Chapter IV

Immunopharmacology

YEAR III Pharm.DDr. V. Chitra

The Immune Response - why and how ?

Discriminate: Self / Non selfDestroy:

Infectious invadersDysregulated self (cancers)

Immunity:Innate, NaturalAdaptive, Learned

Who are involved ?

InnateComplementGranulocytesMonocytes/macrophagesNK cellsMast cellsBasophils

Adaptive:B and T lymphocytesB: antibodiesT : helper, cytolytic, suppressor.

IMMUNE MODIFIERS

Immunosuppressants Immunostimulants

? Immune tolerance

Immunosuppressants

Organ transplantationAutoimmune diseases

Life long useInfection, cancersNephrotoxicityDiabetogenic

Problem

ImmunosuppressantsGlucocorticoids Calcineurin inhibitors

CyclosporineTacrolimus

Antiproliferative / antimetabolic agentsSirolimusEverolimusAzathioprineMycophenolate MofetilOthers – methotrexate, cyclophosphamide, thalidomide and chlorambucil

AntibodiesAntithymocyte globulinAnti CD3 monoclonal antibody

Muromonab

Anti IL-2 receptor antibody –Daclizumab, basiliximab

Anti TNF alpha – infliximab, etanercept

Glucocorticoids

Induce redistribution of lymphocytes –decrease in peripheral blood lymphocyte counts Intracellular receptors – regulate gene transcription Down regulation of IL-1, IL-6Inhibition of T cell proliferation Neutrophils, Monocytes display poor chemotaxisBroad anti-inflammatory effects on multiple components of cellular immunity

USES - Glucocorticoids

Transplant rejectionGVH – BM transplantationAutoimmune diseases – RA, SLE, Hematological conditionsPsoriasisInflammatory Bowel Disease, Eye conditions

Toxicity

Growth retardationAvascular Necrosis of BoneRisk of InfectionPoor wound healingCataractHyperglycemiaHypertension

Calcineurin inhibitors

CyclosporineTacrolimus

Most effective immunosuppressive drugsTarget intracellular signaling pathwaysBlocks Induction of cytokine genes

CyclosporineMore effective against T-cell dependent immune mechanisms – transplant rejection, autoimmunityIV, Oral

UsesOrgan transplantation: Kidney, Liver, HeartRheumatoid arthritis, IBD, uveitisPsoriasisAplastic anemiaSkin Conditions- Atopic dermatitis, Alopecia Areata, Pemphigus vulgaris, Lichen planus, Pyoderma gangrenosum

Toxicity : Cyclosporine

Renal dysfunctionTremorHirsuitismHypertensionHyperlipidemiaGum hyperplasiaHyperuricemia – worsens goutCalcineurin inhibitors + Glucocorticoids = Diabetogenic

Drug Interaction : Cyclosporine

CYP 3A4Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juiceInducers: Rifampicin, Phenytoin

Additive nephrotoxicity: NSAIDs

Tacrolimus

Inhibits T-cell activation by inhibiting calcineurinUse

Prophylaxis of solid-organ allograft rejection

Toxicity - TacrolimusNephrotoxicityNeurotoxicity-Tremor, headache, motor disturbances, seizuresGI ComplaintsHypertensionHyperglycemiaRisk of tumors, infections

Drug interactionSynergistic nephrotoxicity with cyclosporineCYP3A4

Antiproliferative and Antimetabolic drugs

SirolimusEverolimusAzathioprineMycophenolate MofetilOthers:

MethotrexateCyclophosphamideThalidomideChlorambucil

Sirolimus

Inhibits T-cell activation and ProliferationComplexes with an immunophilin, Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR)

SirolimusUses

Prophylaxis of organ transplant rejection along with other drugs

ToxicityIncrease in serum cholesterol, TriglyceridesAnemiaThrombocytopeniaHypokalemiaFeverGI effects Risk of infection, tumors

Drug Interactions: CYP 3A4

Everolimus

Shorter half life compared to sirolimusShorter time taken to reach steady stateSimilar toxicity, drug interactions

AzathioprinePurine antimetaboliteIncorporation of false nucleotide

6 Thio-IMP 6Thio-GMP 6Thio-GTP

Inhibition of cell proliferationImpairment of lymphocyte function

UsesPrevention of organ transplant rejectionRheumatoid arthritis

Toxicity - Azathioprine

Bone marrow suppression-leukopenia, thrombocytopenia, anemiaIncreased susceptibility to infectionHepatotoxicityAlopeciaGI toxicity

Drug interaction: Allopurinol

Mycophenolate Mofetil

Prodrug Mycophenolic acid Inhibits IMPDH – enzyme in guanine synthesisT, B cells are highly dependent on this pathway for cell proliferationSelectively inhibits lymphocyte proliferation, function – Antibody formation, cellular adhesion, migration

Uses - Mycophenolate Mofetil

Prophylaxis of transplant rejectionCombination: Glucocorticoids

Calcineurin Inhibitors

ToxicityGI, Hematological

Diarrhea, Leucopenia

Risk of Infection

Drug Interaction

Decreased absorption when co-administered with antacidsAcyclovir, Gancyclovir compete with mycophenolate for tubular secretion

FTY720

S1P-R agonist – sphingosine 1 receptorReduce recirculation of lymphocytes from lymphatic system to blood and peripheral tissues“Lymphocyte homing” – periphery into lymph nodeProtects graft from T-cell-mediated attack UsesCombination immunosuppression therapy in prevention of acute graft rejection

