Immune-selective anti-inflammatory derivative

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Immune Selective Anti-Inflammatory Derivatives (ImSAIDs) are a class of peptides that have anti-inflammatory properties. ImSAIDs work by altering the activation and migration of inflammatory cells, which are immune cells responsible for amplifying the inflammatory response. [1] [2]

Contents

History

The ImSAIDs represent a new category of anti-inflammatory and are unrelated to steroid hormones or non steroidal anti-inflammatories. The ImSAIDs were discovered by scientists evaluating biological properties of the submandibular gland and saliva. Early work in this area demonstrated that the submandibular gland released a host of factors which regulate systemic inflammatory responses and modulate systemic immune and inflammatory reactions. Early work in identifying factors that played a role in the CST-SMG axis lead to the discovery of a seven amino acid peptide, called the submandibular gland peptide-T. SGP-T was demonstrated to have biological activity and thermoregulatory properties related to endotoxin exposure. [3] SGP-T, an isolate of the submandibular gland, demonstrated its immunoregulatory properties and potential role in modulating the cervical sympathetic trunk-submandibular gland (CST-SMG) axis, and subsequently was shown to play an important role in the control of inflammation.

Mechanisms or ImmunoPharmacology

It is now well accepted that the immune, nervous and endocrine systems communicate and interact to control and modulate inflammation and tissue repair. One of the neuroendocrine pathways, when activated, results in the release of immune regulating peptides from the submandibular gland upon neuronal stimulation from sympathetic nerves. This pathway or communication is referred to as the cervical sympathetic trunk-submandibular gland (CST-SMG) axis, a regulatory system that plays a role in the systemic control of inflammation. [4]

Cellular Effects of feG: The cellular effects of the ImSAIDs are characterized in a number of publications. feG and related peptides are known to modulate leukocyte (white blood cells) activity by influencing cell surface receptors to inhibit excessive activation and tissue infiltration. One lead ImSAID, the tripeptide FEG (Phe-Glu-Gly) and its D-isomer feG are known to alter leukocyte adhesion involving actions on αMβ2 integrin, and inhibit the binding of CD16b (FCyRIII) antibody to human neutrophils. [5] One ImSAID, termed feG, has also been shown to decrease circulating neutrophil and eosinophil accumulation, decrease intracellular oxidative activity and reduced the expression of CD49d after antigen exposure,. [6] [7] [8]

Lead Compound

One SGP-T derivative is a three amino acid sequence shown to be a potent anti-inflammatory molecule with systemic effects. This three amino acid peptide is phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG), have become the foundation for the ImSAID category. [9]

Related Research Articles

<span class="mw-page-title-main">Inflammation</span> Physical effects resulting from activation of the immune system

Inflammation is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

<span class="mw-page-title-main">Granulocyte</span> Category of white blood cells

Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear, that is, they have varying shapes (morphology) of the nucleus ; and are referred to as polymorphonuclear leukocytes. In common terms, polymorphonuclear granulocyte refers specifically to "neutrophil granulocytes", the most abundant of the granulocytes; the other types have varying morphology. Granulocytes are produced via granulopoiesis in the bone marrow.

<span class="mw-page-title-main">Acute-phase protein</span> Class of proteins involved in inflammation

Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase or decrease in response to inflammation. This response is called the acute-phase reaction. The acute-phase reaction characteristically involves fever, acceleration of peripheral leukocytes, circulating neutrophils and their precursors. The terms acute-phase protein and acute-phase reactant (APR) are often used synonymously, although some APRs are polypeptides rather than proteins.

<span class="mw-page-title-main">Submandibular gland</span> Human salivary gland

The paired submandibular glands are major salivary glands located beneath the floor of the mouth. In adult humans, they each weigh about 15 grams and contribute some 60–67% of unstimulated saliva secretion; on stimulation their contribution decreases in proportion as parotid gland secretion rises to 50%. The average length of the normal adult human submandibular salivary gland is approximately 27 mm, while the average width is approximately 14.3 mm.

Anti-inflammatory or antiphlogistic is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as opposed to opioids, which affect the central nervous system to block pain signaling to the brain.

