Immunomodulators (IMs) Mohammed N. Sabir May, 2018

Transcription

1 Immunomodulators (IMs) Mohammed N. Sabir May, 2018

2 Lecture outlines - Introduction - Background - Mechanisms of action - Classification - Examples

3 Introduction IMs are natural or synthetic agents modifying the immune system

4 They may cause:- 1- Augmenting (Immunostimulant and/or immunoenhancer) 2- Restore (immunorestorative)

5 3- Inhibit (immunosuooressant) 4- Or help to produce (adjuvant), the desired immune response.

6 i.e; IMs are substances, biological or synthetics which can stimulate, suppress or modulate the immune system both adaptive and innate.

7 Some of the strongest immune system boosters come from specific healing herbs.

8 Herbal immunomodulators (HI)

9 HI enhance and normalize the nervous and humoral systems.

10 HI includes antioxidants, polysaccharides which have a broad range of therapeutic activity as well as other biologics.

11 In addition to help IS against antigens, bacteria and viruses, they also fight cancer cells. Such aid helps in suppressing the metastasis after surgery.

12 HIs help T-cell function, activate macrophages and help rebuild bone marrow reserves.

13 -An antigen, is a high molecular weight protein or polysaccharides (< Daltons), recognized by the IS as a foreign matter inducing the release of correspondent specific AB.

14 Example of Ag that induce immunogenicity directly are :- - Exotoxins associated with infectious diseases - Proteins - Polysaccharides on cell surface - Capsules of bacteria.

15 The number of distinct determinants on an antigen molecule usually varies with its size and chemical complexity.

16 AB are macromolecules (Immunoglobulin) produced by IS as a reaction to Ags.

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19 Name Types IgA 2 IgD 1 IgE 1 IgG 4 IgM 1 Description Found in mucosal areas, such as the gut, respiratory tract and urogenital tract, and prevents colonization by pathogens. Also found in saliva, tears, and breast milk. Functions mainly as an antigen receptor on B cells that have not been exposed to antigens. It has been shown to activate basophils and mast cells to produce antimicrobial factors. Binds to allergens and triggers histamine release from mast cells and basophils, and is involved in allergy. Also protects against parasitic worms. In its four forms, provides the majority of antibody-based immunity against invading pathogens. The only antibody capable of crossing the placenta to give passive immunity to fetus. Expressed on the surface of B cells (monomer) and in a secreted form (pentamer) with very high avidity. Eliminates pathogens in the early stages of B cell mediated (humoral) immunity before there is sufficient IgG

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21 Lymphocytes

22 The innate immune system (non-specific immune system) and first line of defense, include all the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner.

23 This means that the cells of the innate system recognize and respond to pathogens in a generic way.

24 The adaptive immune response provides the IS with the ability to recognize and remember specific pathogens (to generate immunity), and to mount stronger attacks each time the pathogen is encountered.

25 Adaptive immune system, Highly specialized cells and processes that eliminate or prevent pathogenic growth. The adaptive or "specific" immune system is activated by the non-specific and innate immune system

26 Through adaptive immunity the body's immune system prepares itself for future challenges.

27 CLASS NK cells Helper T cells Cytotoxic T cells γδ T cells FUNCTION Lysis of virally infected cells and tumour cells Release cytokines and growth factors that regulate other immune cells Lysis of virally infected cells, tumour cells and allografts Immunoregulation and cytotoxicity PROPOR TION 7% (2-13%) 46% (28-59%) 19% (13-32%) PHENOTYPIC MARKER(S) CD16 CD56 but not CD3 TCRαβ, CD3 and CD4 TCRαβ, CD3 and CD8 5% (2%-8%) TCRγδ and CD3 B cells Secretion of antibodies 23% (18-47%) MHC class II, CD19 and CD21

28 Mechanisms of action of IMs A- Immunoglobulin and T-cell receptor rearrangements creating diversity as well as uniqueness of the immune response. B- Complexity of the MHC (HLA) system and its role in antigen presentation and restriction of effector cytotoxic cells.

29 Mechanisms of action of IMs C- Signal transduction and selection of Th1 and Th2 types of cellular response. D- Elimination of offending agent by the effector arm of the immune response.

30 Mechanisms of action of IMs E- Other proposed mechanisms involves antioxidant, anti-inflammatory or suppression of inflammatory reactions

31 The IMs in the body activates the macrophages and granulocytes, thereby increasing the phagocytosis. In such case; it is important that the stimulating agent must remain in contact with reactive cell for some time.

32 The activated macrophages displays not only a secretory cell and acts as a cytotoxic effector cell.

33 The major role in the amplification of the nonspecific immunological defense is played by lysosomal enzymes secreted by activated macrophages, the component of the complement system

34 It is assumes that a part from changes in the cellular metabolism of phospholipids PLs, FAs, and PGs as well as camp, cgmp plays essential role.

