immuno-pharmacology dr. dalia el tanbouly. immunopharmacology: study of drugs that modulate immune...

Immuno-PharmacologyImmuno-Pharmacology

Dr. Dalia El Tanbouly

• 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).

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.

Types of Immune Response:

Innate (natural):• 1st line defense • Non-specific.

Adaptive (acquired): • Specific.• Have memory.• Subdivided into:

– Humoral (B-lymphocytes).– Cellular (T-lymphocytes).

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

• Onset upon re-exposure: the same.

• Memory: Absent

• Onset upon re-exposure: quicker.

• Memory Present

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.

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

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.

Abnormal Immune Response:

• Abnormal impaired immune response → Immunodeficiency.

• Abnormal exaggerated immune response: Hypersensitivity reactions. Autoimmune diseases.

Antibody - Antibody - mediatedmediated

Cell - mediatedCell - mediated

TypeType VI: VI: DTHDTHType I: Atopy, Allergy, Anaphylactic HS,

immediate

Type II: Cytotoxic

Type III: Immune complex

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)

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

Synthesis & release of:

• Arachidonic acid metabolites Arachidonic acid metabolites

LTsLTs PGs - TXPGs - TX

Lipoxygenase

Cyclo-oxygenase

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

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

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 .

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

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

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

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)

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

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)

MechanismMechanism

(Immune Complex)

Self moleculeSelf molecule Non-self moleculeNon-self molecule

Antibody-mediated AID

(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

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

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)

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

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)

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?

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

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?

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

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

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….

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

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

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

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

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

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)

PIP2DAG

IP3

[Ca2+]

PLPLCC

TCRTCR

PKC

DAG

NFATNFATnn

CalcineurinCalcineurinNFATNFAT

ccNFATNFAT

ccPO4

NFATNFATcc

IL-2 gene

IL-2

AgWhat is calcineurin? What is calcineurin?

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

PIP2DAG

IP3

[Ca2+]

PLPLCC

TCRTCR

PKC

DAG

NFATNFATnn

CalcineurinCalcineurin

NFATNFATcc

NFATNFATcc

PO4

IL-2 gene

CalcineuCalcineurin rin

InhibitoInhibitorr

ImmunophillinImmunophillin

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

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

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 + --

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

Sirolimus Sirolimus (Rapamycin)(Rapamycin)

EverolimusEverolimus

mTORmTOR inhibitors

mTORmTOR inhibitors

PurinePurine synthesis inhibitors

PurinePurine synthesis inhibitors

AzathioprineAzathioprine

Mycophenolate Mycophenolate mofetilmofetil

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?

IL-2RIL-2R

mTORImTORIImmunophillinImmunophillin

IL-2IL-2

ProliferationProliferation

mTOmTORR

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

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

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

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)

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

+ 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

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)

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

Genetically engineered protein molecules

1. Antibodies

2. Fusion proteins

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

NomenclatureNomenclatureNomenclatureNomenclature

HumanHumanAnimalAnimal HumanizedHumanizedChimericChimeric

…….ximab…….ximab …….zumab…….zumab …….umab…….umab…….omab…….omab

…….amab…….amab

…….emab…….emab

More antigenicMore antigenic less antigenicless antigenic

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

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

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

Adverse Adverse EffectsEffects

Adverse Adverse EffectsEffects

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

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

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

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