1. By Alaa Ibrahim

2. An immune system is a system of biological structures and processes within an organismthat protects against disease by identifyingand killing pathogens and tumor cells. Detects a wide variety of agents, fromviruses to parasitic worms. Needs to distinguish them from theorganisms own healthy cells and tissues. Detection is complicated as pathogens can evolve rapidly, producing adaptations that avoid the immune system. 3. Layered defenseThe immune system protects organisms from infectionwith layered defenses of increasing specificity.physical barriers prevent pathogens such from entering the organism.If a pathogen breaches these barriers, the innate immunesystem provides an immediate, non-specific response. If pathogens successfully evade the innate response, vertebrates possess a third layer of protection, the adaptive immune system, activated by the innateresponse. Specific and has an immunological memoryso immune system mount faster and strongersubsequent attacks. 4. Components of the immune system Innate immune system Adaptive immune systemExposure leads to Lag time betweenimmediate maximal exposure and maximalresponseresponseCell-mediated andhumoral Cell-mediatedandcomponentshumoral componentsNo immunologicalExposure leads tomemoryimmunological memoryResponse isnon-specificPathogen andantigenspecific responseFound in nearlyall forms Found only invertebratesof life 5. IMMUNOPHARMACOLOGY 2 major components of theimmune system: INNATE Physical skin, mucus membrane Biochemical complement, lyzosyme Cellular macrophages, neutrophils ADAPTIVE Antibodies HUMORAL immunity T-lymphocyte CELL MEDIATED immunity 6. IMMUNOPHARMACOLOGY 0psonized bacteria Macrophage APC B lymphocyte T lymphocyteIL-4,IL-5 IL-2IL-2 TH1 IFN- IFN-TH2 TNF- IFN- Plasma Cells: ActivatedActivated-IgG- IgM Activated MemoryMacrophageCytotoxic TB Cells - IgA - IgD NK cells cell CELL-MEDIATED IMMUNITY HUMORAL IMMUNITY 7. Antibody structure 8. Antigen presenting cell 9. CYTOKINES Definition:Cytokines are soluble hormone-likeproteins that allow for communicationbetween cells and the external environment. The term cytokine, orimmunocytokine, was used initially toseparate a group of immunomodulatoryproteins, called also immunotransmitters,from other growth factors that modulate the proliferation and bioactivities of non- immune cells . 10. The cytokines are important components of the immune system. They act in concert with specific cytokine inhibitors andsoluble cytokine receptors to regulate thehuman immune response. Their physiologicrole in inflammation and pathologic rolein systemic inflammatory states are nowwell recognized. 11. Cytokines are secreted by white blood cells aswell as variety of other cells (fibroblasts, endothelial cells, epithelial cells, etc.) inresponse to inducing stimuli, and are not constitutively expressed. Cytokines comprise: (1) Interleukins initially thought to be producedexclusively by leukocytes, (2) Lymphokines, initially thought to be produced exclusively by lymphocytes, (3) Monokines initially thought to be producedexclusively by monocytes, 12. (4) Interferon, initially thought to be involved inantiviral responses. (5) colony stimulating factors, initially thought to support the growth of cells in semi-solid media. (6) Chemokines thought to be involved in Chemotaxis, and a variety of other proteins and tumor necrosis factor (TNF). The term Type-1 cytokines refers to cytokines produced by Th1 cells while Type-2 cytokines are those produced byTh2 cells. Type-1 cytokines include IL2, IFN-, IL12 and TNF-beta, while Type-2 cytokines include IL4, IL5, IL6,IL-9, IL10, and IL13 . 13. It has been shown that a number of viral infectious agents exploit the cytokine repertoire of organisms to evade immuneresponses of the host. Virus-encoded factorsappear to affect the activities of cytokines in at least four different ways: (1) by inhibiting the synthesis and release ofcytokines from infected cells; (2) by interfering with the interaction between cytokines and their receptors. 14. (3) by inhibiting signal transmission pathways of cytokines. (4) and by synthesizing virus-encodedcytokines that antagonize the effects of host cytokines mediating antiviral processes. An imbalance in cytokine production or cytokine receptor expression and/ordysregulation of a cytokine processcontributes to various pathologicaldisorders. 