The Effect of Glucosaminylmuramyl Dipeptide Injection to Mice on the Course of Tuberculous Infection and in vitro Superoxide Anion Production

Abstract

Immunotherapy as an adjunct to chemotherapy is of interest for optimizing therapeutic regimens for tuberculosis. In this context, we investigated the influence and mode of action of glucosaminylmuramyl dipeptide (GMDP) in mouse experimental models. Intermittent injections of GMDP to Mycobacterium tuberculosis-infected mice reduced the viable bacilli in the lungs, but increased the counts in the spleens at 16 weeks, but not at earlier harvests after infection. Injections of GMDP selectively ameliorated also in the lungs the spontaneous relapse of infection following chemotherapy. The mode of GMDP action was examined in respect of superoxide anion production. The O^––₂ production by phorbol myristate-induced peritoneal macrophages in vitro was reduced by preinjection of mice with 100 μg of GMDP. Notably, this outcome contrasts and can also override the previously known enhancing effect of MDP on O^––₂ production. The inhibitory activity of GMDP became even more pronounced when testing macrophages from Mycobacterium bovis BCG-infected mice. However, these results do not explain readily the grounds for the contrasting effects of GMDP on the growth patterns of tubercle bacilli in the lungs and spleens. Although the observed effects on bacillary counts have been modest, such action of GMDP could represent a beneficial adjunct to suitably formulated chemotherapeutic regimens.

Neutrophils Are the Predominant Infected Phagocytic Cells in the Airways of Patients With Active Pulmonary TB

“…Nonetheless, new chemotherapeutic candidates with in vitro activity are often prioritized based on their activity in Mtb -infected macrophages. [14][15][16] The aim of this study was therefore to quantify the location of Mtb bacilli in various clinical specimens, including samples from sputum, BAL fl uid, and cavities, refl ecting the bacterial populations in patients with active TB. We examined whether the bacilli were intracellular or extracellular and which cell types were primarily infected.…”

Prevention of the post-chemotherapy relapse of tuberculous infection by combined immunotherapy

“…This regimen is known to abrogate almost completely CFU counts in the lungs and spleen, followed by a rapid spontaneous relapse ('regrowth') of tubercle bacilli within a period of 2-4 weeks. 3 …”

“…Using a short regimen of incomplete (non-sterilizing) chemotherapy, muramyl dipeptide was reported to reduce the relapse partially in the lungs, but not in the spleens of mice. 3 Treatment of TB patients with recombinant IL-2 4 or Mycobacterium vaccae 5 failed to improve chemotherapy.…”

Local Immune Responses in Tuberculosis

“…Interestingly, immunotherapy using inoculation of glucosaminylmuramyl dipeptide in the period after the chemotherapy alleviated the relapse of Mtb infection in the lungs while enhancing the infection in the spleen, hence shifting the localization of the infection between these two organs (Venkataprasad et al, 1997). Of the possible mechanisms considered, reactivation was enhanced by C5 depletion, associated with reduced secretion of TNF-α and chemokines (KC, MIP-2, and MIP-1α) (Jagannath et al, 2000) and with increased levels of IL-10 (Turner et al, 2002).…”