T Cell Monitoring of Chemotherapy in Experimental Rat Tuberculosis▿
| Autor: | Maxime Herve, Amit Singhal, Damian Guang Foo, Véronique Dartois, Jie Yee Siew, Pablo Bifani, Luis R. Camacho, Hui Chien Tay |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Enzyme-Linked Immunospot Assay
Tuberculosis T-Lymphocytes Population Antitubercular Agents Drug Evaluation Preclinical Mycobacterium tuberculosis Efficacy Interferon-gamma Antigen Bacterial Proteins Drug Resistance Multiple Bacterial Drug Discovery medicine Isoniazid Potency Animals Pharmacology (medical) Experimental Therapeutics Rats Wistar education Antibiotics Antitubercular Pharmacology education.field_of_study Antigens Bacterial biology business.industry medicine.disease biology.organism_classification bacterial infections and mycoses Virology Rats Disease Models Animal Infectious Diseases Drug development Immunology Female Rifampin business medicine.drug |
| Popis: | Mycobacterium tuberculosis is the causative agent of a pulmonary epidemic that is estimated to infect one-third of the world’s population and that has an increased incidence of multidrug resistance. The evaluation of new chemical entities against M. tuberculosis is hampered by the lack of biological tools to help predict efficacy, from early drug development to clinical trials. As the rat is the animal species of choice in the pharmaceutical industry, we have developed a rat model of acute and chronic phases of M. tuberculosis infection for drug efficacy testing. In this model, we have evaluated the impact of tuberculosis drugs on T cell response using the enzyme-linked immunospot assay methodology. Infected rats treated with isoniazid (INH) or rifampin (RIF) responded to therapy, the potency of which was comparable to that seen in the mouse. Peripheral blood mononuclear cells from infected rats produced gamma interferon (IFN-) in response to RD-1 antigens, such as the 6-kDa early secretory antigen target (ESAT-6) and the 10-kDa culture filtrate protein (CFP-10). A decrease in IFN- spot-forming cells (SFCs) was consistently observed in response to drug treatment. In both the acute- and chronic-phase models, the T cell response was more sensitive to ESAT-6 than to CFP-10. The SFC count in response to ESAT-6 appears to be an indicator of bacterial killing in the rat. Collectively, our data suggest that the ESAT-6 response could be used as a potential surrogate of drug efficacy in the rat and that such a readout could help shorten drug testing during preclinical development. Mycobacterium tuberculosis infection is among the world’s leading infectious diseases, causing about 2 million deaths annually. The emergence of multidrug-resistant M. tuberculosis strains along with the increase of HIV coinfected cases worsens the situation (42). In countries with a high incidence of tuberculosis (TB), TB control programs rely on a diagnostic methods and drugs that have been developed decades ago and that are inadequate to effectively control the epidemic. The urgent need to develop new diagnostic tools as well as new therapeutic interventions is hampered by long clinical trials, where markers of infection and drug response are lacking (38). |
| Databáze: | OpenAIRE |
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