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Immunotherapeutic role of Ag85B as an adjunct to antituberculous chemotherapy.

Sheikh JA, Khuller GK, Verma I - J Immune Based Ther Vaccines (2011)

Bottom Line: Therapeutic effect of Ag85B was found to be comparable to that of short term dosage of antituberculous drugs (ATDs).This therapy was found to be effective even in case of drug persisters.The therapeutic effect is associated not only with initiating a Th1 response but also with switching the insufficient Th2 immune status to the more protective Th1 response.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. induvermabio@gmail.com.

ABSTRACT

Background: Immunotherapy to enhance the efficiency of the immune response in tuberculosis patients and to eliminate the persisters could be an additional valuable strategy to complement anti-mycobacterial chemotherapy. This study was designed to assess the immunotherapeutic potential of Ag85B as an adjunct to chemotherapy and its effect against active and persister bacteria left after therapy in mouse model of tuberculosis.

Methods: 6-8 week old female Balb/c mice were infected with Mycobacterium tuberculosis and treated with chemotherapy or immunotherapy. Protective efficacy was measured in terms of bacterial counts in lungs and spleen. Immune correlates of protection in terms of Th1 and Th2 cytokines were measured by ELISA.

Results: Therapeutic effect of Ag85B was found to be comparable to that of short term dosage of antituberculous drugs (ATDs). The therapeutic effect of ATDs was augmented by the simultaneous treatment with rAg85B and moreover therapy with this protein allowed us to reduce ATD dosage. This therapy was found to be effective even in case of drug persisters. The levels of antigen specific IFNγ and IL-12 were significantly increased after immunotherapy as compared to the basal levels; moreover antigen specific IL-4 levels were depressed on immunotherapy with Ag85B.

Conclusion: We demonstrated in this study that the new combination approach using immunotherapy and concurrent chemotherapy should offer several improvements over the existing regimens to treat tuberculosis. The therapeutic effect is associated not only with initiating a Th1 response but also with switching the insufficient Th2 immune status to the more protective Th1 response.

No MeSH data available.


Related in: MedlinePlus

Increased protection in animals as depicted by numbers of viable CFUs of M. tuberculosis H37Rv in the lungs of M. tuberculosis H37Rv infected animals receiving adjunctive immunotherapy. Two weeks post chemotherapy/immunotherapy, lungs and spleen from treated and untreated M. tuberculosis H37Rv infected animals were isolated and cultured on Middlebrook 7H11 agar plates. Results are expressed as mean log10 CFUs ± standard deviation of 5 animals per group tested individually. Statistical analysis of the results was carried out by Student's t test. ***p< 0.001, **p< 0.01 compared to untreated animals. Basal level represents CFU after two weeks of infection. (ATD: Antituberculous Drugs; IT: Immunotherapy; O/W: Once Weekly)
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Figure 2: Increased protection in animals as depicted by numbers of viable CFUs of M. tuberculosis H37Rv in the lungs of M. tuberculosis H37Rv infected animals receiving adjunctive immunotherapy. Two weeks post chemotherapy/immunotherapy, lungs and spleen from treated and untreated M. tuberculosis H37Rv infected animals were isolated and cultured on Middlebrook 7H11 agar plates. Results are expressed as mean log10 CFUs ± standard deviation of 5 animals per group tested individually. Statistical analysis of the results was carried out by Student's t test. ***p< 0.001, **p< 0.01 compared to untreated animals. Basal level represents CFU after two weeks of infection. (ATD: Antituberculous Drugs; IT: Immunotherapy; O/W: Once Weekly)

Mentions: Mice infected with the M. tuberculosis H37Rv strain were treated with either rAg85B protein or Ag85B-DNA (Figure 1), and the therapeutic effects were expressed as the bacterial load in the spleen and lung (Figure 2 & Table 1). Compared with the adjuvant immunized control group, rAg85B significantly reduced the bacterial numbers in the spleen and lung (p< 0.001), and was equally effective to that of 'short term' chemotherapy. The adjunctive effect of immunotherapy and chemotherapy was much more pronounced as compared to adjuvant immunized control group (p< 0.001) showing effective cumulative effect on bacterial eradication (Table 1). Although the effect was not additive as marginal decrease in CFU count was not statistically significant when compared to ATD or IT alone. However no significant reduction in CFUs with Ag85B-DNA immunotherapy was observed (data not shown). Further efforts were made to mimic the process of chemotherapy dosage reduction by delivery of drug dosage just once a week with simultaneous immunotherapy and a significant reduction in CFU was observed as compared to that of control (p< 0.01). These findings suggest that immunotherapy could be effectively used as an adjunct to chemotherapy and drug dosage can be considerably reduced to once a week with concomitant immunotherapy, as the CFU reduction was same as that of the group where ATD was given daily (Figure 2).


