immuno-pharmacology dr. dalia el tanbouly. immunopharmacology: study of drugs that modulate immune...
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Immuno-PharmacologyImmuno-Pharmacology
Dr. Dalia El Tanbouly
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• Immunopharmacology: study of drugs that modulate immune response (↑ or ↓).
• Immune system consists of:
– Organs:1ry(Thymus, bone marrow) 2ry (spleen, lymph nodes)
– Cell types: neutrophils, monocytes, natural killer cells, etc.
– Molecules: complement component.
• Communication among elements:– Surface receptors– Soluble molecules (cytokines).
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Targets of Immune Response:– Invading organisms.– Growing neoplastic cells.
• Immune system must distinguish self from non-self.
• Foreign substances that elicit a specific immune response are called antigens.
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Types of Immune Response:
Innate (natural):• 1st line defense • Non-specific.
Adaptive (acquired): • Specific.• Have memory.• Subdivided into:
– Humoral (B-lymphocytes).– Cellular (T-lymphocytes).
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Characteristics of Innate & Characteristics of Innate & Acquired Immune ResponsesAcquired Immune Responses
Innate:• Onset: Immediate.• Does not require priming.• Effectors:Physical: skin and mucous
membranes.Cellular: macrophages, neutrophils,
mast cells, natural killer cells, etc.
Biochemical: cytokines, lysozymes and complement (cell lysis (MAC), opsonization C3b, chemotaxis C5a)
Acquired:
• Onset: Days to weeks.
• Require priming.
• Effectors:Cellular:
– B-lymphocytes.– T-lymphocytes.
• T helpers (CD4).• T cytotoxic (CD8).
– Phagocytes (APC).Biochemical:cytokines, lysozymes, complement
and immunoglobulins
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• Onset upon re-exposure: the same.
• Memory: Absent
• Onset upon re-exposure: quicker.
• Memory Present
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CytokinesCytokines• Soluble small peptides used by the immune
system to communicate & influence cellular functions.
• Involved in innate & adaptive immunity. • Chemokines: low molecular weight cytokines act
as chemoattractants e.g Interleukin-8 (IL-8), which induces neutrophils to leave the
bloodstream and enter into the surrounding tissueMonocyte chemoattractant protein-1 (MCP-1) which induces
monocytes to leave the bloodstream and enter the surrounding tissue to become tissue macrophages.
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TH
TH1
ActivatedNK cell
ActivatedCytotoxic T cell
IL-2
IL-2
Memory B-cells
IL-2
IL-2, INF-γ, TNF-β
IL-1, TNF-α (pro inflammatory cytokines) IL-12 IL-8Ingestion and killing microbesDamage cellsRemove cellular debris
-Neutralization of microbes and toxins-Opsonization of antigens for phacocytosis by macrophages and neutrophils.-Activation of classical pathway of complement (lysis)-Antibody-dependent cellular cytotoxicity by NK cells.
TH1/TH2
IgEIgAIgGIgM
IL-2, IL-4, IL-5,
INF-γ
Kill virus infected cells ant
tumor cells
Activated macrophages
APC
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Examples of some cytokines:
• IL-1 & TNF-α (pro inflammatory cytokines) increase vascular permeability promoting inflammation.
• IL-2 (T cell growth factor): T- cell proliferation and differentiation into effector and memory cells.
• IL-4 (B cell growth factor): TH2 derived growth factor, essential for IgE production
• IFNs (α, β ): Possess antiviral effects.
• IFNγ: Macrophage activation, essential for IgG production, possess antiviral effects.
• IL-12: Produced by macrophage promoting TH1 differentiation.
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Abnormal Immune Response:
• Abnormal impaired immune response → Immunodeficiency.
• Abnormal exaggerated immune response: Hypersensitivity reactions. Autoimmune diseases.
