1988 Fiscal Year Final Research Report Summary
Necrotic inflammatory reaction induced by muramyl dipeptide.
| Project/Area Number |
62570191
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
細菌学
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| Research Institution | Department of Biochemistry, Shimane Medical University |
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Principal Investigator |
NAGAO Shigeki Dept. of Biochem., Shimane Med. Univ., Assistant, 医学部, 助手 (50112131)
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| Co-Investigator(Kenkyū-buntansha) |
YAGAWA Katsuro Research Institute for Diseases of the Chest, Faculty of Medicine, Kyushu Univ.,, 医学部, 助手 (90183665)
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| Project Period (FY) |
1987 – 1988
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| Keywords | Necrotic reaction / Tubercle bacilli / Muramyldipeptide / preparatory injection / MDP / MDP / モルモット |
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| Research Abstract |
In the course of studies aimed at determining whether MDP was antigenic or not, a hitherto unreported phenomenon was noticed.
Intravenous or intracutaneous injection (a provacative injection) of muramyl dipeptide (MDP) caused severe inflammation, with hemorrhage and necrosis in the foot pads of guinea pigs, where tubercle bacilli in water-oil emulsion (a preparatory injection) had been injected 4-5 wks earlier. Development of delayed hypersensitivity to protein antigens by provocative injection may be important for preparation.
We examined a variety of analogs and derivatives of muramylpeptides for their ability to provoke this reaction. A maximum and a minimum structure responsible for the necrotic reaction were found to be N-acetylglycosaminyl- (1-4)-N-acetyl-muramyl-tripeptide (GlcNAc-MurNAc-L-Ala-D-isoGln-mesoA2pm) and MDP, respectively.
Introduction of some acyl groups, especially the stearoyl group, to the 6-0 position of the muramic acid or the peptide moiety of muramylpeptides increased the necrosis-inducing activity of the parent molecules.
Modification of the - or -carboxyl groups of the glutamic acid residues of muramylpeptides tended to decrease their necrosis-inducing ability.
Analogs and derivatives of muramylpeptides which are capable of inducing necrosis at a primed site, with few exceptions, exhibited powerful adjuvant activity in guinea pigs. However, the reverse was not necessarily true. Slight modification of the chemical structure of MDP enhanced or supressed the provoking ability of MDP. Thus, development of clinically useful MDP derivatives without this detrimental effect may be possible.
Although this reaction appears to be similar to the Shwartzman reaction, the two reactions were found to differ from each other in several important points. Mechanism(s) operating in the phenomenon is not known.
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