Uveitis induction in the rabbit by muramyl dipeptides

Abstract

Intraocular inflammation (uveitis) was produced in rabbits by intravenous or subcutaneous treatment with N-acetylmuramyl-L-alanyl-D-isoglutamine and several of its synthetic analogs at doses of -0.2 mg/kg in saline. A dose-dependent increase in permeability of the ocular blood-aqueous barrier as measured by leakage of protein or fluoresceinated dextran from the serum into the eye was observed from 2 to 14 h after glycopeptide treatment. Peak response occurred at approximately 3 h postdose. The lowest dose found to produce maximal vascular leakage for the most active glycopeptide analogs was 1 mg/kg. The adjuvant-inactive L-L stereoisomer of N-acetylmuramyl-L-alanyl-D-isoglutamine was inactive, even at doses as high as 10 mg/kg. Analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine which were homologous in the lactyl side chain were found to cause less uveitis. Chronic biweekly intravenous treatment of rabbits for 1 month with either N-acetyl-L-aaminobutyryl-D-isoglutamine or its lipophilic 6-O-stearoyl derivative at 1 mg/kg, but not with murabutide, resulted in leukocytic inflammatory lesions unique to the uveal tract of the eye. The uveitis was potentially reversible and occurred with decreased severity as long as 2 months after cessation of chronic treatment. Vascular leakage but not cellular infiltrate in the choroid could be modulated by pharmacologic means.

Effect of muramyl peptides on mitochondrial respiration

“…Thus, in addition to inflammatory and autoimmune reactions, muramyl peptides with toxic profile are demonstrated, in this study, to alter the mitochondrial function. Moreover, it is of importance to note that the maximum in vivo effect of MDP and some of its derivatives on mitochondrial respiration was observed 2 h after administration, a time peak which has been reported for several of the toxicological effects of MDP in vivo [9,11,26].…”

Vaccine adjuvants: Current state and future trends

“…Systemic reactions include nausea, fever, adjuvant arthritis, uveitis, eosinophilia, allergy, anaphylaxis, organ specific toxicity and immunotoxicity (i.e. the liberation of cytokines, immunosuppression or autoimmune diseases) 22 , 23 . Unfortunately, potent adjuvant action is often correlated with increased toxicity, as exemplified by the case of FCA which although potent is too toxic for human use.…”

“…Different species of bacteria used as a source of adjuvants include Mycobacterium spp., Corynebacterium parvum , C. granulosum , Bordetella pertussis and Neisseria meningitidis . Unfortunately, as whole alive or killed microorganisms these are too toxic to be used as human adjuvants 23 . However, much of the adjunvanticity of these bacteria is mediated by N‐acetyl muramyl‐L‐alanyl‐D‐isoglutamine, also called MDP.…”

Role of bacterial debris in inflammatory diseases of the joint and eye

“…More recently it has been demonstrated that systemic injection of MDP in the rabbit also elicits modulation of the blood-aqueous barrier (Waters et al 1986, Fox et al 1990). Since MDP is found in Gram positive (as well as Gram negative) bacterial cell walls it has been hypothesized that Gram positive bacteria might also play a role in causing uveitis in man.…”

“…For exayple, LPS stimulates production of prostaglandins within the eye after systemic administration (Battacherjee & Phylactos 1977, Herbort et al 1988. Although it has not been directly demonstrated that MDP will stimulate synthesis of intra-ocular prostaglandins, pharmacologic inhibitors of prostaglandin synthetase will inhibit MDP-mediated uveitis (Waters et al 1986).…”