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Antibody - Antibody - mediatedmediated
Cell - mediatedCell - mediated
TypeType VI: VI: DTHDTHType I: Atopy, Allergy, Anaphylactic HS,
immediate
Type II: Cytotoxic
Type III: Immune complex
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1st exposure
to allergen
1st exposure
to allergen
Abnormal IgE
production
IgE fixed on the surface of mast cells or basophils via
fcR(Sensitization)
2nd exposure
to allergen
2nd exposure
to allergen
Cross linking of fcR through membrane-
bound IgE by allergen
MechanismMechanism
Ca2+ influxCa2+
influx
(Atopy - Allergy – Anaphylactic - Immediate)
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HistamineHistamine
Degranulation of mast/basophil cells
Release of stored (preformed)stored (preformed) mediators
Ca2+ influxCa2+ influx
+ Heparin + Proteolytic enzymes + ECF + Serotonin
Immediate phase response
Immediate phase response
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Synthesis & release of:
• Arachidonic acid metabolites Arachidonic acid metabolites
LTsLTs PGs - TXPGs - TX
Lipoxygenase
Cyclo-oxygenase
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Immediate PhaseImmediate Phase
HistamineHistamine
LTCLTC44 / LTD / LTD44
Vasodilatation, Vascular permeability, transient contraction of smooth muscle
Prolonged smooth muscle contraction Bronchoconstriction - Bronchial secretions
Mucosal edema
Histamine – Kinins Histamine – Kinins - PG- PG
Vasodilatation -
Vascular permeability edema
Proteasese Proteasese Tissue damage – inflammation
Cytokines ( TNFCytokines ( TNFαα- - IL-4), LTBIL-4), LTB44
Attraction of leucocytes (eosinophils & neutrophils )The attracted eosinophils & neutrophils release proteases & mediators
Late phase response
Late phase response
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Clinical ManifestationsClinical Manifestations
LOCALLOCAL SYSTEMICSYSTEMIC
At the sites in which mast cells accumulate
At the sites in which mast cells accumulate
Main organ affected
Disease
Skin Skin (contact)(contact)
Eczema - Urticaria (hives)
Nose & Nose & Eyes Eyes (contact)(contact)
Rhinitis, Conjunctivitis (hay fever)
Lung Lung (inhalati(inhalation)on)
Allergic bronchial asthma
GIT GIT (ingestioi(ingestioin)n)
Allergic gastroenteropathy
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Changes these self structures Changes these self structures to be antigenicto be antigenic
MechanismsMechanisms
(Ab mediated cytotoxicity)
which may be non self molecules
Drug or microbial toxin (hapten) is Drug or microbial toxin (hapten) is passively passively adsorbedadsorbed onto cell
membrane Production of antibody Production of antibody (IgG (IgG or IgM)or IgM) that is directed that is directed
against itagainst it
OR a self molecules Antibody-mediated AID
Generated by actions of antibodies usually IgG or IgM against an epitope on host cell membrane or extracellular matrix .
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The bound antibody stimulates the cell damage by a number of effector mechanisms
Antibody-Dependent Cell-mediated CytotoxicityAntibody-Dependent Cell-mediated Cytotoxicity
MechanismsMechanisms
(Cytotoxic)
Antibody-Dependent disruption of cellular function:e.g.: Antibodies against cell surface receptor, which may be blocking or stimulating antibodies
Antibody-Dependent disruption of cellular function:e.g.: Antibodies against cell surface receptor, which may be blocking or stimulating antibodies
Antibody-Dependent Phagocytosis of target cellAntibody-Dependent Phagocytosis of target cell
Antibody-Dependent Complement Activation Antibody-Dependent Complement Activation
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Antibody-Dependent Cell-mediated CytotoxicityAntibody-Dependent Cell-mediated Cytotoxicity
Antibody-Dependent Phagocytosis of target cellAntibody-Dependent Phagocytosis of target cell
Target Target CellCell
FCR
Phagocyte
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RBC RBC
RBC
RBC with drug RBC with drug adsorbed on its adsorbed on its
surfacesurface
IgGIgG Ag/Ab reactionAg/Ab reaction
Complement Complement activationactivation
Formation of MACFormation of MACHemolysisHemolysis
Antibody-Dependent Complement Activation Antibody-Dependent Complement Activation
C
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1.1. Myasthenia gravisMyasthenia gravis (autoantibodies against Ach receptors in MEP).
