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Biomedical subjects

L Chedid

Publications and source records attributed to L Chedid.

At least 127 records · Page 7Linked to original sources
PubMed1981

Persistent enhancement of cell-mediated and antibody immune responses after administration of muramyl dipeptide derivatives with antigen in metabolizable oil.

Circulating antibody titers can be increased when the antigen is administered in an aqueous medium with N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide). Results reported here show that cell-mediated immunity can be demonstrated when this synthetic adjuvant or an active analog is injected with an antigen (ovalbumin) in metabolizable squalane emulsion. Under these conditions a lipophilic derivative of muramyl dipeptide was shown to be even more active and to enhance long-lasting immune responses.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1981

Nonspecific enhancement of host defenses against infection: experimental evidence of a new order of efficacy and safety.

Enhancement of nonspecific host defenses against bacterial challenge has been a long-standing goal often thwarted by variable efficacy, inconsistent bioassay, and paradoxic immunosuppression. Muramyl dipeptide provides enhanced survival after intravenous challenge with less than 8 x 10(3) Klebsiella, as well as improved local control of infection at sites of intramuscular bacterial injection, with and without a surgical foreign body. No depression of host response was seen over wide ranges of doses and intervals. Muramyl dipeptide provides a new order of efficacy and safety and warrants continued careful assessment.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1981

Studies on visceral Leishmania tropica infection in BALB/c mice. I. Clinical features and cellular changes.

The visceral and lethal infection produced in BALB/c mice by Leishmania tropica (major) is accompanied by splenomegaly, anaemia and reversal of albumin-to-globulin ratio. The percentages of both B and T cells are decreased in the spleen. The spleen and lymph nodes become populated with large Ig-, Thy 1.2- 'null' cells. The similarity of some of these parameters with those produced in human kala-azar is discussed.

Animals↗
PubMed1980

Central pyrogenic activity of muramyl dipeptide.

Fever can be elicited in the rabbit by the intravenous administration of relatively large doses of a synthetic immunoadjuvant, N-acetylmuramyl-L-alanyl-D-isoglutamine, or muramyl dipeptide (MDP). This response could be mediated by endogenous pyrogen because MDP has been shown to induce their production both in vivo and in vitro. The results reported here show that intracisternal injection of minute amounts of MDP could elevate fever without activating the release of endogenous pyrogen in the plasma or in the cerebrospinal fluid. Moreover, indomethacin inhibited hyperthermia produced by intracerebroventricular administration of MDP. Therefore, our findings argue in favor of a direct effect of the glycopeptide on the thermoregulatory centers besides its indirect effect through the production of leukocytic pyrogen. This molecule apparently represents the minimal requirement for the pyrogenicity of bacterial peptidoglycan because administration, even by the intracerebral route, of a mixture of muramic acid and of its dipeptide moiety did not elicit fever.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Antiviral response elicited by a completely synthetic antigen with built-in adjuvanticity.

In a previous study we demonstrated that antiviral response against the coliphage MS-2 can be elicited by immunization with a synthetic antigen consisting of a conjugate (P2-A -- L) of a synthetic fragment (P2) of the virus coat protein attached to a synthetic polymeric carrier. The antiviral response was induced when the antigen was administered in complete Freund's adjuvant or when it was administered in incomplete adjuvant, provided that a peptidoglycan was covalently attached to it. In the present study we demonstrate the adjuvant effect of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) in this system. Immunization with a mixture of MDP and P2-A -- L brought about only slight enhancement in the titer of neutralizing antibodies, as compared to the immunization with P2-A -- L in saline. The best results were achieved when the MDP was chemically conjugated to P2-A -- L. This completely synthetic material, when administered in aqueous solution, yielded highly inactivating antiserum with a titer similar to that obtained with complete Freund's adjuvant in the absence of MDP. MDP-P2-A -- L elicited also a humoral immune response to MDP, but with much lower titer than that induced by complete Freund's adjuvant containing P2-A -- L only. It was also observed that the capacity of MDP-P2-A -- L to increase resistance against infection was more than a 100-fold greater than that of unconjugated MDP.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Efficient genetically controlled formation of antibody to a synthetic antigen [poly(LTyr, LGlu)-poly(DLAla)- -poly(LLys)] covalently bound to a synthetic adjuvant (N-acetylmuramyl-L-alanyl-D-isoglutamine).

