Enhancement of Non-specific Resistance to Pseudomonas Pneumonia by a Synthetic Derivative of Muramoyl Dipeptide in Immunosuppressed Guinea Pigs

Abstract

A synthetic derivative of muramoyl dipeptide, 6-O-stearoyl-N-acetylmuramoyl-L-alanyl-D-isoglutamine [L18-MDP(A)], showed a protective effect against bacteraemic and non-bacteraemic pneumonia caused by Pseudomonas aeruginosa in immunosuppressed guinea pigs. In about half of the animals treated with the compound before infection, death from bacteraemic pneumonia produced by intratracheal inoculation of P. aeruginosa was delayed for 7 d, although all of the animals infected without prior treatment with the compound died within 4 d of infection. Multiplication of the organisms in the lung was also suppressed for at least 10 d by treatment with the compound when the animals inhaled an aerosol of P. aeruginosa. In contrast, in untreated animals the numbers of bacteria in the lung gradually increased from 10(6) to 10(9) c.f.u. g-1, and a few animals in which the organism increased to 10(9) c.f.u. g-1 had died by 6 and 10 d after infection. In both healthy and immunosuppressed animals, the accumulation of polymorphonuclear leukocytes (PMNs) in a subcutaneous air-pouch injected with heat-killed organisms was augmented by subcutaneous treatment with L18-MDP(A) 1 d before bacterial injection. The phagocytic activity of peritoneal PMNs was also increased by treatment with this compound. The augmentation of protective mechanisms against pseudomonas pneumonia by L18-MDP(A) may be attributed at least partly to the increased chemotactic and phagocytic activity of PMNs.

Gerbu adjuvant modulates the immune response and thus the course of infection in C56BL/6 mice immunised with Echinococcus multilocularis rec14-3-3 protein

“…The lack of TLR ligation/activation was supposed to initiate a Th2-oriented humoral immune response, which in E. multilocularis-infected man and mice may-at least partiallyaccount for the AE-specific (mixed Th1/Th2) immune orientation. Several MDP derivates also revealed the ability of re-stimulating immuno-suppressed mice, rats, and guinea pigs (Osada et al 1982). A variety of TLRs were found to be expressed on DCs (Rock et al 1998), allowing DCs to recognise PAMPs, like LPS.…”

Synergistic effects of romurtide and cefmenoxime against experimental Klebsiella pneumonia in mice

“…These protective effects and the synergism of L18 with antimicrobial agents have been found in various animal infectious models including those for S. aureus, Pseudomonas aeruginosa, Escherichia coli, and C. albicans. However, previous reports concluded that all the positive effects of L18 were found only when L18 was administered before infections (13,14,17,18,(20)(21)(22). In our study, we found significant improvement of the survival rate only when L18 was administered prophylactically, but we found a higher survival rate than that of the CMX control and clear synergistic effects of L18 and CMX even when L18 was administered after infections.…”

“…L18 is a newly developed derivative of MDP and has been reported to be efficacious in activating nonspecific host defenses against some bacterial and candidal infections in both normal and immunosuppressed animals (13,14,17,18,(20)(21)(22). The survival rates and bacteriological and histopathological findings in the lungs of the mice treated with L18 and CMX in this study indicate that L18 has clear synergistic effects in prophylaxis and in treatments of acute pulmonary Klebsiella infections.…”

“…Recent studies on the biological activities of MDP have revealed that, in addition to its adjuvant activity for induction of humoral and celluiar immunity, it enhances host resistance to certain infections (3-6, 11, 12, 23). Romurtide, N2-[(N-acetyl-muramoyl)-Lalanyl-D-isoglutaminyl]-M6-stearoyl-L-lysine (L18), is a new synthetic MDP derivative which, when administered parenterally or orally prior to infection, has also been found to enhance the host resistance of mice against various microbial pathogens (13,14,17,16,18,(20)(21)(22).…”

Translation of peptidoglycan metabolites into immunotherapeutics

“…101 Similarly, 6-O-stearoyl-MDP enhanced host resistance against both E. coli and C. albicans infection in immunocompromised mice treated with either X-ray irradiation or cyclophosphamide 102 and limited P. aeruginosaassociated pneumonia in immunocompromised guinea pigs. 103 Nonspecific protection was observed as well during viral infections. Romurtide and B30-MDP 8 were found to limit infection by herpes simplex virus type 1, 104 herpes simplex virus type 2 105 and vaccinia virus.…”