2.2. Hashimoto’s thyroiditisHashimoto’s thyroiditis (autoantibodies against thyroid cells).
Examples of Antibody-mediated AIDExamples of Antibody-mediated AID
(Cytotoxic)
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Examples of Drug-induced T2HSRExamples of Drug-induced T2HSR
(Cytotoxic)
Examples:•Penicillin – phenacetin – quinidine adsorbed on RBC surface hemolysis Hemolytic anemia•Quinine adsorbed on platelet surface platelet lysis thrombocytopenia
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SalmonellaSalmonella lipopolysaccaride endotoxin adsorbed on RBC hemolysis. (Hapten)
Example of Microbial induced T2HSRExample of Microbial induced T2HSR
(Cytotoxic)
Streptococcus Streptococcus is rich in an antigen called M protein. IgG and IgM generated against streptococcus M protein can cross-react with cardiac tissues and valves of the heart impair cardiac functions (cross reactivity)
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MechanismMechanism
(Immune Complex)
Self moleculeSelf molecule Non-self moleculeNon-self molecule
Antibody-mediated AID
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(Immune Complex)For antigen that is circulating in the blood:For antigen that is circulating in the blood:
ExogenousExogenous
Post Streptococcal Glomerulonephritis Streptococcal cell wall antigens immune comlplex Nephritis
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Endogenous (AID)Endogenous (AID)
Rheumatiod arthritis caused by deposition of immune complexes in joints. The IgG in the immune complexes can become an antigen, stimulating the production of IgM against the bound IgG. The anti-IgG IgM is also termed the rheumatoid factor extensive damage to bone and cartilage and joint dysfunction. cartilage and joint dysfunction
Systemic lupus erythematosus (SLE)Arises from autoantibodies formed against fragments of single or double stranded DNA and some chromosomal proteins (e.g. histones). Because these molecules are widespread throughout the body, the inflammation is broadly distributed Nephritis Nephritis, Skin lesions and Arthritis
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1. CD4+ (Th-1)-mediated:
1.CD4+ (Th-1) cells interact with processed presented antigen Release of cytokines (e.g. IFN - TNFβ) Activation of macrophages
2.Activated macrophages release:• Lytic enzymes, inflammatory cytokines (e.g. TNFα, IL-1)
Inflammatory response & Tissue injury.• IL-12 Stimulates Th-1 to release more IFN - TNFβ
Continual cycle
Chronic exposure to the antigen Excessive accumulation & activation of macrophages Giant cells Epithelioid cells Granuloma formation (The attempt of the body to isolate a site of persistent
stimulus)
1. CD4+ (Th-1)-mediated:
1.CD4+ (Th-1) cells interact with processed presented antigen Release of cytokines (e.g. IFN - TNFβ) Activation of macrophages
2.Activated macrophages release:• Lytic enzymes, inflammatory cytokines (e.g. TNFα, IL-1)
Inflammatory response & Tissue injury.• IL-12 Stimulates Th-1 to release more IFN - TNFβ
Continual cycle
Chronic exposure to the antigen Excessive accumulation & activation of macrophages Giant cells Epithelioid cells Granuloma formation (The attempt of the body to isolate a site of persistent
stimulus)
MechanismMechanism
(Delayed)
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2. CD8+ (CTL)-mediated:
CD8+ cells interact with processed presented antigen Release of killing enzymes cytolysis & inflammatory responses.
2. CD8+ (CTL)-mediated:
CD8+ cells interact with processed presented antigen Release of killing enzymes cytolysis & inflammatory responses.
MechanismMechanism
(Delayed)
• Chronic infectious diseases: (bacterial – viral – protozoal - fungal).