The synthetic polypeptide antigen poly(LTyr, LGlu)-poly(DLAl)- -poly(LLys)[T,G)-A- -L] was covalently linked to N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), which is the minimal adjuvant-active structure that can substitute for Mycobacteria in complete Freund's adjuvant. When injected in aqueous solution into mice, the completely synthetic conjugate elicited significant antibody responses specific to (T,G)-A- -L, whereas (T,G,)-A- -L alone administered under the same conditions did not lead to antibody production. The conjugate was much more efficient in eliciting (T,G)-A- -L responses than was a mixture of DMP and (T,G)-A- -L. One hundred micrograms of MDP mixed with 10 micrograms of (T,G)-A- -L resulted in production of (T,g)-A- -L-specific antibodies. However, the titers obtained were much lower than those observed with 10 micrograms of the conjugate, MDP-(T,G)-A- -L, which contained less than 1 microgram of MDP. MDP was enhanced when the mixture was administered in incomplete Freund's adjuvant, the adjuvant did not significantly affect the (T,G)-A- -L-specific antibody responses in mice immunized with MDP-(T,G)-A- -L. The isoelectric focusing pattern of antibodies obtained with MDP-(T,G)-A- -L was similar to that obtained after immunization with (T,G)-A- -L in complete Freund's adjuvant. The pattern of high-responder and low-responder mice to (T,G)-A- -L, the immune response to which is genetically controlled, was retained when MDP-(T,G)-A- -L was used as the immunogen. Conjugation of (T,G)-A- -L was creased the immunogenicity of MDP and affected its biological properties. It is thus possible to obtain efficient immune responses to synthetic polypeptide antigens that produce poor reactions when injected in aqueous solution by conjugating them to small molecular weight synthetic adjuvants.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Induction of resistance to Schistosoma mansoni by natural cord factor and synthetic lower homologues.

Resistance to schistosomiasis in mice can be acquired either specifically, by primary infection with Schistosoma mansoni, or nonspecifically, by treatment with a variety of unrelated agents such as bacille Calmette-Guérin. Several immunoadjuvants related to mycobacteria were examined for their ability to induce resistance to schistosomiasis. Natural cord factor (6,6'-trehalose dimycolate), a 100-carbon synthetic cord factor analogue, and dipalmitate trehalose induced significant protection. Trehalose dibehenate and muramyl dipeptide did not induce consistent protection. Since protection acquired by primary schistosomal infection or by any of these potentiating agents is partial, their possible additive effect was evaluated. The resistance of mice with schistosomiasis that were injected with trehalose dipalmitate and challenged with schistosomal cercariae was increased, as assayed by recovery of schistosomula from the lungs and of adult worms from the portal system. Thus, these synthetic adjuvants not only induce partial protection against schistosomiasis, but also significantly enhance acquired immunity in mice with primary infections.

Adjuvants, Immunologic↗
PubMed1980

Effect of indomethacin on increased resistance to bacterial infection and on febrile responses induced by muramyl dipeptide.

The pyrogenicity in the rabbit and the ability to stimulate nonspecific resistance to bacterial infection in the mouse of muramyl dipeptide (MDP), a synthetic immunoadjuvant, are known to be enhanced when the glycopeptide has been conjugated to a carrier. The effects of indomethacin on fever induced by MDP or its conjugated derivative were studied. Indomethacin reduced febrile responses to MDP or its derivative, although it did not decrease production of endogenous pyrogen in vivo or in vitro. When incubated with rabbit peritoneal cells, indomethacin suppressed the elevation in prostaglandin levels usually induced by MDP. When administered to mice, indomethacin alone stimulated resistance to bacterial infection and, under appropriate conditions, had a strong synergistic effect when combined with free or conjugated MDP. The results demonstrate that neither pyrogenicity nor increased prostaglandin levels are prerequisites for immunopotentiation by synthetic glycopeptides.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Macrophage stimulation in vitro by an inactive muramyl dipeptide derivative after conjugation to a multi-poly(DL-alanyl)-poly(L-lysine) carrier.

It has been previously reported that N-acetyl-muramyl-L-alanyl-D-isoglutamine (MDP), which represents the minimal structure that can substitute for mycobacteria in Freund complete adjuvant, activated macrophages in vitro and in vivo. In the present study we show that, in contrast to MDP, the nonadjuvant MDP(DD) stereoisomer has no effect on cytostatic activity of thioglycolate-induced macrophages as measured by uptake of [3H]thymidine. However, surprisingly, after conjugation to an inert carrier, multi-poly(DL-alanyl)-poly(L-lysine), this compound activates macrophages in vitro and becomes at least as effective as MDP. It has also been shown in other studies that after conjugation MDP(DD) remained devoid of antigenicity and of adjuvant activity although such a conjugate could increase resistance to infection. It, therefore, appears that there exists no correlation between the structure required for adjuvant activity and the structure required for macrophage activation or for enhancement of nonspecific immunity.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Induction of antibodies directed against self and altered-self determinants by a synthetic adjuvant, muramyl dipeptide and some of its derivatives.

