Immunostimulant activities of a lipophilic muramyl dipeptide derivative and of desmuramyl peptidolipid analogs

Abstract

The unmunostimulant properties of a new muramyl dipeptide (MDP) derivative bearing a lipophilic moiety on the C-terminal end of the peptide chain are described. It is shown, in particular, that 1,0-(acetylmuramyl-L-alanyl-D-isoglutamine-L-alanyl)-glycerol-3-mycolate had increased immunostimulant activity in comparison with MDP. It induced hypersensitivity even when administered with an antigen in saline, and it gave higher protection against bacterial infections than did MDP. A quite unexpected finding was obtained with the corresponding desmuramyl compound 1,0-(L-alanyl-D-isoglutamine-L-alanyl)-glycerol-3-mycolate, which had no activity in producing humoral antibodies but was just as active as the muramic acid-containing compound in stimulating nonspecific resistance to bacterial infections. It was not pyrogenic. Modifications of the peptide moiety or the lipid moiety of this peptidolipid led to decrease, or even loss, of activity. These results show the importance of the N-acetyhnuramyl moiety in MDP for humoral antibody production. The peptidolipid l,O-(L-alanyl-D-isoglutamine-Lalanyl)-glycerol-3-mycolate is the first member of a new category of nonspecific immunostimulants.

Vaccine adjuvants: Current state and future trends

“…The adjuvanticity of MDP depends on the administration conditions 11 , 49 . In saline, it mainly enhances humoral immunity 20 , 50 , 51 whilst when incorporated into liposomes or mixed with glycerol it induces strong cellular immunity 52 . MDP activates many different cell types including macrophages, leucocytes, mastocytes, endothelial cells and fibroblasts inducing the secretion of cytokines such as IL‐1, B‐cell grow factor and fibroblast activating factor.…”

Non‐specific immune response of Nile tilapia, Oreochromis nilotica, to the extracellular products of Mycobacterium spp. and to various adjuvants

“…There are numerous reports of microbial products which have the ability to stimulate the phagocytic activity of these cells. Such immunostimulants include Bacille Calmette-Guerin (BCG) (Sher, Chaparas, Greenberg & Bernard 1975), Corynebacterium parvum (Berd 1978), endotoxin (Dubos & Schaedler 1956), glucan (Reynolds, Kastello, Harrington, Crabbs, Peters, Jemski, Scott & Luzio 1980), Nocardia rubra cell wall skeleton (Masuno, Ito, Ogura, Hirano, Yamawaki, Azuma & Yamamura 1979) and synthetic products, such as muramyl dipeptide and its analogues (Parant, Audibert, Chedid, Level, Lefrancier, Choay & Lederer 1980;Fraser-Smith, Eppstein, Larsen & Matthew 1983;Saiki, Tokushima, Nishimura, Nishimura, Yamamura & Azuma 1983). Cipriano & Pyle (1985) showed increased protection in eastern brook trout, Salvelinus fontinalis (Mitchell), when injected with Freund's incomplete adjuvant (FIA) and EcF1, a (Francis & Ellis 1994).…”

Plant-derived glycoalkaloids protect mice against lethal infection withSalmonella typhimurium

“…Indeed, muramyldipeptide administered i.p. 1-3 days before challenge with the same microbial dose (2 LD 50 ) was able to protect only 50% of the mice (Chedid et al, 1982;Parant et al, 1980;Parant et al, 1992). Mytilan, another non-specific high molecular weight polysaccharide derived from Mydia (sea plant), enhanced survival rates (75-100%) when challenged with 1 LD 50 dose (Zaporozhets et al, 1981).…”