• Contact dermatitis: (haptens + skin proteins immunogen).• Graft rejection.• AID: Multiple sclerosis (Myelin basic
protein) and Crohn's disease
ExamplesExamples
Leprosy
Contact Contact dermatitisdermatitisGraft rejection
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1.1. Molecular mimicryMolecular mimicry
2.2. Activation of anergized auto-reactive T-cellsActivation of anergized auto-reactive T-cells
3.3. Loss of suppression of auto-reactive T-cellsLoss of suppression of auto-reactive T-cells
4.4. Alteration of normal proteins Alteration of normal proteins
5.5. Release of sequestered antigensRelease of sequestered antigens
MechanismsMechanismsMechanismsMechanisms
When the body produces When the body produces immune response immune response against itselfagainst itself (i.e. loss of self-tolerance)(i.e. loss of self-tolerance)
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Some pathogens (bacteria or virus) have Some pathogens (bacteria or virus) have epitopes that epitopes that close similar close similar to normal protein in to normal protein in
host tissuehost tissue
1. Molecular 1. Molecular mimicrymimicry
Cross-reactivityCross-reactivity
Infection is frequently associated with Infection is frequently associated with development of autoimmunity…Why?development of autoimmunity…Why?
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Rheumatic feverRheumatic fever
following following Streptococcus pyogenes Streptococcus pyogenes infection infection
Molecular mimicry between Molecular mimicry between M proteinM protein of of S. pyogenesS. pyogenes & & the the myosinmyosin of of cardiaccardiac muscle & to some degree with muscle & to some degree with
molecules on molecules on jointsjoints & & kidneyskidneys. .
Antibodies against Antibodies against M proteins M proteins cross-reactcross-react with myosin with myosin in myocardium & joint tissue in myocardium & joint tissue Rheumatic fever. Rheumatic fever.
1. Molecular 1. Molecular mimicrymimicry
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Macrophages that are activated by infection Macrophages that are activated by infection generate elevated levels of cytokines that may generate elevated levels of cytokines that may
activate activate anergized auto-reactive T-cell anergized auto-reactive T-cell
2. Activation of anergized auto-2. Activation of anergized auto-reactive T-cellreactive T-cell
Infection is frequently associated with Infection is frequently associated with development of autoimmunity…Why?development of autoimmunity…Why?
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Tolerance to self protein can be induced by Tolerance to self protein can be induced by regulatory (suppressor)regulatory (suppressor) cells which diminish the cells which diminish the
activity of possible auto-reactive T cells.activity of possible auto-reactive T cells.
Decrease in no. of regulatory cells (as Decrease in no. of regulatory cells (as happen happen with agewith age) ) Increases the risk of activation of Increases the risk of activation of
auto-reactive T cells auto-reactive T cells Autoimmunity. Autoimmunity.
3. Loss of suppression of auto-reactive 3. Loss of suppression of auto-reactive T cellsT cells
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Self ProteinsSelf Proteins
Formation of neoantigen to immune system Formation of neoantigen to immune system elicit immune responses elicit immune responses
4. Alteration of normal proteins4. Alteration of normal proteins
HaptenHaptenSmall molecule that stimulates the production of antibody molecules only when conjugated to a larger molecule, called a carrier molecule.
e.g. drug-induced hemolytic anemia. Drugs capable of causing hemolytic anemia include: penicillin, cephalosporins, sulfonamide, quinine
NeoantigensNeoantigens
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5. Release of sequestered antigens5. Release of sequestered antigens
Some self-molecules are normally sequestered (hidden) Some self-molecules are normally sequestered (hidden) from immune system by from immune system by specialized specialized anatomicanatomic structure: structure:
• Certain tissuesCertain tissues (sperm, lens). (sperm, lens).
Release or exposure of the hidden self-molecules to immune Release or exposure of the hidden self-molecules to immune system & elicit immune responses.system & elicit immune responses.
Damage by Infection-Chemical-Radiation….
