Potentiation of Host Defense Mechanism Against Infection by a Cytokine Inducer, an acyl‐MDP Derivative, MDP‐Lys(L18) (Romurtide) in Mice and Humans

Azuma, Ichiro; Otani, Tomoyuki

doi:10.1002/med.2610140403

Cited by 20 publications

(13 citation statements)

References 45 publications

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“…Consequently, the response is rapid, and it is effective against rapidly mutating pathogens or parasites with variable arrays of surface antigens. Activated macrophages also induce the synthesis and secretion of cytokines like interleukin-1ß (IL-1ß) and tumor necrosis factor-· (TNF·) [24]. Besides signaling other cells of the immune system to the presence of infection, these cytokines also initiate physiological responses including fever and sleep, which also promote resistance [25].…”

Section: Introductionmentioning

confidence: 99%

Effects of Muramyl Peptides on Macrophages, Monokines, and Sleep

Pabst

Beranová-Giorgianni

Krueger

1999

Neuroimmunomodulation

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Muramyl peptides are fragments of peptidoglycan from the cell walls of bacteria. Because of their unique chemistry, the immune system recognizes that muramyl peptides are products of bacteria, and it responds by becoming activated to resist infection. This resistance to infection is nonspecific, and extends to unrelated species of bacteria, fungi, and viruses. A key mechanism of the resistance to infection is activation of macrophages. Macrophage activation results in increased production of microbicidal oxygen radicals like superoxide and peroxide, and in increased secretion of inflammatory cytokines like interleukin-1β and tumor necrosis factor-α. These cytokines, besides activating neutrophils, B lymphocytes, and T lymphocytes, act on the central nervous system to induce physiological responses like fever and sleep. These physiological responses also aid in combating infection. Muramyl peptides also activate macrophages and other cells of the immune system to kill cancer cells. Muramyl peptides and similar agents will become more important as therapeutic agents in the future, due to increasing resistance of microbes to antibiotics, and increasing numbers of patients with immunodeficiencies.

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Section: Introductionmentioning

confidence: 99%

Effects of Muramyl Peptides on Macrophages, Monokines, and Sleep

Pabst

Beranová-Giorgianni

Krueger

1999

Neuroimmunomodulation

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“…Hence, efforts are being made in order to generate immunomodulatory compounds that conserve protective “boosting” activity with minimal toxicity. Examples include Murabutide, MDP-Lys (L18) (also known as Romurtide) and L-MTP-PE (also known as Mifamurtide), three MDP derivatives with low toxicity, which are promising for the treatment of various infections and cancers such as HIV and osteosarcoma [6], [7], [35]–[38]. In this study, we have shown that the natural MDP derivative N -glycolyl MDP has a more potent antiviral activity against IAV than the classical N -acetyl MDP, consistent with the finding that N -glycolylation of MDP increases its NOD2-stimulating activity [28].…”

Section: Discussionmentioning

confidence: 99%

Muramyl Dipeptide Induces NOD2-Dependent Ly6Chigh Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection

et al. 2012

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Bacterial peptidoglycan-derived muramyl dipeptide (MDP) and derivatives have long-recognized antiviral properties but their mechanism of action remains unclear. In recent years, the pattern-recognition receptor NOD2 has been shown to mediate innate responses to MDP. Here, we show that MDP treatment of mice infected with Influenza A virus (IAV) significantly reduces mortality, viral load and pulmonary inflammation in a NOD2-dependent manner. Importantly, the induction of type I interferon (IFN) and CCL2 chemokine was markedly increased in the lungs following MDP treatment and correlated with a NOD2-dependent enhancement in circulating monocytes. Mechanistically, the protective effect of MDP could be explained by the NOD2-dependent transient increase in recruitment of Ly6Chigh “inflammatory” monocytes and, to a lesser extent, neutrophils to the lungs. Indeed, impairment in both Ly6Chigh monocyte recruitment and survival observed in infected Nod2-/- mice treated with MDP was recapitulated in mice deficient for the chemokine receptor CCR2 required for CCL2-mediated Ly6Chigh monocyte migration from the bone marrow into the lungs. MDP-induced pulmonary monocyte recruitment occurred normally in IAV-infected and MDP-treated Ips-1-/- mice. However, IPS-1 was required for improved survival upon MDP treatment. Finally, mycobacterial N-glycolyl MDP was more potent than N-acetyl MDP expressed by most bacteria at reducing viral burden while both forms of MDP restored pulmonary function following IAV challenge. Overall, our work sheds light on the antiviral mechanism of a clinically relevant bacterial-derived compound and identifies the NOD2 pathway as a potential therapeutic target against IAV.

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“…However, the pyrogenic and arthritogenic effects of MDP preclude its use in humans (2). In order to take advantage of its immunomodulatory properties but to minimize the risk of side effects, nontoxic MDP derivatives have been generated, such as the adamantylamide dipeptide (AdDP), MDP-Lys(L18), murabutide (ester derivate), and glucosaminylmuramyl dipeptide (1,18).…”

Section: Muramyl Dipeptide (Mdp; N-acetylmuramyl-l-alanyl-d-iso-mentioning

confidence: 99%

Immune Modulator Adamantylamide Dipeptide Stimulates Efficient Major Histocompatibility Complex Class I-Restricted Responses in Mice

Becker

Nörder

Guzmán

et al. 2007

Clin Vaccine Immunol

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Adamantylamide L-alanyl-D-isoglutamine (AdDP) is a synthetic adjuvant which belongs to the family of the desmuramyl peptides. AdDP exerts its adjuvant properties when it is administered either by the parenteral or by the mucosal route, leading to the elicitation of strong humoral responses at both the systemic and the mucosal levels. However, very little is known about the effect of AdDP on cellular immunity. Here we demonstrate that AdDP is able to stimulate cellular responses, which are characterized by the release of gamma interferon by CD8؉ T cells when they are restimulated with a major histocompatibility complex class I-restricted peptide and strong in vivo lymphocyte-mediated cytotoxic activity. The capacity of AdDP to stimulate the elicitation of both cellular and humoral adaptive responses makes this adjuvant a promising tool for the development of mucosal vaccine formulations.

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Potentiation of Host Defense Mechanism Against Infection by a Cytokine Inducer, an acyl‐MDP Derivative, MDP‐Lys(L18) (Romurtide) in Mice and Humans

Cited by 20 publications

References 45 publications

Effects of Muramyl Peptides on Macrophages, Monokines, and Sleep

Effects of Muramyl Peptides on Macrophages, Monokines, and Sleep

Muramyl Dipeptide Induces NOD2-Dependent Ly6Chigh Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection

Immune Modulator Adamantylamide Dipeptide Stimulates Efficient Major Histocompatibility Complex Class I-Restricted Responses in Mice

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