SUMMARYEarlier studies in patients with pulmonary TB have revealed a higher production of Th1 cell type cytokines in moderate TB, with predominant Th2-like responses in advanced disease. Given the influence of IL-12 in T cell differentiation, as well as the roles of transforming growth factor-beta (TGFb), nitric oxide and tumour necrosis factor-alpha (TNF-a ) in the immune response against intracellular pathogens, we decided to analyse the interferon-gamma (IFN-g), IL-4, IL-12, TGF-b , TNF-a and nitrite concentrations in culture supernatants of PBMC from TB patients showing different degrees of lung involvement. The sample population comprised 18 untreated TB patients with either moderate (n 9) or advanced (n 9) disease and 12 age-and sex-matched healthy controls (total population (patients and controls) 12 women, 18 men, aged 37^13 years (mean^s.d.)). PBMC were stimulated with whole sonicate from Mycobacterium tuberculosis and the supernatants were collected on day 4 for measurement of cytokine and nitrite levels. Antigen-stimulated IFN-g, TGF-b and TNF-a production was found to be significantly increased in TB patients, both moderate and advanced, compared with the controls. Levels of IFN-g were significantly higher in moderate disease than advanced cases, whereas advanced cases showed significantly higher IL-12, TGF-b and TNF-a concentrations when compared with cases of moderate TB. Nitrite levels were also increased in TB patients and the increase was statistically significant when advanced cases were compared with controls. These findings may contribute to a clearer picture of the net effect of cytokine interactions in TB, essential for a better understanding of the immunopathological mechanisms underlying the distinct clinical forms of the disease.
We report the first study of triple-dose immunotherapy with heat-killed Mycobacterium vaccae (SRL 172) combined with short-course, directly observed chemotherapy in newly diagnosed pulmonary tuberculosis patients. The study was carried out in Rosario, Argentina, where single-dose immunotherapy with M. vaccae has previously been shown effective. Twenty-two HIV seronegative patients, sputum-positive for tubercle bacilli, entered a randomised and partly blinded trial. Twelve patients received injections of SRL 172 and 10 patients received placebo on days 1, 30 and 60 of chemotherapy. All patients were followed up clinically, by sputum bacteriology, chest radiography and haematology. Patients receiving SRL 172 showed faster and more complete clinical improvement, accelerated disappearance of bacilli from sputum, better radiological clearance and a more rapid fall in ESR, than did those receiving placebo. Follow-up continued for a year after therapy and no patient failed treatment or relapsed. Special investigations included longitudinal assessments of respiratory bursts and expression of CD11b on separated polymorphonuclear and mononuclear leukocytes. Tumour necrosis factor alpha (TNF-alpha) was measured in the supernates of cultured cells and both TNF-alpha and interleukin-4 (IL-4) were measured in serum samples. Immunotherapy recipients showed a significantly faster return towards normal values in all the immunological parameters, than did placebo recipients. The results are consistent with a regulatory activity on cellular immunity, reducing the influence of Th2 and enhancing Th1 to the benefit of the patients. This could allow a reduced period of chemotherapy without loss of efficacy and help to prevent the development of multi-drug resistance.
A research investigation to evaluate the potential of an oral preparation of Mycobacterium vaccae SRL172 (NCTC 11659) as an immunotherapeutic has been carried out in ten patients with moderate to advanced pulmonary tuberculosis at Carrasco Hospital, Argentina. Comparison was made between oral and injected M.vaccae sharing a mutual control group. Clinical, bacteriological, hematological, radiological and immunological assessments all showed comparable benefits for both injected and oral treatment over those achieved with chemotherapy alone. The only significant difference between results of injected and oral M.vaccae was the failure of the latter to reduce TNF-alpha production by cultured mononuclear cells. A more intensive regime for the oral preparation was used, which as an addition to the directly observed therapy, short-course, treatment should improve results in both drug susceptible and drug-resistant cases. A Phase II Good Clinical Practice trial is now required.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.