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ClassificationsClassificationsClassificationsClassifications
OrganOrgan-specific-specific Non-organNon-organ-specific-specific
ONE organ is subjected to
immunological attack
ONE organ is subjected to
immunological attack
MORE than one organ is subjected to immunological attack
(i.e. systemic or diffuse)
MORE than one organ is subjected to immunological attack
(i.e. systemic or diffuse)
Crohn’s disease (intestine)Hashimoto’s thyroiditisGraves diseaseT1DM (insulin-dependant)
Crohn’s disease (intestine)Hashimoto’s thyroiditisGraves diseaseT1DM (insulin-dependant)
SLERheumatoid arthritisSLERheumatoid arthritis
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ClassificationsClassificationsClassificationsClassifications
Humoral-associated autoimmune disease
Cell mediated-autoimmune disease
Pernicious anemiaMyasthenia gravisHashimoto’s thyroiditisGraves diseaseSystemic lupus erythematosus
Pernicious anemiaMyasthenia gravisHashimoto’s thyroiditisGraves diseaseSystemic lupus erythematosus
Insulin dependent diabetes mellitusCrohn’s diseaseMultiple sclerosis
Insulin dependent diabetes mellitusCrohn’s diseaseMultiple sclerosis
N.B Rheumatiod arthritis provides an example of autoimmune disease that involves both humoral and cell-mediated injury
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Therapeutic UsesTherapeutic UsesTherapeutic UsesTherapeutic Uses
Used to Used to the immune the immune responseresponse in in
TransplantationTransplantation
Autoimmune diseases Autoimmune diseases
ImmunoImmunosuppressive Drugssuppressive DrugsImmunoImmunosuppressive Drugssuppressive Drugs
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Common Adverse EffectsCommon Adverse EffectsCommon Adverse EffectsCommon Adverse Effects
Nonspecifically suppress the Nonspecifically suppress the entire immune system entire immune system
risks ofrisks ofInfections Infections
Cancers Cancers
ImmunoImmunosuppressive Drugssuppressive DrugsImmunoImmunosuppressive Drugssuppressive Drugs
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Drug ClassesDrug ClassesDrug ClassesDrug Classes
2. 2. Calcineurin Calcineurin inhibitorsinhibitors
3. 3. Antiproliferative/antimetabAntiproliferative/antimetab
olitesolites4. 4. Antibodies/Fusion Antibodies/Fusion proteinsproteins
1. 1. GlucocorticoidsGlucocorticoids
ImmunoImmunosuppressive Drugssuppressive DrugsImmunoImmunosuppressive Drugssuppressive Drugs
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It is a cytoplasmic It is a cytoplasmic phosphatasephosphatase enzyme enzyme involved in antigen-triggered synthesis of IL-2involved in antigen-triggered synthesis of IL-2
(& IL-2R & other cytokines as IL-3, IFN-(& IL-2R & other cytokines as IL-3, IFN-))
It is a cytoplasmic It is a cytoplasmic phosphatasephosphatase enzyme enzyme involved in antigen-triggered synthesis of IL-2involved in antigen-triggered synthesis of IL-2
(& IL-2R & other cytokines as IL-3, IFN-(& IL-2R & other cytokines as IL-3, IFN-))
T cells growth and T cells growth and differentiation. differentiation.
What is calcineurin? What is calcineurin?
e.g. Cyclosporin(CsA) - Tacrolimus (TAC)
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PIP2DAG
IP3
[Ca2+]
PLPLCC
TCRTCR
PKC
DAG
NFATNFATnn
CalcineurinCalcineurinNFATNFAT
ccNFATNFAT
ccPO4
NFATNFATcc
IL-2 gene
IL-2
AgWhat is calcineurin? What is calcineurin?
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inactive active
Phosphorylated NFAT (Nuclear
Factor of Activated T
Lymphocytes)
Calcineurin
(phosphatase)
Dephosphorylated NFAT
Mechanism of actionMechanism of action
Cyclosporin Tacrolimus
immunophilins
(-)
Nucleus
NFAT-GENE complex
(+)
↑ IL-2 synthesis
Prototypic T-cells growth and
differentiation factor
(+)cyclophilin FKBP-12
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PIP2DAG
IP3
[Ca2+]
PLPLCC
TCRTCR
PKC
DAG
NFATNFATnn
CalcineurinCalcineurin
NFATNFATcc
NFATNFATcc
PO4
IL-2 gene
CalcineuCalcineurin rin
InhibitoInhibitorr
ImmunophillinImmunophillin
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Cyclosporine - TacrolimusCyclosporine - Tacrolimus
NephrotoxicityNephrotoxicity (major) (major) HepatotoxicityHepatotoxicity
Renal & Liver functions should be Renal & Liver functions should be periodically monitored periodically monitored
NeurotoxicityNeurotoxicity (tremor, hallucinations, (tremor, hallucinations, seizures).seizures).
