title: T cell monitoring of chemotherapy in experimental rat tuberculosis.
abstract: 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-γ) 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-γ 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.
authors.affiliation: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors.forename: Damian Guang
authors.initials: DG
authors.lastname: Foo
authors.forename: Hui Chien
authors.initials: HC
authors.lastname: Tay
authors.forename: Jie Yee
authors.initials: JY
authors.lastname: Siew
authors.forename: Amit
authors.initials: A
authors.lastname: Singhal
authors.forename: Luis
authors.initials: L
authors.lastname: Camacho
authors.forename: Pablo
authors.initials: P
authors.lastname: Bifani
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.forename: Maxime
authors.initials: M
authors.lastname: Hervé
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology / Q000627:therapeutic use; D000942:Antigens, Bacterial / Q000276:immunology*; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D024901:Drug Resistance, Multiple, Bacterial; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D007538:Isoniazid / Q000494:pharmacology / Q000627:therapeutic use; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D012293:Rifampin / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy* / Q000276:immunology* / Q000382:microbiology
chemical_list: D000904:Antibiotics, Antitubercular; D000942:Antigens, Bacterial; D000995:Antitubercular Agents; D001426:Bacterial Proteins; C117940:CFP-10 protein, Mycobacterium tuberculosis; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D007371:Interferon-gamma; D007538:Isoniazid; D012293:Rifampin