis often results in poor compliance and emergence of drug-resistant strains. So, improved therapeutic strategy is urgently needed. Immunotherapy could be beneficial for the effective management of the disease. Previously we showed the protective efficacy of Mycobacterium indicus pranii (MIP) when given as prophylactic vaccine in animal models of tuberculosis.MethodsWe sought to investigate whether MIP can be used as an adjunct to the chemotherapy in guinea pig models of tuberculosis. Efficacy of MIP was evaluated when given subcutaneously or by aerosol.ResultsMIP-therapy as an adjunct to the chemotherapy was found to be effective in accelerating bacterial killing and improving organ pathology. MIP-immunotherapy resulted in higher numbers of activated antigen-presenting cells and lymphocytes in the infected lungs and also modulated the granulomatous response. Early increase in protective Th1 immune response was observed in the immunotherapy group. Following subsequent doses of MIP, decrease in the inflammatory response and increase in the immunosuppressive response was observed, which resulted in the improvement of lung pathology.ConclusionMIP immunotherapy is a valuable adjunct to chemotherapy for tuberculosis. Aerosol route of immunotherapy can play a crucial role for inducing immediate local immune response in the lung.
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