HyperglycemiaHyperglycemia & diabetes & diabetes
Adverse EffectsAdverse EffectsAdverse EffectsAdverse Effects
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Cyclosporine - TacrolimusCyclosporine - Tacrolimus
HypertensionHypertension
Hyperkalemia Hyperkalemia avoid use of K-sparing avoid use of K-sparing diuretics.diuretics.
Anaphylactoid reactions Anaphylactoid reactions
HirsutismHirsutism
Gum hyperplasiaGum hyperplasia
HypercholesterolemiaHypercholesterolemia
Hyperuricemia Hyperuricemia
Adverse EffectsAdverse EffectsAdverse EffectsAdverse Effects
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CsACsA TACTACPotencyPotency 1x 100x100x
GC co-administrationGC co-administrationHigher dose
required
Lower dose Lower dose required required SE of GCsSE of GCs
NephrotoxicityNephrotoxicity + ++
Blood glucoseBlood glucose Glucose intolerance
DM
Hirsutism Hirsutism + --
Gum hyperplasiaGum hyperplasia + --
HypercholesterolemiHypercholesterolemiaa
+ --
HyperuricemiaHyperuricemia + --
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Cyclosporine - TacrolimusCyclosporine - Tacrolimus
Co-administration of NSAIDs and any drug that causes Co-administration of NSAIDs and any drug that causes nephrotoxicitynephrotoxicity nephrotoxicitynephrotoxicity
Cyclosporine + tacrolimusCyclosporine + tacrolimus nephrotoxicity (Wait for at least nephrotoxicity (Wait for at least 24h24h if switching if switching from cyclosporine to tacrolimus).from cyclosporine to tacrolimus).
Calcineurin inhibitors especially tacrolimus + Calcineurin inhibitors especially tacrolimus + glucocorticoidsglucocorticoids risk of diabetes. risk of diabetes.
Drug InteractionsDrug InteractionsDrug InteractionsDrug Interactions
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Sirolimus Sirolimus (Rapamycin)(Rapamycin)
EverolimusEverolimus
mTORmTOR inhibitors
mTORmTOR inhibitors
PurinePurine synthesis inhibitors
PurinePurine synthesis inhibitors
AzathioprineAzathioprine
Mycophenolate Mycophenolate mofetilmofetil
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mTORmTOR: : mmammalian ammalian TTarget arget OOf f RRapamycinapamycin
A key A key protein kinase enzymeprotein kinase enzyme responsible for responsible for cell-cycle progression cell-cycle progression Cell proliferationCell proliferation
What is mTOR? What is mTOR?
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IL-2RIL-2R
mTORImTORIImmunophillinImmunophillin
IL-2IL-2
ProliferationProliferation
mTOmTORR
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Sirolimus - Sirolimus - EverolimusEverolimus Mechanism of Mechanism of
actionactionMechanism of Mechanism of
actionaction
Blocks cell-cycle progressionBlocks cell-cycle progression induced by IL-2 & other T-cell induced by IL-2 & other T-cell
growth factors. growth factors. (Inhibits the cellular response to (Inhibits the cellular response to
IL-2)IL-2)
Sirolimus immunophilins
G1
(-)mTOR
S
FKBP-12
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Hypercholesterolemia (may Hypercholesterolemia (may require ttt) require ttt)
Myelosuppression Myelosuppression anemia, leukopenia, anemia, leukopenia, thrombocytopeniathrombocytopenia
Fever, delayed wound healing, & Fever, delayed wound healing, & GIT effects.GIT effects.