<span class="mw-page-title-main">Chemokine</span> Small cytokines or signaling proteins secreted by cells

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

<span class="mw-page-title-main">Superantigen</span> Antigen which strongly activates the immune system

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. Superantigens act by binding to the MHC proteins on antigen-presenting cells (APCs) and to the TCRs on their adjacent helper T-cells, bringing the signaling molecules together, and thus leading to the activation of the T-cells, regardless of the peptide displayed on the MHC molecule. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

<span class="mw-page-title-main">Interleukin 8</span> Mammalian protein found in Homo sapiens

Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel-Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.

<span class="mw-page-title-main">Innate immune system</span> One of the two main immunity strategies

The innate, or nonspecific, immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

<span class="mw-page-title-main">Complement component 5a</span> Protein fragment

C5a is a protein fragment released from cleavage of complement component C5 by protease C5-convertase into C5a and C5b fragments. C5b is important in late events of the complement cascade, an orderly series of reactions which coordinates several basic defense mechanisms, including formation of the membrane attack complex (MAC), one of the most basic weapons of the innate immune system, formed as an automatic response to intrusions from foreign particles and microbial invaders. It essentially pokes microscopic pinholes in these foreign objects, causing loss of water and sometimes death. C5a, the other cleavage product of C5, acts as a highly inflammatory peptide, encouraging complement activation, formation of the MAC, attraction of innate immune cells, and histamine release involved in allergic responses. The origin of C5 is in the hepatocyte, but its synthesis can also be found in macrophages, where it may cause local increase of C5a. C5a is a chemotactic agent and an anaphylatoxin; it is essential in the innate immunity but it is also linked with the adaptive immunity. The increased production of C5a is connected with a number of inflammatory diseases.

<span class="mw-page-title-main">Sialadenitis</span> Medical condition

Sialadenitis (sialoadenitis) is inflammation of salivary glands, usually the major ones, the most common being the parotid gland, followed by submandibular and sublingual glands. It should not be confused with sialadenosis (sialosis) which is a non-inflammatory enlargement of the major salivary glands.

<span class="mw-page-title-main">Integrin alpha M</span> Mammalian protein found in Homo sapiens

Integrin alpha M (ITGAM) is one protein subunit that forms heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B). The second chain of αMβ2 is the common integrin β2 subunit known as CD18, and integrin αMβ2 thus belongs to the β2 subfamily integrins.

<span class="mw-page-title-main">Cathepsin G</span> Protein-coding gene in the species Homo sapiens

Cathepsin G is a protein that in humans is encoded by the CTSG gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response.

<span class="mw-page-title-main">CXCL5</span> Mammalian protein found in Homo sapiens

C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.

<span class="mw-page-title-main">Formyl peptide receptor 2</span> Protein-coding gene in the species Homo sapiens

N-formyl peptide receptor 2 (FPR2) is a G-protein coupled receptor (GPCR) located on the surface of many cell types of various animal species. The human receptor protein is encoded by the FPR2 gene and is activated to regulate cell function by binding any one of a wide variety of ligands including not only certain N-Formylmethionine-containing oligopeptides such as N-Formylmethionine-leucyl-phenylalanine (FMLP) but also the polyunsaturated fatty acid metabolite of arachidonic acid, lipoxin A4 (LXA4). Because of its interaction with lipoxin A4, FPR2 is also commonly named the ALX/FPR2 or just ALX receptor.

<i>N</i>-Formylmethionine-leucyl-phenylalanine Chemical compound

N-Formylmethionyl-leucyl-phenylalanine is an N-formylated tripeptide and sometimes simply referred to as chemotactic peptide is a potent polymorphonuclear leukocyte (PMN) chemotactic factor and is also a macrophage activator.

<span class="mw-page-title-main">CLEC4A</span> Protein-coding gene in humans

C-type lectin domain family 4 member A is a protein that in humans is encoded by the CLEC4A gene.

'Staphylococcus aureus delta toxin is a toxin produced by Staphylococcus aureus. It has a wide spectrum of cytolytic activity.