15. :properties of cytokines ** Cytokines are short-lived and may actlocally either on the same cell secreted it(autocrine), on other cells (paracrine) or like hormones they may actsystemically (endocrine) 16. Cytokines interact in a network by: a- including each other (cascade-like activity) b- transmodulating cytokine cell surface receptors c- interacting synergistically, additively or antagonistically on cell function- cytokines are nonspecific andantigen-independent in mode of activity 17. All cytokine receptor have thetypical receptor structure: an extra cellular domain, single membrane-spanning domain & a cytoplasmicdomain. Cytokines may exhibit considerable overlap in their biologic effects onlymphoid, myeloid & connective tissue 18. classifications of **: cytokines 1- proinflammatory cytokines:- make the disease worse because they producefever, inflammation, tissue destruction & sometimes shock & death including IL-1, IL-6,IL-12 & GM-CSF G-CSF, IFN- & TNF- 19. Anti-inflammatory -2:cytokines Potent activators of B- Lymphocytes.Include IL-1 receptor antagonist, IL-4, IL-6, IL-11 & IL-13. They are anti-inflammatory cytokines bytheir ability to suppress genes for proinflammatory cytokines such asIL-1, TNF & chemokines. 20. 3- Growth factors: Such as platelet-derived growth factor (PDGF), transforming growth factor-(TGF-) & Epidermal growth factor (EGF)influence the proliferation of manystructural cells such as fibroblasts & airway smooth muscle cells. 21. Functional Categories of **Cytokines Cytokines classified according to their biologicactions into three groups:1) Mediators and regulators of innate immunity- Produced by activated microphages and NK cellsin response to microbial infection.- they act mainly on endothelial cells and leukocytes to stimulate the early inflammatory response to microbes. 22. 2) Mediators and regulators of acquired immunity:- Produced mainly by T lymphocytes in response to specificrecognition of foreign antigens.- They include IL-2, IL-4, IL-5,, IL-13, IFN, Transforming growthfactor- (TGF-) and lymphotoxin (TNF- ).3) Stimulators of haematopoiesis: - Produced by bon marrow, stormal cells, leukocytes. - Stimulate growth and differentiation of leukocytes. - Stem cell factor, IL-3, IL-7, GM-CSF. 23. (Interferons (IFNs* Interferons (IFNs): are proteins secreted in responseto viral infections or other stimuli* They include:- INF- produced by leucocytesinduced by virus infected cells- INF- produced by fibroblasts- INF- produced by NK cells,TH1 cells, CD8 T-cells 24. : Action of INF- and IFN-- Prevent viral replication- Increase MHC-I expression on viral infectedcells helping their recognition by CD8 Tcells- Increase cytotoxic action of Nk cells - Inhibit cell proliferation and tumor growth 25. : Action of IFN- Activate Macrophages. Increase expression of MHC-I and II on APCs. Enhance cytotoxic actions of Nk cells. Promote production of TH1 and inhibitsproliferation of TH2. 26. summary of selected cytokines **CytokineActionsIL-1NK cells -Attract Enhance activity of- neutrophil&macrophageIL-2antigen-primed Induce proliferation of-T-cellsNK cells Enhance activity of-IFN- macrophages & NK enhance activity of -cells - increased expression ofMHCmolecules - enhance production ofIgG2aIFN- cytotoxic effect ontumor cells - induces -cytokine secretion in the inflammatoryresponse 27. IMMUNOPHARMACOLOGY ABNORMAL IMMUNE RESPONSES: HYPERSENSITIVITY AUTOIMMUNITY IMMUNODEFICIENCY 28. :Immune activation cascade **1- Signal-1APC activates specific receptors on outer surface of T-cell (CD3)2- Signal-2 : Costimulation of CD80:86 on APC to T-lymphocytes3- Signal-3:Activation of different cellular pathway in T-cells themost important is calcium calcineurin pathway whereintracellular Ca++ activates calcineurin. 29. Activated calcium calcineurin activatesinactive (phosphprylated) NFATc intoactivated (dephosphorylated) NFATc4- Signal-4 NFATc associates with other nuclear factorsleading to activation of genes encodingcytokines5- gene expression leads to IL-2 & IL-2 receptorsrelease6- IL-2 activates lymphocytes proliferation 30. Immunosuppressive drugs ** Immunosuppressive drugs can be categorizedaccording to their mechanism of action to: Some agents interfere with cytokines production or action. Others disrupt cell metabolism , preventing lymphocyte proliferation . Mono- or polyclonal antibodies block T-cellsurface molecules. 31. - Earlier immuno-suppressant suppress both humoral & cell mediated immunity but recent drugs suppress lymphocyte function by drugs or antibodies aginstimmunoproteins.- No single agent is used but 2-4 combination drugs or agent withdifferent mechanisms of actions whichdisturb various level of Tcell activation. 