An additional adverse effect noted An additional adverse effect noted with everolimus is angioedemawith everolimus is angioedema
Adverse Adverse EffectsEffects
Adverse Adverse EffectsEffects
Sirolimus - Sirolimus - EverolimusEverolimus
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Cyclosporine + sirolimusCyclosporine + sirolimusSirolimusSirolimus cyclosporine-induced cyclosporine-induced nephrotoxicity.nephrotoxicity.Cyclosporine Cyclosporine sirolimus-induced sirolimus-induced hyperlipidemia & myelosuppression.hyperlipidemia & myelosuppression.(Administration of two drugs should be separated (Administration of two drugs should be separated by time). by time).
Drug InteractionsDrug InteractionsDrug InteractionsDrug Interactions
Sirolimus - Sirolimus - EverolimusEverolimus
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AzathioprinAzathioprinee
Azathioprine Azathioprine 6-mercaptopurine 6-mercaptopurine
lymphocyte lymphocyte proliferationproliferation. .
Mechanism of Mechanism of actionaction
Mechanism of Mechanism of actionaction
de novo de novo purinepurine synthesis synthesis
↓ ↓ DNA synthesis DNA synthesis (S-phase)
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Myelosuppression Myelosuppression leukopenia (common),leukopenia (common),thrombocytopenia (less common),thrombocytopenia (less common),&/or anemia&/or anemia (uncommon).(uncommon).
Hepatotoxicity (mild)Hepatotoxicity (mild)
Alopecia, skin eruptionsAlopecia, skin eruptions
GIT toxicity (N,V) GIT toxicity (N,V)
Pancreatitis Pancreatitis
Adverse Adverse EffectsEffects
Adverse Adverse EffectsEffects
AzathioprinAzathioprinee
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+ Allopurinol+ Allopurinol xanthine oxidase inhibitor xanthine oxidase inhibitor level of azathioprine …SO….. azathioprine level of azathioprine …SO….. azathioprine dose must be decreased or avoid these dose must be decreased or avoid these combination). combination).
Drug InteractionsDrug InteractionsDrug InteractionsDrug Interactions
AzathioprinAzathioprinee
Azathioprine 6-MP
6-thiouric acid urine
Xan OxXan Ox
+ Myelosuppressive drugs+ Myelosuppressive drugs risk of risk of myelosuppressionmyelosuppression
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Mycophenolate Mycophenolate mofetilmofetil
Mycophenolate Mycophenolate mofetilmofetil
lymphocyte lymphocyte proliferation & functionproliferation & function
Mechanism of Mechanism of actionaction
Mechanism of Mechanism of actionaction
de novo de novo guanineguanine synthesissynthesis
Selective, non-competitive, reversible inhibition forSelective, non-competitive, reversible inhibition for inosine monophosphate dehydrogenaseinosine monophosphate dehydrogenase
Mycophenolic acid (MPA) (Active drug)Mycophenolic acid (MPA) (Active drug)
Mycophenolate mofetil (Prodrug)Mycophenolate mofetil (Prodrug)
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B & T lymphocytes are highly dependent on B & T lymphocytes are highly dependent on de novo de novo purine purine biosynthesis pathway for cell biosynthesis pathway for cell
proliferation, while other cell types can proliferation, while other cell types can generate purines through other pathways generate purines through other pathways
B & T lymphocytes are highly dependent on B & T lymphocytes are highly dependent on de novo de novo purine purine biosynthesis pathway for cell biosynthesis pathway for cell
proliferation, while other cell types can proliferation, while other cell types can generate purines through other pathways generate purines through other pathways
Mycophenolate Mycophenolate mofetilmofetil
Mycophenolate Mycophenolate mofetilmofetil Mechanism of Mechanism of
actionactionMechanism of Mechanism of
actionaction
Adverse Effects: GIT effects, leukopenia and anemia
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Genetically engineered protein molecules
1. Antibodies
2. Fusion proteins
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PolyPolyclonclonalal