Immunotherapeutic role of Ag85B as an adjunct to antituberculous chemotherapy.

Sheikh JA, Khuller GK, Verma I - J Immune Based Ther Vaccines (2011)

Increased protection in animals as depicted by numbers of viable CFUs of M. tuberculosis H37Rv in the lungs of M. tuberculosis H37Rv infected animals receiving adjunctive immunotherapy. Two weeks post chemotherapy/immunotherapy, lungs and spleen from treated and untreated M. tuberculosis H37Rv infected animals were isolated and cultured on Middlebrook 7H11 agar plates. Results are expressed as mean log10 CFUs ± standard deviation of 5 animals per group tested individually. Statistical analysis of the results was carried out by Student's t test. ***p< 0.001, **p< 0.01 compared to untreated animals. Basal level represents CFU after two weeks of infection. (ATD: Antituberculous Drugs; IT: Immunotherapy; O/W: Once Weekly)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3142482&req=5

Figure 2: Increased protection in animals as depicted by numbers of viable CFUs of M. tuberculosis H37Rv in the lungs of M. tuberculosis H37Rv infected animals receiving adjunctive immunotherapy. Two weeks post chemotherapy/immunotherapy, lungs and spleen from treated and untreated M. tuberculosis H37Rv infected animals were isolated and cultured on Middlebrook 7H11 agar plates. Results are expressed as mean log10 CFUs ± standard deviation of 5 animals per group tested individually. Statistical analysis of the results was carried out by Student's t test. ***p< 0.001, **p< 0.01 compared to untreated animals. Basal level represents CFU after two weeks of infection. (ATD: Antituberculous Drugs; IT: Immunotherapy; O/W: Once Weekly)
Mentions: Mice infected with the M. tuberculosis H37Rv strain were treated with either rAg85B protein or Ag85B-DNA (Figure 1), and the therapeutic effects were expressed as the bacterial load in the spleen and lung (Figure 2 & Table 1). Compared with the adjuvant immunized control group, rAg85B significantly reduced the bacterial numbers in the spleen and lung (p< 0.001), and was equally effective to that of 'short term' chemotherapy. The adjunctive effect of immunotherapy and chemotherapy was much more pronounced as compared to adjuvant immunized control group (p< 0.001) showing effective cumulative effect on bacterial eradication (Table 1). Although the effect was not additive as marginal decrease in CFU count was not statistically significant when compared to ATD or IT alone. However no significant reduction in CFUs with Ag85B-DNA immunotherapy was observed (data not shown). Further efforts were made to mimic the process of chemotherapy dosage reduction by delivery of drug dosage just once a week with simultaneous immunotherapy and a significant reduction in CFU was observed as compared to that of control (p< 0.01). These findings suggest that immunotherapy could be effectively used as an adjunct to chemotherapy and drug dosage can be considerably reduced to once a week with concomitant immunotherapy, as the CFU reduction was same as that of the group where ATD was given daily (Figure 2).

Bottom Line: Therapeutic effect of Ag85B was found to be comparable to that of short term dosage of antituberculous drugs (ATDs).This therapy was found to be effective even in case of drug persisters.The therapeutic effect is associated not only with initiating a Th1 response but also with switching the insufficient Th2 immune status to the more protective Th1 response.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India. induvermabio@gmail.com.

ABSTRACT

Background: Immunotherapy to enhance the efficiency of the immune response in tuberculosis patients and to eliminate the persisters could be an additional valuable strategy to complement anti-mycobacterial chemotherapy. This study was designed to assess the immunotherapeutic potential of Ag85B as an adjunct to chemotherapy and its effect against active and persister bacteria left after therapy in mouse model of tuberculosis.

Methods: 6-8 week old female Balb/c mice were infected with Mycobacterium tuberculosis and treated with chemotherapy or immunotherapy. Protective efficacy was measured in terms of bacterial counts in lungs and spleen. Immune correlates of protection in terms of Th1 and Th2 cytokines were measured by ELISA.

Results: Therapeutic effect of Ag85B was found to be comparable to that of short term dosage of antituberculous drugs (ATDs). The therapeutic effect of ATDs was augmented by the simultaneous treatment with rAg85B and moreover therapy with this protein allowed us to reduce ATD dosage. This therapy was found to be effective even in case of drug persisters. The levels of antigen specific IFNγ and IL-12 were significantly increased after immunotherapy as compared to the basal levels; moreover antigen specific IL-4 levels were depressed on immunotherapy with Ag85B.

Conclusion: We demonstrated in this study that the new combination approach using immunotherapy and concurrent chemotherapy should offer several improvements over the existing regimens to treat tuberculosis. The therapeutic effect is associated not only with initiating a Th1 response but also with switching the insufficient Th2 immune status to the more protective Th1 response.

No MeSH data available.


Related in: MedlinePlus