Initial Therapy Anti-ischemic and Analgesic therapy Anti-platelet therapy Anti-coagulant therapy.
Anti-cytokine therapy
description
Transcript of Anti-cytokine therapy
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
ANTI-CYTOKINE THERAPY
Zoltan BalajthyMolecular Therapies- Lecture 8
Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of DebrecenIdentification number: TÁMOP-4.1.2-08/1/A-2009-0011
Learning objectives of chapter 8. As the reason of many common diseases is the appearance of inflammatory process in our body (rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, insulin-dependent diabetes melitus, psoriasis, sepsis), the significance of anti-cytokine therapy is interpreted through the understanding both the processes and mechanisms of inflammation.
Topics in chapter 8
8.1. Development of septic shock and subsequent failure of organMigration of neutrophil from vascular space to tissuesEffects of IL-1 , -β and TNF Stream Of cytolkines in sepsis
8.2. Development of inflammatory response Synthesis of lipid mediatorsIniciation of cytokine synthesis of inflammationSynthesis of NO controlled by cytokine
8.3. Role of the Liver in Maintenance of HomeostasisAcute phase response, acute phase proteins (APP)
8.4. Time-Course of the Inflammatory Response During SepsisEndothelial Activation, Coagulation and Fibrin Clot Formation
8.5. Collapse of Homeostasis
8.6. Anti-Cytokine Therapy
8.7. Cancer therapy and monoclonal antibodies
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8.8. How Can Immunity Be Applied for Treatment
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Cytokines share the following characteristics: they have very high affinity for their specific receptor; they act in a paracrine or autocrine fashion and are potent at picomolar to nano-molar concentrations.
Today, cytokines have been classified into several classes based on structural or functional similarities: monokines, lymphokines, interleukins, colony stimulating factors, interferons,tumor necrosis factors and chemokines.
Characteristic feature of cytokines: they take part of natural immunity, hematopoiesis,activation of lymphocyte, differentiation and initiation of inflammation.
In many common diseases cytokine overproduction would happen giving the key targets for anti-cytokine treatments.
Cytokine receptor family: hematopoietin, interferon, TNF, IL-1, TGF- and chemokine receptors.β
Characterization of cytokines
Cytokines are proteins of size ranging from 50 to 500 amino-acids in average, and are major molecular messengers for communication between cells. More than 200 cytokineshave been identified and cloned.
Infection, Trauma, BurnsRelase of Endotoxines orEcosanoids, Complement
Activation
Inflammatory Cytokine Storm
Small Mediator Molecules, vascular resistance ↓
Hypotension, Acidosis, Decreased Tissue Oxygenation
Myocardial Suppression, Refractory Shock, Organ Ischemia
Multiple Organ Failure, Disseminated Intravascular Coagulation, Death
8.1. Development of Septic Shock and Subsequent Failure of OrganTÁMOP-4.1.2-08/1/A-2009-0011
endothelium smooth muscle
systemic circulation
TNF IL-1
extravascular space
capillary leak
PAF PG NO ELAM IL-8■■■■■■■■■■■■■■■■■■■■■■■■
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neutrophil emigration into tissue
neutrophil degranulationand tissue damage
circulating neutrophils
Migration of Neutrophil From Vascular Space to TissuesTÁMOP-4.1.2-08/1/A-2009-0011
HYPOTENSION
TISSUE INJURY
ORGAN FAILURE
DEATH
C5a
TNF
IL-1IL-6
Stream Of Cytolkines in SepsisTÁMOP-4.1.2-08/1/A-2009-0011
Results of IL-1 and β
Fever
Myalgias and Joint Pain
Headach
Loss of Appetite and Confusion
Mild Hypertension at Low Concentration of IL-1
Hypotension at Increased Concentration of IL-1
Hemodynamic shock at High Concentration of IL-1
IL-1 , IL-1 , and the (IL-1RA)α β (interleukin-1 receptor antagonist) play important role in regulation of immune functions and inflammation process. Both IL-1 and IL-1 are α β pro-inflammatory cytokines produced by macrophages, monocytes, fibroblasts and dendritic cells
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Effect of Adrimistration of TNF
Core Body Temperature Increases
Neutrophil Count Decreasing at the Early Phase
White Blood Cells Count Increases in the Late Phase
Mean Arterial Blood Pressure Decrease (Hypotensison)
Coagulation Parameters Increase
Mental Status Declines
Myalgias / arthralgias
TNF (Tumor necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.The primary role of TNF is in the regulation of immune cells. TNF is able to induce apoptotic cell death, to induce inflammation, and to inhibit tumorigenesis . A TNF can bind to TNF-R in homotrimer form that can activate MAPK, NFκB or cell death signaling.