PolyPolyclonclonalal
MonoMonoclonalclonalMonoMonoclonalclonal
Against Against severalseveral
antigens on surface antigens on surface
of lymphocytes or of lymphocytes or thymocytesthymocytes
(CD3,CD4,CD8, TCR)(CD3,CD4,CD8, TCR)
Against specific
antigen on surface antigen on surface
of lymphocytes
Against specific
cytokinecytokine or
serum componentserum component
Example:Example:
Antithymocyte Antithymocyte globulin -globulin -
Antilymphocyte Antilymphocyte globulinglobulin
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NomenclatureNomenclatureNomenclatureNomenclature
HumanHumanAnimalAnimal HumanizedHumanizedChimericChimeric
…….ximab…….ximab …….zumab…….zumab …….umab…….umab…….omab…….omab
…….amab…….amab
…….emab…….emab
More antigenicMore antigenic less antigenicless antigenic
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Mechanism of Mechanism of actionaction
Mechanism of Mechanism of actionaction
Lymphocyte cytotoxicity (complement-
mediated and cell-mediated)
Lymphocyte cytotoxicity (complement-
mediated and cell-mediated)
Lymphocyte function
block
Lymphocyte function
block
Against surface Against surface antigens on antigens on lymphocytelymphocyte
Against Against cytokine or cytokine or
serum serum componentscomponents
Block function of cytokine or
serum component
Block function of cytokine or
serum component
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1. Antithymocyte globulin:
• Source: IgG from serum of rabbits immunized with human thymocytes.
• Mechanism: direct cytotoxicity to circulating lymphocytes ➙ by direct cytotoxicity (both complement and cell-mediated) and block lymphocyte function
PolyclonalPolyclonal
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1. Muromonab-CD3:
Source: mouse monoclonal antibodies.
• Mechanism: Binding to the CD3 protein results in a disruption of T-lymphocyte function, because access of antigen to the recognition site is blocked.
• Depletion of lymphocytes due to direct cytotoxicity.
MonoMonoclonalclonalAgainst antigen on surface antigen on surface of lymphocytes
MonoMonoclonalclonalAgainst antigen on surface antigen on surface of lymphocytes
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Adverse Adverse EffectsEffects
Adverse Adverse EffectsEffects
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2. IL-2 receptor antagonist(Daclizumab and Basiliximab).• Binds to IL-2 receptors → ↓ IL-2-induced T
lymphocytes activation.• Basiliximab is about 10-fold more potent than
daclizumab
3. IL-1 receptor antagonist (Anakinra)• it binds to the IL-1 receptors → preventing actions
of IL-1.• Anakinra treatment leads to a modest reduction
in the signs and symptoms of moderately to severely active rheumatoid arthritis
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1. Anti-TNF reagents (Infliximab, Adalimumab)
• Mechanism: Binds to TNF-α → prevent binding of TNF-α to its receptor → inhibits its pro-inflammatory effects
• used in rheumatoid arthritis.
MonoMonoclonalclonal Against cytokinecytokine
MonoMonoclonalclonal Against cytokinecytokine
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SolubleSoluble human human TNF-TNF- receptor receptor Fused to Fused to
FcFc domain of human domain of human IgGIgG
Binds to TNF-Binds to TNF-
Prevents interaction of TNF-Prevents interaction of TNF- with its with its receptorsreceptors
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APC
TH
IL-2
IL-2 R
Cell cycle progressionG1-S
T cell proliferation
Macrophage
Antithymocyte globulinMuromonab
Inhibit IL-2 synthesis
-
Destruction of T lymphocytes
-
Calcineurin inhibitorsCyclosporine - TacrolimusCyclosporine - Tacrolimus
Block IL-2 receptors (Daclizumab-Basiliximab)
IL-1, TNF-α
Chronic inflammatory tissue injury
Block cytokine stimulated cell proliferation
-
mTOR inhibitorsSirolimus and everolimus
Inhibit purine synthesis
-
AzathioprineMycophenolate mofetil
-Anti IL-1 receptorAnakinra -
Anti TNF-αInfliximab, AdalimumabEtanercept