35 Many IMs have several sites of action and the primary effect, if one exists, is usually not apparent. As a consequence, they are capable of stimulating or suppressing both the humoral and cellular immune systems.

36 Many factors affects the response of the host qualitatively and quantitatively to IMs:- 1- Duration. 2- Dose. 3- Frequency. 4- Rout of administration. 5- Host characteristics.

37 IMs are under development for the treatment of those diseases in which an abnormal immune response plays an important pathological role including: -Cancer -Autoimmune diseases -Natural or acquired immune deficiency syndrome.

38 The use of immune stimulant adjunct to chemotherapy for control and prevention of infections holds great promise.

39 Classification of IMs On the basis of their clinical uses, herbal IMs are classified as: I. Immunoadjuvants. II. Immunostimulant. III. Immunosuppressant.

40 Chemical classification: I. Low molecular weight compounds (Alkaloids, terpenoids, plant phenols, quinines and saponin). II. High molecular weight compounds (Polysaccharides, peptides and lectins).

41 III. Miscellaneous compounds (Volatile oils, pollens, allergens, enzymes, coloring agents and biological response modifiers).

42 Drugs inhibits angiogenesis

43 Axitinib (Inlyta ) Bevacizumab (Avastin ) Cabozantinib (Cometriq ) Everolimus (Afinitor ) Lenalidomide (Revlimid ) Lenvatinib mesylate (Lenvima ) Pazopanib (Votrient ) Ramucirumab (Cyramza ) Regorafenib (Stivarga ) Sorafenib (Nexavar ) Sunitinib (Sutent ) Thalidomide (Synovir, Thalomid ) Vandetanib (Caprelsa ) Ziv-aflibercept (Zaltrap )

44 Examples on herbal IMs

45 Isoprenosine (immunestimulant) Used with antiviral to stimulate immune response through its action as cytokines Used to control the severity and duration of the viral infection.

46 Allium sativum (Liliaceae) Contain organosulfur compounds Inhibits the growth of tumors in animals and modulate the activity of diverse chemical carcinogens through neutralizing their oxidative actions.

47 Such action may be attributed to activation of natural killers (NKs) cells, stimulating of T-lymphocytes and enhances production of IL-2.

48 Aloe vera (Liliaceae) Contain several pharmacological active ingredients (carboxypeptides and Salicylates and acemannan). They has anti-inflammatory action through inhibiting arachedonic acid pathway via cyclooxygenase.

49 It also contain (Acemannan) which is the major carbohydrate fraction. Acemannan enhances the production of IL-1 and TNF-α from peripheral macrophages.

50 Andrographis paniculata (Acanthaceae) Ethanolic extract and purified diterpenoid (Andragrapholides) include significant stimulation of antibody response. It also stimulate macrophages migration and phagocytosis.

51 Azadirachta indica (Meliaceae) A wild grown tree in India, it possesses significant nonspecific immunostimulant properties through mobilization of leukocytes and phagocytosis. Also increasing IgM, IgG titers and enhances macrophage migration.

52 Rhizomes of Curcuma longa (Zingiberaceae) Contains (diferuloyl methane)

53 It possesses anti-inflammatory and chemopreventive actions against cancer cells through inhibition of cell growth.

54 Ocimum gratissimum (Lamiaceae) Improve phagocytosis without affecting the humoral or cell-mediated immune system.

55 Panax ginseng (Araliaceae) Through a number of saponin glycosides which possess adaptogenic activity. It is immunostimulant through macrophage migration antibody plaque forming cells and heme agglutinating antibody titer against RBCs.

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73 Colony-stimulating factors (CSFs) are glycoproteins that bind to receptor proteins on the surfaces of hemopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentiate into a specific kind of blood cell (usually white blood cells)

74 endothelial cells. Interleukins are a group of cytokines (signaling molecules) that expressed by leukocytes. They promote the development and differentiation of T, B, and hematopoietic cells. The majority of interleukins are synthesized by helper CD4+ T lymphocytes, as well as through monocytes, macrophages, and

75 Interferons (IFNs) are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites or tumor cells. They allow for communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.

76 IFNs belong to the large class of glycoproteins known as cytokines. Interferons are named after their ability to "interfere" with viral replication within host cells.

77 IFNs have other functions: 1-Activation of immune cells, such as natural killer cells and macrophages. 2-Increase recognition of infection or tumor cells by up-regulating antigen presentation to T lymphocytes

78 3-Increase the ability of uninfected host cells to resist new infection by virus. Certain host symptoms, such as aching muscles and fever, are related to the production of IFNs during infection.

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