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IL-1 and TNF Synergism
Hypotension ans Schock
Prostaglandin Production
Cytotoxicity / Tumor necrosis
Muscle proteolysis
Lactic acidosis
Anti-cytokines to Reduce Mortality in Sepsis
Antibodies to TNF
Soluble Receptors of TNF
IL-1 receptor antagonist
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Inflammatory Cytokines and Anti-Cytokines
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phospholipids of plasma membrane
arachidonate
PLA2, Phospholipases A2 cleaves
leukotrienes(LTA4 - LTE4)
lipoxygenases
prostglandin H2(PGH2)
other prostaglandins(PGD2, PGE2)
prostacyclin(PGI2)
thromboxanes(TXA2)
cyclooxigenase (COX -1)
prostaglandin synthetase
prostacyclin synthase thromboxane synthase
Arachidonate is the major precursor of several classes of signal molecules: prostaglandins, prostacyclins, thromboxanes, and
leukotrienes
8.2. Development of Inflammatory ResponseSynthesis of Lipid Mediators
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lysed bacterialcells
LPS
LPS binding protein(plasma)
LPS - LPS binding proteincomplex (LBP)
TLR-4CD14
LPS-LPB
LPS-LPB
NFκBpathway
CD14, CD11/18, TLR-2/TLR-4LPS Receptors
Inflammatorycytokines
Development of Inflammatory Response I.
r r rr r r rrr
rrr
rrrr rrrr
lipoteichoicacid
peptidoglycan -lipoteichoic acid
cytoplasm membrane
(TLR)
lipopolysaccharide (LPS)
neutrophil
monocyte
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adaptorprotein
β p65 p50
IκB
IκB proteasomal degradation
p65 p50
p65 p50transcription
nukleus
IκK complex
phosphorilation p p
nuclear translocation
receptor activation
transcription of inflammatory genes (IL8, IL6, TNF)
Toll-like receptor
NFκB
Iniciation of Cytokine Synthesis of Inflammation
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cytokine
L-arginine
nitric oxide
NO activates soluble guanylate cyclase
GTPcGMP
degreased cytoplasmic Ca2+
receptor
Vasodilatation
Smooth musclecell
Endothelialcells
iNO synthaseL-arginine
nitric oxide
cGMP
receptor
iNO synthase
GTPcGMP
degreased cytoplasmic Ca2+
NO activates soluble guanylate cyclase
Blood stream
Synthesis of NO controlled by cytokine
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Cells associated with initiating the acut phase response are neutrophilsmonocytes and macrophages
Released IL-1, TNF and IL-6 reach the central nervous system and the liver.
Acut phase proteins produced by liver cells:
Complement proteinsCoagulation proteinsProteinase inhibtorsOpsonins
Serum amyloid A (SAA)C-reactive protein (CRP)
8.3. Role of the Liver in Maintenance of Homeostasis, (Inflammation)TÁMOP-4.1.2-08/1/A-2009-0011
Blood vessel
Blood vessel
Bone marrow
Prostaglandins
Cytokines
Fever
Sickness behaviour
IL1β,IL6, TNF
Infection
Cytokines, chemokinesprostaglandines
Acute phaseresponse
Monocytes, neutrophils
Complement proteinsCoagulation proteinsProteinase inhibtors
Opsonins
Lungs
Liver
Acute Phase ResponseTÁMOP-4.1.2-08/1/A-2009-0011
LIVER
TNF-IL-1IL-6
ACUTE PHASE PROTEINS
Complement proteins:C3, C5 and C1 inhibitor (6-8 X)
Coagulation proteins:Fibrinogen (2-4 x)Von Willebrand factor
Protein inhibitors:Plasminogen activator inhibitor I2-antiplasmin
Metal-binding proteins:Haptoglobulin, ceruloplasmin (1.5-2 x)
Negative APRs: albumin, transferin (0.4-0.5 X)
Major APRs:Serum amyolid A (100-1000 X)C-reactive proteinSerum amyloid P component (SAP)
Inflammatory mediators that modulate hepatic APR synthesis TÁMOP-4.1.2-08/1/A-2009-0011
8.4. Time-Course of the Inflammatory Response During SepsisTÁMOP-4.1.2-08/1/A-2009-0011
Induction of proinflammatory cytokines
tissue factor
TLR-4CD14
TLR-4
CD14
LPS-LPBLPS-LPB
LPS-LPBLPS-LPB
LPS-LBP
Activation of NFκB
Pathway
tissue factor
VII a+
TNFIL-1
Platelet-activating factor (PAF),arachidonic acid, leukotriens,
Plasminogen activator inhibitor
Directtissue injury
Microvascularcoagulopathy
Gram-negative bacteria
Gram-pozitive bacteria
CD 14receptor
Toll-like receptor
lipopolysaccharide, endotoxin (LPS)
lipoteichoicacid
inflammatory response
Endothelial Activation, Coagulation and Fibrin Clot Formation I.TÁMOP-4.1.2-08/1/A-2009-0011
Factor IXa +
Factor VIIIa
INTRINSIC TENÁZ
Thrombin (IIa)Protrombin (II)
Fibrinogen Fibrinfibrin clot formation
VII a+
Tissue Factor
EXTRINSIC TENÁZ (X-ÁZ)
Factor Xa +
Factor Va
PROTHROMBINASE
Factor VIII +
Factor V
Factor IX
Factor X +
Profactors (V és VIII) activation
Zimogenes (IX és XIII) activation
Coagulation Response
(+)
(+)
VII +
Tissue Factor(+)
TFPITissue Factor
Pathway Inhibitor(-)
Fibrinolysis
Aktivated pFrofactors Inactivation of (Va és VIIIa)
PAI-1(Plasminogen activator
inhibitor 1)
Plasmin
Plasminogen
Plasminogenactivators
activatedprotein C
(-)
(-)
Pathways of Procoagulation Anticoagulation Pathway
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Endothelial Activation, Coagulation and Fibrin Clot Formation II.
