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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The mechanism of action of mifamurtide involves the simulation of bacterial infection by binding to NOD2 receptors on the surface of white cells, thus causing their activation, including increased production of TNF-α, interleukins 1, 6, 8, and 12, and other cytokines, as well as ICAM-1 (the Intercellular Adhesion Molecule 1). The activated white cells appear to have a degree of selectivity for attacking cancer cells rather than other healthy cells, although the precise mechanism is not fully understood. NOD2 is a pattern recognition receptor found on many types of white blood cells but mainly on monocytes and macrophages. One of its functions is to recognize muramyl dipeptide, a component of bacterial cell walls, and to initiate an immune response. Mifamurtide has similar receptor binding and activating properties while having the advantages of longer plasma half-life and ease of administration in liposome form.
Treatment of Chronic Fatigue Syndrome
Published in Jay A. Goldstein, Chronic Fatigue Syndromes, 2020
Numerous peptides and proteins have serotonin binding sites which may modify their activity. These include GnRH, ACTH 4-10, and myelin basic protein. Muramyl dipeptide, important in slow-wave sleep induction, also binds to these sites, which are probably some, but not all, of the 5HT receptor subtypes. Glycopeptides such as muramyl dipeptide could have a neurotransmitter or hormonal function. The possibility exists that various peptides may mimic the function of 5-HT in normal physiology.114 The implications of such a finding for PM network theory have hardly been explored. The common report of CFS patients that they feel better (or worse) when taking antibiotics may relate to alteration of substances such as muramyl dipeptide produced by gut flora.
Blastomycosis
Published in Rebecca A. Cox, Immunology of the Fungal Diseases, 2020
Muramyl dipeptide is the minimal structure required for the adjuvant effect of cell-wall preparations from mycobacteria.83 This compound augments both cellular immunity and humoral immunity.83, 84 Treatment of Balb/c mice with 200 μg of muramyl dipeptide or its desmethyl analogue beginning 4 d prior to intranasal inoculation with 73 CFU of Blastomyces yeasts reduced mortality from 70% in controls to 5% and 40%, respectively. When the challenge dose was increased to 243 CFU, neither compound altered mortality. Pretreatment of C3H/HeJ or DBA/2 with either compound did not reduce mortality.85
Tuberculosis vaccine BCG: the magical effect of the old vaccine in the fight against the COVID-19 pandemic
Published in International Reviews of Immunology, 2022
Ashok Aspatwar, Wenping Gong, Shuyong Wang, Xueqiong Wu, Seppo Parkkila
In addition to the human studies showing nonspecific effects of BCG against pathogens and cancers, the experiments in mice also provide evidence that BCG enhances protection against viral infections (Table 2). It has been shown in vitro that mouse macrophages sensitized by BCG were more effective in reducing the titers of influenza virus than control macrophages [42]. In addition, an in vivo study in mice showed that BCG confers protection against influenza virus infection, and the effect is independent of IFN-γ [42]. Recent studies also showed that the use of BCG enhances the protection against Influenza A virus by increasing the levels of efferocytosis by alveolar phagocytes and leads to reduced inflammation and lung injury compared to the control group [43]. A single intradermal BCG dose has also been shown to protect against Herpes simplex virus 2 (HSV2) in a controlled newborn mouse model [41]. In another study, administration of muramyl dipeptide (MDP), a component of mycobacterial cell wall and known activator of IL-1α and IL-1β [54], protected mice against Vaccinia virus and HSV2. Interestingly, the conferred protection was independent of IFN-γ induction and was mediated by peritoneal macrophages [49]. Similarly, the mice given the MDP component of mycobacterial peptidoglycan were protected against the infection by Murine respirovirus or Sendai virus [51].
A Novel Pathogenic NOD2 Variant in a Mother and Daughter with Blau Syndrome
Published in Ophthalmic Genetics, 2021
Filipa G Rodrigues, Harry Petrushkin, Andrew R Webster, Maria Bickerstaff, Elena Moraitis, Dorota Rowczenio, Juan I. Aróstegui, Mark Westcott
Muramyl dipeptide (MDP), a degradation product of ubiquitous bacterial cell wall peptidoglycan, is the NOD2 ligand (19). The engagement of MDP to the LRR region unfolds the receptor from the autoinhibited state and oligomerization through the exposed NACHT domain occurs, leading to activation and further engagement of receptor-interacting protein kinase 2 (RIP2) and downstream signalling through interaction between the CARD domains. Downstream molecules nuclear factor kB (NF-kB) and mitogen-activated protein kinase (MAPK) are activated, resulting in the production of inflammatory cytokines such as interleukin-1b (IL-1b), IL-6, TNF-alpha, IL-18 molecules, and others (19,22). More recently, NOD2 was shown to harbour a T cell-intrinsic function in the suppression of Th17 immunity and experimental uveitis (23).
Inflammatory bowel disease manifestations in spondyloarthritis: considerations for the clinician
Published in Expert Review of Clinical Immunology, 2021
Ennio Lubrano, Michele Maria Luchetti, Devis Benfaremo, Daniele Mauro, Francesco Ciccia, Fabio Massimo Perrotta
A recent meta-analysis showed that the risk of developing CD was increased to 17.1 times in NOD2 homozygotes or compound heterozygotes and to 2.4 times in simple NOD2 heterozygotes. Three major variants in the NOD2 gene have been identified (i) a frameshift mutation at position 1007 (1007fs); (ii) a conversion from glycine to arginine to the amino acid residue 908 (G908R); and (iii) a conversion from arginine to tryptophan to the amino acid residue 702 (R702W). All three mutations are found in or near the LRR domain that recognizes the muramyl dipeptide. Indeed, patients with ileal CD showed reduced levels of antimicrobial peptides derived from Paneth cells with dysfunctional aspects of the cells themselves. Although Paneth cells appear to be involved in the pathogenesis of SpA, as they are activated to produce antimicrobial peptides [30] and represent the main source of IL-23 in the intestine of patients with SpA [31], NOD2 variants do not significantly affect the risk of developing SpA, but may influence susceptibility to, and clinical manifestations of intestinal inflammation in SpA [32].