32. I- selective inhibitor of cytokine:production & function A) Cyclosporine: ** Source & nature: - lipophilic cyclic polypeptide extracted from soil fungus** Uses:1 - Prevent rejection of kidney, liver & cardiac allogeneictransplants: Prevent acute phase rejection specially when taken with corticosteroids & mycophenolate mofetil.2- Alternative to methotrexate for severe active rheumatoidarthritis. 3- In patient with psoriasis not respond to other drugs. 33. :mechanism of action **Cyclosporine enters T- lymphocyte to bind with cyclophillin forming complex which bindsto & inhibits calcineurin that responsible fordephosphorylation & activation of NFATc (cytosolicNuclear Factor of Activated T-cell) so this NFATccannot enter the nucleus so decrease productionof IL-2 & IL-2 receptors essential for proliferation of T- cells. 34. ** Pharmacokinetics:- Oral or I.V infusion- Hepatic metabolism by CYP3A4 to inactive metabolitesexcreted billiary ** Adverse effects:- Nephrotoxicity: irreversible in 15% of patients- Hepatotoxicity- Viral infection due to herpes group or cytomegalovirus (CMV)- Anaphylactic reactions on parentral administration- Hypertension, hyperlipidema , hyperkalemia, hirsutism& gum hyperplasia 35. :(B( Tacrolimus :(FK506Differs from cyclosporine in the following: 1- Preferred than cyclosporine due to : a- more potent.b- lower dose of corticosteroids is needed so less toxicity.c- ointment preparation has been approved for moderate to severe atopic dermatitis. 2- Mechanism of action as cyclosporine but bind to different immunophyllin (FK-binding protein(FKBP1-2) ) .3- Pharmacokinetics: as cyclosporine but better bioavailability. 4- Adverse effects: Mainly neurotoxic & insulin dependent diabetes mellitus but less C.V.S toxicity & no hirsutism or gum hyperplasia. 36. ( C( Sirolimus: (earlier name rapamycin ** Source & nature:Macrolide obtained from fermentations of soil mold. ** Uses:1-In combination with cyclosporine & corticosteroids inrenal transplantation values:a- lower doses of drugs so less toxicity. b- combination of CsA & SRL has synergistic effect as SRLacts later in immune activation cascade .N.B) to limit toxicity of CsA, SRL usually is used during calcineurin inhibitor withdrawal protocols. 2- Due to its anti-proliferative effect: SRL-coated stentsinserted into cardiac Vasculature inhibit restenosis of bloodvessels by proliferation of endothelial cells. 37. ** Mechanism of action: Binds to the same cytolpasmic binding protein ofTAC ( KFBP) but not form complex with calcineurinbut form complex with mTOR ( mammaliantarget of rapamycin) mTOR is kinase enzyme responsible for:a- T-cell proliferation by promote transmission ofcells from G1 to S phase of cell cycle b- DNA repairc- Regulator in protein translationbinding of SRL to mTOR inhibits T-cell proliferation 38. N.B) CsA & TAC inhibits IL-2 production while SRL inhibits IL-2 function** Adverse effects: Hyperlipidemia Headache Leucopenia Thrombocytopenia Impaired wound healing 39. II- Immunosuppressiveantimetabolites :Usually used in combination with corticosteroids & calcineurin inhibitors CsA & TAC : A- Azathioprine:** mechanism of action:Prodrug converted to 6-mercaptopurine (6-MP) then to corresponding nucleotide, thioinosinic acid which interferes with purines synthesis which are essential for proliferationof lymphocytes.** was widely used in organ transplantation. ** adverse effects:- Bone marrow suppression - nausea & vomiting ** Captopril & cotrimoxazole exaggerate leukopenic response while allopurinol inhibitthe metabolism of azathioprine . 40. B- Mycophenolate mofetil ( MMF(:- Replace azathioprine in organ transplantation because it ismore safe & more efficacious. ** Mechanism of action: Potent reversible uncompetitive inhibitor of inosinemonophosphate dehydrogenase so blocking the de novo formation of guanosine phosphate so deprive proliferating T-& B-cells of a key precursor required for nucleic acid synthesis. ** Adverse effects: diarrhea , nausea & vomiting abdominal pain, leucopenia & anemia higher risk of CMV infection 41. C- Enteric coated:mycophenolate sodium In order to minimize gastrointestinal effects associated with MMF so used delayedrelease formulation of active drugmycophenolic acid 42. ** Mono- and Poly-clonal Antibodies Prepared by either immunization of rabbits or horses with human lymphoid cells (producing a mixture of polyclonal antibodies directed against a number of lymphocyte antigens) or by hybidromatechnology ( producing antigen-specific,monoclonal antibodies) 43. N.B) Recombinant DNA technology can also be used to replace part of the mouse genesequence with human genetic material thushumanizing antibodies produced. Replace of FC portion of animal antibodies by human FC region not affect on antigenspecificity.N.B) The name of monoclonal antibodies contain muro if they are from murine (mouse) source and xi or iz if they are humanized. 