Toxicity

LymphopeniaNegative chronotropic effect

S1P-receptor on human atrial myocytes

Antibodies

Against lymphocyte cell-surface antigensPolyclonal / Monoclonal

Antibodies

Antithymocyte GlobulinMonoclonal antibodies

Anti-CD3 Monoclonal antibody (Muromonab-CD3)Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab)Campath-1H (Alemtuzumab)

Anti-TNF AgentsInfliximabEtanerceptAdalimumab

LFA-1 Inhibitor (lymphocyte function associated)Efalizumab

Anti-thymocyte Globulin

Purified gamma globulin from serum of rabbits immunized with human thymocytesCytotoxic to lymphocytes & block lymphocyte function

UsesInduction of immunosuppression –transplantationTreatment of acute transplant rejection

ToxicityHypersensitivity Risk of infection, Malignancy

Anti-CD3 Monoclonal Antibody

Muromonab-CD3Binds to CD3, a component of T-cell receptor complex involved in

antigen recognitioncell signaling & proliferation

Muromonab-CD3

Antibody treatment

Rapid internalization of T-cell receptor

Prevents subsequent antigen recognition

Uses

Treatment of acute organ transplant rejection

Toxicity“Cytokine release syndrome”High fever, Chills, Headache, Tremor, myalgia, arthralgia, weaknessPrevention: Steroids

Anti-IL-2 Receptor Antibodies

Daclizumab and BasiliximabBind to IL-2 receptor on surface of activated T cells Block IL-2 mediated T-cell activation

UsesProphylaxis of Acute organ rejection

ToxicityAnaphylaxis, Opportunistic Infections

Campath-1H (Alemtuzumab)

Targets CD52 – expressed on lymphocytes, monocytes, MacrophagesExtensive lympholysis – Prolonged T & B cell depletion

UsesRenal transplantation

Anti-TNF Agents

TNF – Cytokine at site of inflammation

InfliximabEtanerceptAdalimumab

Infliximab

UsesRheumatoid arthritisChron’s disease – fistulaePsoriasisPsoriatic arthritis Ankylosing spondylosis

ToxicityInfusion reaction – fever, urticaria, hypotension, dyspnoeaOpportunistic infections – TB, RTI, UTI

EtanerceptFusion proteinLigand binding portion of Human TNF-αreceptor fused to Fc portion of human IgG1

UsesRheumatoid arthritis

Moderate to severely active crohn’s disease

Adalimumab Recombinant human anti-TNF mAb

LFA-1 Inhibitor - Efalizumab

Monoclonal Ab Targeting Lymphocyte Function Associated AntigenBlocks T-cell Adhesion, Activation, Trafficking

UsesOrgan transplantationPsoriasis

Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation

DRUG SITE OF ACTIONGlucocorticoids Glucocorticoid response elements in

DNA (regulate gene transcription)Muromonab- CD3T-cell receptor complex (blocks

antigen recognition)Cyclosporine Calcineurin (inhibits phosphatase

activity)Tacrolimus Calcineurin (inhibits phosphatase

activity)Azathioprine Deoxyribonucleic acid (false

nucleotide incorporation)Mycophenolate Mofetil Inosine monophosphate

dehydrogenase (inhibits activity)Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated

T-cell activation)Sirolimus Protein kinase involved in cell-cycle

progression (mTOR) (inhibits activity)

Immunostimulants

LevamisoleThalidomideBCGRecombinant Cytokines

InterferonsInterleukin-2

Levamisole

AntihelminthicRestores depressed immune function of B, T cells, Monocytes, MacrophagesAdjuvant therapy with 5FU in colon cancer

ToxicityAgranulocytosis

Thalidomide

Birth defectContraindicated in women with childbearing potentialEnhanced T-cell production of cytokines – IL-2, IFN-γNK cell-mediated cytotoxicity against tumor cells

USE:Multiple myeloma

Bacillus Calmette-Guerin

Live, attenuated culture of BCG strain of Mycobacterium BovisCarcinoma Bladder

Adverse Effects HypersensitivityShockChills

Interferons

AntiviralImmunomodulatory activityBind to cell surface receptors –initiate intracellular events

Enzyme inductionInhibition of cell proliferationEnhancement of immune activitiesIncreased Phagocytosis

Interferon alpha-2b

Hairy cell leukemiaMalignant melanomaKaposi sarcomaHepatitis B

Adverse reactionsFlu-like symptoms – fever, chills, headacheCVS- hypotension, ArrhythmiaCNS- depression, confusion

Interleukin-2 (aldesleukin)

Proliferation of cellular immunity –Lymphocytosis, eosinophilia, release of multiple cytokines – TNF, IL-1, IFN-γ

UsesMetastatic renal cell carcinomaMelanomaToxicityCardiovascular: capillary leak syndrome, Hypotension

Immunization

VaccinesImmune GlobulinRho (D) Immune Globulin

Immunization

Active – Stimulation with an AntigenPassive – Preformed antibody

Active immunization

VaccinesAdministration of antigen as a whole, killed organism, or a specific protein or peptide constituent of an organismBooster dosesAnticancer vaccines – immunizing patients with APCs expressing tumor antigen.

Immune Globulin

IndicationsIndividual is deficient in antibodies – immunodeficiencyIndividual is exposed to an agent, inadequate time for active immunization

RabiesHepatitis B

Nonspecific immunoglobulinsAntibody-deficiency disorders

Specific immune globulinsHigh titers of desired antibodyHepatitis B, Rabies, Tetanus

Rho (D) Immune Globulin

Antibodies against Rh(D) antigen on the surface of RBCRh-negative women may be sensitized to “Foreign” Rh antigen on fetal RBC Anti-RH Antibodies produced in mother can damage subsequent fetuses by lysing RBC’s Hemolytic disease of newborn