b
Tissue Factor
c
Factor IXa +
Factor VIIIa
Thrombin
Factor IX
Prothrombin
Fibrinogen Fibrin Fibrin Clot
endothelium
TLR-4CD14
TLR-4
CD14
TLR-4
CD14TLR-4
CD14 LPS-LPB
LPS-LPB
LPS-LPBLPS-LPB
LPS-LPBLPS-LPB
LPS-LBP
CD14
TLR-4
Inflammatory Response
to Infection
Thrombotic Response
to Infection
Fibrinolytic Response
to Infection
organism
Tissue Factor
VII a+
Factor XFactor Xa
+Factor Va
Factor VIII
Factor V
Activation of NFκB
Pathway
inflammatory response
Induction of proinflammatory cytokines
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b
Tissue Factor
c
Factor IXa +
Factor VIIIa
ThrombinProtrombin
Fibrinogen Fibrin
endothelium
TLR-4CD14
TLR-4
CD14
TLR-4
CD14TLR-4
CD14 LPS-LPB
LPS-LPB
LPS-LPBLPS-LPB
LPS-LPBLPS-LPB
LPS-LBP
CD14
TLR-4
organism
Tissue Factor
VII a+
Factor Xa +
Factor Va
Factor VIII
Factor V
TAF1(thrombin activated fibrinolysis inhibitor)
PAI-1(plasminogen activator
inhibitor 1)
fibrinolysis
inhibition
TNFIL6, IL1TNF
IL6, IL1
inflammatory response
inflammatory response
Activation of NFκB
Pathway
Induction of proinflammatory cytokines
fibrin clot formation
Coagulation, Fibrin Clot Formation and Inhibition of Fibrinolysis
Inflammatory Response
to Infection
Thrombotic Response
to Infection
Fibrinolytic Response
to Infection
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b
Tissue Factor
c
Factor IXa +
Factor VIIIa
ThrombinProthrombin
Fibrinogen Fibrin
endothelium
TLR-4CD14
TLR-
4
CD14
TLR-4
CD14TLR-4
CD14 LPS-LPB
LPS-LPB
LPS-LPBLPS-LPB
LPS-LPBLPS-LPB
LPS-LBP
CD14
TLR-4
organism
Tissue Factor
VII a+
Factor Xa +
Factor Va
Factor VIII
Factor V
TAF1(thrombin activated fibrinolysis inhibitor)
PAI-1(plasminogen activator
inhibitor 1)
TNFIL6, IL1TNF
IL6, IL1
thrombospondin
protein Sprotein C
Protein C Catalyzed InactivationDegreased
rolling
activatedprotein C
Endogenous Activated Protein C Has Multiple Mechanisms of Action
Activation of NFκB
Pathway
inflammatory response
inflammatory response
Inflammatory Response
to Infection
Thrombotic Response
to Infection
Fibrinolytic Response
to Infection
fibrinolysis
inhibition
fibrin clot formation
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TLR-4CD14
TLR-
4
CD14
LPS-LPBLPS-LPB CD14
TLR-4
HMGB1
RAGE VCAM ICAM
NF-κB
PAI-1tPA
TNF-
MCP-1IL-8
MCP-1IL-8
ICAM
Neutrophil adherence
Regulation offibrinolysis
TNF-IL-1aIL-1bIL-6
Pro-inflammatorycytokines andchemokines
monocytesmacrophages
LPS
Contribution of high-mobility group box 1(HMGB1) to sepsis
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Increased Coagulation
Increased Inflammation
Decreased FibrinolysisProinflammatory mediatorsTissue factor expressionThrombin productionEndothelial injury
Increased PAI-1Increased TAFReduced Protein C
PAI : plasminogen activator inhibitorTAFI: thrombin activated fibrinolysis inhibitor
Homeostasis
8.5 Collapse of Homeostasis
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Infection SIRS SepsisSeverSepsis
SepticShock
Development of Septic Shock and Organ Failure
MitochondrialDisfunction
OrganDisfunction
Multiple Organ Failer
Death
MicrovascularCoagulation/Thrombosis
SIRS: systemic inflammatory response syndrome
antibodies (anti-IL-6R)
Anticomplement Monoclonal Antibody
Soluble Receptor (Enbrel)
Receptor Antagonists (IL-1RA)
IL-6 Antagonist
Cytokines Antagonists (IL-10, IL-11, IL-13)
TACE, ICE inhibittors
Drotrecogin alfa
8.6. Anti-Cytokine Therapy
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See: Anti-cytokine therapeutics: history and update.Ratsimandresy RA, Rappaport J, Zagury JF.Curr. Pharm. Des. 2009;15(17):1998-2025. Review.