44. A( Antithymocyte globulins:((ATG Thymocytes are developed from thymus and acts as precursors of T-cells. ATG prepared by immunization of large rabbits or horses with human lymphoid cells soconsidered polyclonal. Rabbit is usually preferred than horses as morepotent. 45. - The produced antibodies bind to surface of circulating T-lymphocytes which then undergocomplement mediated destruction or antibody-dependent cytotoxicity orapoptosis. - ATG used with immunosuppressive drugs attime of transplantation to prevent early phase ofgraft rejection.Also used to treat severe rejection episodes incorticosteroids-resistant cases. N.B) Because humoral mechanism still active antibodies can beformed against these foreign protein. 46. Monoclonal antibodies: Monoclonal antibodies (mAb or moAb) are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parentcell. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the non- proprietary drug name ends in mab. 47. : ProductionHybridoma cell production:Monoclonal antibodies are typically made by fusing myeloma cells with the spleen cellsfrom a mouse that has been immunized with the desired antigen. However, recent advances have allowed the use of rabbit B- cells. Polyethylene glycol is used to fuse adjacent plasma membranes, but the success rate is low so a selective medium in which only fused cells can grow is used. 48. This mixture of cells is then diluted and clones are grown from single parent cells on microtitre wells. The antibodies secreted by the differentclones are then assayed for their ability to bind to the antigen (with a test such as ELISA orAntigen Microarray Assay). The mostproductive and stable clone is then selected for future use. The hybridomas can be grown indefinitely in a suitable cell culture media, or they can beinjected in mice (in the peritoneal cavity, the gut), they produce tumors containing an antibody-rich fluid called ascites fluid. 49. Recombinant: Recombinant antibody engineering involves the use of viruses or yeast to createantibodies, rather than mice. These techniques rely on rapid cloning of immunoglobulingene segments to create libraries ofantibodies with slightly different amino acid sequences from which antibodies with desiredspecificities can be selected 50. Examples of monoclonal antibody drugs 51. Trastuzumab(Herceptin) 52. Humanized monoclonal antibodies thatacts on the HER2neu (erbB2) receptors. As inhibition of cell growth bytrastuzumab is limited to HER2-positive cancers, testing tumors forHER2 expression became integral toselecting patients HER2 testing of breast cancer patientsbecomes a routine 53. Mechanism of action: 54. Uses:Herceptin is used mainly to treat women withbreast cancer. It may be used in the early stages to increasethe chances of a cure. It also used in metastatic breast cancer.In most cases it is used in combination withchemotherapeutic agents paclitaxel ordocetaxel. 55. Cetuximab (Erbitux) 56. Mechanism of action: 57. Cetuximab attaches to the EGFRs andprevents the receptors from being activated. This stops the cells from dividing. therefore stop the cancer cells from growing. Cetuximab also make the cancer cells moresensitive to chemotherapy and radiotherapy Tests may be done to find the level of EGFR in the tumour cells before cetuximab is given. 58. IMMUNOSTIMULATIO N In contrast to immunosuppressive agents thatinhibit the immune response, a few immunostimulatory drugs have beendeveloped with applicability to infection, immunodeficiency, and cancer. Problems with such drugs include systemic (generalized) effects at one extreme or limitedefficacy at the other. 59. LevamisoleIt was synthesized originally as an anthelminticbut appears to "restore" depressed immunefunction of B-lymphocytes, T-lymphocytes, monocytes, and macrophages.Its only clinical indication is as adjuvant therapy with 5-fluorouracil after surgicalresection in patients with stage C colon cancer, where it occasionally has been associated with fatal agranulocytosis. 