<span class="mw-page-title-main">Ocular immune system</span> Immune system of the human eye

The ocular immune system protects the eye from infection and regulates healing processes following injuries. The interior of the eye lacks lymph vessels but is highly vascularized, and many immune cells reside in the uvea, including mostly macrophages, dendritic cells, and mast cells. These cells fight off intraocular infections, and intraocular inflammation can manifest as uveitis or retinitis. The cornea of the eye is immunologically a very special tissue. Its constant exposure to the exterior world means that it is vulnerable to a wide range of microorganisms while its moist mucosal surface makes the cornea particularly susceptible to attack. At the same time, its lack of vasculature and relative immune separation from the rest of the body makes immune defense difficult. Lastly, the cornea is a multifunctional tissue. It provides a large part of the eye's refractive power, meaning it has to maintain remarkable transparency, but must also serve as a barrier to keep pathogens from reaching the rest of the eye, similar to function of the dermis and epidermis in keeping underlying tissues protected. Immune reactions within the cornea come from surrounding vascularized tissues as well as innate immune responsive cells that reside within the cornea.

<span class="mw-page-title-main">Formyl peptide receptor 1</span> Protein-coding gene in the species Homo sapiens

Formyl peptide receptor 1 is a cell surface receptor protein that in humans is encoded by the formyl peptide receptor 1 (FPR1) gene. This gene encodes a G protein-coupled receptor cell surface protein that binds and is activated by N-Formylmethionine-containing oligopeptides, particularly N-Formylmethionine-leucyl-phenylalanine (FMLP). FPR1 is prominently expressed by mammalian phagocytic and blood leukocyte cells where it functions to mediate these cells' responses to the N-formylmethionine-containing oligopeptides which are released by invading microorganisms and injured tissues. FPR1 directs these cells to sites of invading pathogens or disrupted tissues and then stimulates these cells to kill the pathogens or to remove tissue debris; as such, it is an important component of the innate immune system that operates in host defense and damage control.

References

  1. ↑ Bao, F; John, SM; Chen, Y; Mathison, RD; Weaver, LC (2006). "The tripeptide phenylalanine-(D) glutamate-(D) glycine modulates leukocyte infiltration and oxidative damage in rat injured spinal cord". Neuroscience. 140 (3): 1011–22. doi:10.1016/j.neuroscience.2006.02.061. PMID   16581192.
  2. ↑ Mathison, RD; Befus, AD; Davison, JS; Woodman, RC (Mar 2003). "Modulation of neutrophil function by the tripeptide feG". BMC Immunol. 4: 3. doi: 10.1186/1471-2172-4-3 . PMC   152650 . PMID   12659660.
  3. ↑ Mathison, RD; Malkinson, T; Cooper, KE; Davison, JS (May 1997). "Submandibular glands: novel structures participating in thermoregulatory responses". Can J Physiol Pharmacol . 75 (5): 407–13. doi:10.1139/y97-077. PMID   9250374.
  4. ↑ Mathison, R; Davison, JS; Befus, AD (Nov 1994). "Neuroendocrine regulation of inflammation and tissue repair by submandibular gland factors". Immunol Today. 15 (11): 527–32. doi:10.1016/0167-5699(94)90209-7. PMID   7802923.
  5. ↑ Mathison, RD; Christie, E; Davison, JS (May 2008). "The tripeptide feG inhibits leukocyte adhesion". J Inflamm (Lond). 5: 6. doi: 10.1186/1476-9255-5-6 . PMC   2408570 . PMID   18492254.
  6. ↑ Dery, RE; Ulanova, M; Puttagunta, L; Stenton, GR; James, D; Merani, S; Mathison, R; Davison, J; Befus, AD (Dec 2004). "Frontline: Inhibition of allergen-induced pulmonary inflammation by the tripeptide feG: a mimetic of a neuro-endocrine pathway". Eur J Immunol. 34 (12): 3315–25. doi:10.1002/eji.200425461. PMID   15549777.
  7. ↑ Mathison, RD; Davison, JS (Jun 2006). "The Tripeptide feG Regulates the Production of Intracellular Reactive Oxygen Species by Neutrophils". J Inflamm (Lond). 3 (1): 9.
  8. ↑ Mathison, R; Lo, P; Tan, D; Scott, B; Davison, JS (Dec 2001). "The tripeptide feG reduces endotoxin-provoked perturbation of intestinal motility and inflammation". Neurogastroenterol Motil. 13 (6): 599–603. doi:10.1046/j.1365-2982.2001.00294.x. PMID   11903921.
  9. ↑ Dery RE, Mathison R, Davison J, Befus AD. "Inhibition of allergic inflammation by C-terminal peptides of the prohormone submandibular rat 1 (SMR-1). Int Arch Allergy Immunol. 2001 an-Mar;124(1-3):201-4.
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