8.7 Cancer therapy and monoclonal antibodies
Monoclonal antibodies have been seen as a breakthrough in cancer therapy. However, there are problems with their use. These include the targeting of theantibody to the tumor. There are few if any molecules that are cancer-cell-specific and many markers of cancer are merely up-regulated or mutated forms of natural cellular products. Additionally, cancers are heterogeneous with respect to antigen production and therefore an antibody may not recognize every cancer cell. Sadly, removal of all cancer cells is a prerequisite for a cure. One of the first tasks is therefore the recognition of a target molecule on the cancer.
Herceptin in breast cancer therapy see: Cell Cycle and Cancer Therapy, p53
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8.8. How Can Immunity Be Applied for Treatment?
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Immunity is a specific system dealing with defensive mechanism. It is useful for prevention, via destroying of foreign body that enters or invades into the human body before it can generate further problems. However, the present concept transform to the usage of immunity for medical treatment. The immunotherapy is a new highlight in immunology. There are many forms of immune-related treatments.
A. Immunomodulation Therapy: Immunomodulation therapy is a new way of treatment making use of modification of immunity systern to help curative process of some diseases. This is widely used for several treatments.
Immunosuppressants: inhibits immune response in organ transplantation and autoimmune diseases.
The drugs are:- Calcineurin inhibitors (Specific T-cell inhibitors). Cyclosporine (Ciclosporin), - Antiproliferative drugs (Cytotoxic drugs). Azathioprine, Cyclophosphamide, Methotrexate, - Glucocorticoids. Prednisolone and others- Antibodies. Muromonab CD3, Antithymocyte globin (ATG), Rho (D) immuneglobin, Efalizumab.
ImmunostimulantsIncrease the immune response, useful in infections, immunodeficiency (for example, AIDS) and cancers.
Immunostimulant drugs:They stimulate the immune system to fight against immunodeficiencies (like AIDS), infections and cancers.
- Levamisole. An antihelmintic drug that also restores functions of B lymphocytes, T lymphocytes, monocytes and macrophages. Hence it has been used in colon cancer along with 5-FU.
- Thalidomide. Different effects of this old drug have been utilized in conditions such as:Erythema nodosum leprosum: Anti-inflammatory effectMultiple myleoma: Anti-angiogenesisRheumatoid arthritis: Anti TNF effect.
- BCG. Used in carcinoma bladder.
- Recombinant cytokines. Interferons: In tumors and chronic hepatitis B and C
interleukin 2 (aldeslukin): has been used in renal cell carcinoma and melanoma
B. Antibody Treatment :
Antibody treatment is any treatment making use of administration of immunoglobulin or antibody. This is famous for a long time. Direct passive immunization is the good example. The most well-know situations are tetanus antitoxin injection and rabies immunoglobulin for preventive and therapeutic purposes. See chapter 6.
C. Therapeutic Vaccination
Indeed vaccine is used for prevention and described as an active immunization. However, the present role of vaccine changes to more usefulness in curative treatmentprocess. Vaccination against human papilloma virus infection to prevent the development of tumors.
D. Cytokine Treatment
Cytokine treatment or cytokine therapy is another mode of immune - related treatment.Indeed, cytokine is a product in cellular process of cell-mediated immunity process. Cytokine treatment is used for medical treatment of many diseases especially for many viral infections. This is comparable to antibody treatment, which makes usefulness of humoral immunity for treatment.
E. Gene TherapySee chapter 4. and 10.