60. Thalidomide Known for the severe, life-threatening birthdefects it caused when administered topregnant women. For this reason, it isavailable only under a restricted distributionprogram and can be prescribed only by specially licensed physicians who understandthe risk of teratogenicity if thalidomide isused during pregnancy. Thalidomide shouldnever be taken by women who are pregnant or who could become pregnant while taking the drug. 61. It is indicated for the treatment of patientswith erythema nodosum leprosum and alsois used in conditions such as multiplemyeloma. Its mechanism of action isunclear. Reported immunologic effects vary substantially under different conditions. For example, thalidomide has been reported todecrease circulating TNF- in patients witherythema nodosum leprosum, severerefractory rheumatoid arthritis. 62. Bacillus Calmette-Guerin(BCG(:Live bacillus Calmette-Guerin is an attenuated,live culture of the bacillus of Calmette and Guerin strain of Mycobacterium bovis, thatinduces a granulomatous reaction at the site of administration. By unclear mechanisms,this preparation is active against tumors and is indicated for treatment and prophylaxis of carcinoma in situ of the urinary bladderAdverse effects include hypersensitivity,shock, chills, fever, malaise, and immune complex disease. 63. Recombinant Cytokines Interferons: Although interferons (alpha,beta, and gamma) initially were identified by their antiviral activity, these agents also haveimportant immunomodulatory activities: Induction of certain enzymes. Inhibition of cell proliferation. Enhancement of immune activities, including increased phagocytosis by macrophages andaugmentation of specific cytotoxicity by Tlymphocytes. 64. Recombinant interferon alfa-2b (IFN-alpha 2, INTRON A)Produced and secreted by cells in response toviral infections and other inducers. Interferon alfa-2b is indicated in the treatment of a variety of tumors, including hairy cell leukemia, malignant melanoma, follicular lymphoma, and AIDS-related Kaposis sarcoma.It also is indicated for infectious diseases,chronic hepatitis B & in combination withribavirin for treatment of chronic hepatitisC. 65. Side effects: Flu-like symptoms, including fever, chills, and headache, are the most common adverse effects after administration.Other adverse reactions involving the cardiovascular system (hypotension, arrhythmias, and rarely cardiomyopathyand myocardial infarction) and CNS (depression, confusion) are less-frequent side effects. 66. Interferon beta-1a (AVONEX, REBIF),and interferon beta-1b (BETASERON),have antiviral and immunomodulatory properties.They are FDA approved for the treatment ofrelapsing and relapsing-remitting multiplesclerosis to reduce the frequency of clinicalexacerbations . The mechanism of their action in multiple sclerosis is unclear. Flu-like symptoms (fever, chills, myalgia) andinjection-site reactions have been common adverseeffects. 67. **Tumor necrosis factor (TNF ( inhibitors : Infliximab: A monoclonal antibody against tumor necrosis factor alpha (TNF). Infliximab was approved by the U.S. Foodand Drug Administration (FDA) for the treatment of psoriasis, Crohns disease, ankylosing spondylitis, psoriatic arthritis,rheumatoid arthritis and ulcerative colitis. 68. Mechanism of action: 69. EtanerceptEtanercept is a dimeric molecule, and this dimeric structure is necessary for itsproper therapeutic activity. To reduces the effect of naturally present TNF, and hence is a TNF inhibitor, functioning as a decoy receptor thatbinds to TNF. 70. Drug allergy **(immunological reactions to:(drugs Drug reactions mediated by immune responses may have different mechanisms thus any of the four major types of hypersensitivity can be associated with allergic drug reactions:Type I: IgE-mediated acute allergic reactions to stings, pollens, & drugs including anaphylaxis, urticaria, angioedma. IgE is fixed to tissue mast cell. 71. Type II:Drugs modify host proteins eliciting antibody responses to modified protein. These allergicresponse involve IgG& IgM in which the antibody become fixed to a host cell which isthen subject to complement-dependent lysisor to antibody-dependent cellular cytotoxicity. Type-III:Drugs may cause serum sickness which involvesimmune complexes containing IgG & is multisystem complement-dependent vascuilitis that may result in urticaria. 72. Type-IV: Cell-mediated allergy is the mechanism involved in allergic contact dermatitis from topicallyapplied drugs or induration of the skin at site of an antigen injected intradermally. 73. Thank you