In a serum free, 2-mercaptoethanol supplemented culture medium muramyl dipeptide (MDP) is able to increase the number of plaque-forming cells (PFC) directed against syngeneic, bromelain-treated red blood cells (br-MRBC) and against an autoantigen, mouse albumin. The non-specific stimulation of anti-br-MRBC PFC by MDP, as by bacterial lipopolysaccharide (LPS), can be observed in spleen cell populations depleted of adherent and phagocytic cells, and in nu/nu spleen cell cultures. However, the kinetics of the induction of anti-br-MRBC PFC in murine spleen cell cultures in presence of LPS or of MDP are not identical. Moreover, MDP is able to stimulate C3H/He Orl (LPS low-responder strain) cells. Thus, the mechanisms of non-specific stimulation by MDP or by LPS could be different. Experiments done with thirteen structural analogues of MDP showed that there exists a good correlation between the adjuvant activity and the ability to induce anti-br-MRBC PFC.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Influence of indomethacin on various immunopharmacological effects of muramyl dipeptide (MDP).

Muramyl dipeptide (MDP) is a low molecular (less than 500 daltons) synthetic analogue of a streptococcal peptidoglycan subunit. It was demonstrated to be the minimal structure essential for eliciting the adjuvant effect ascribed to Freund's complete adjuvant (FCA). MDP was likewise shown to represent the minimal requirement for peptidoglycan-induced changes in temperature and it was at first concluded that there was an almost perfect correlation between pyrogenicity and adjuvant activity. However, other experiments showed that certain MDP derivatives were as adjuvant active without eliciting a febrile response in the rabbit. Moreover an anti-inflammatory substance such as indomethacin completely inhibits the pyrogenic effect of MDP but does not affect or even enhance various of its immunostimulant properties. Inhibition of MDP-induced fever is not associated with modification of leucopenia or production of circulating endogenous pyrogens observed after MDP injection. Indomethacin incubated with peritoneal macrophage cultures at a dose which blocks prostaglandin synthesis, does not decrease the production by MDP of endogenous pyrogens.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Stimulation of the in vivo dinitrophenyl antibody response to the DNP conjugate of L-glutamic acid60-L-alanine30-L-Tyrosine10 (GAT) polymer by a synthetic adjuvant, muramyl dipeptide (MDP): target cells for adjuvant activity and isotypic pattern of MDP-stimulated response.

Specific anti-dinitrophenyl (DNP) response to DNP-conjugated L-glutamine60-L-alanine30-L-tyrosine10 (DNP-GAT) was obtained in GAT-responder mice by using synthetic N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) as adjuvant. Significant levels of anti-DNP antibodies were observed during a secondary response to DNP-GAT, when both antigen and MDP were used for priming. In this system, MDP was able to prime the carrier-specific T cells but not the hapten specific B cells. The study of the isotypic pattern of the anti-DNP response shows that MDP stimulates only the appearance of specific anti-DNP IgG1 plaque-forming cells. Anti-DNP plaque-forming cells were stimulated in animals primed with DNP-GAT in Freund's complete adjuvant or in Maalox-pertussis and used as control IgG1, IgG2a, and IgG2b.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1980

Inhibition of mitogen-induced polyclonal activation by by a synthetic adjuvant, muramyl dipeptide (MDP).

A synthetic adjuvant, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), was previously shown to enhance polyclonal antibody response in murine spleen cell cultures. When MDP was added to the culture together with a potent murine B cell mitogen (such as bacterial lipopolysaccharide (LPS)), it inhibited completely the LPS-induced polyclonal activation without affecting either the 3H-thymidine incorporation or the number of blast cells in cultures. Strong suppression of mitogen-induced polyclonal activation by MDP was obtained by using a large range of cell concentrations in cultures and over various dosage levels of the stimulating mitogens (LPS and NWSM). An inhibition could be obtained even when MDP was added 24 hr after the addition of the mitogen, and highly significant suppression was observed in the absence of cell division in the cultures.

Acetylmuramyl-Alanyl-Isoglutamine↗