IMMUNOMODULATORS Dr. Ahmed M. Alafeefy. The Immune Response - why and how ? Discriminate: Self / Non...

Dr. Ahmed M. Alafeefy

The Immune Response - why and how ?Discriminate: Self / Non selfDestroy:

Infectious invadersDysregulated self (cancers)

Immunity:Innate, NaturalAdaptive, Learned

• Innate immune response – first line of defense against an antigenic

insult. Includesdefenses like physical (skin), Biochemical (complement, lysozyme,

interferons)cellular components (neutrophils, monocytes,macrophages).

• Adaptive immune responsea) Humoral immunity - Antibody production –killing extracellular organisms.b) Cell mediated immunity – cytotoxic / killer Tcells – killing virus and tumour cells.

Who are involved ?Innate

ComplementGranulocytesMonocytes/macrophages

NK cellsMast cellsBasophils

Adaptive: B and T lymphocytes

B: antibodiesT : helper, cytolytic, suppressor.

ABNORMAL IMMUNERESPONSE

• Hypersensitivity reactionsType 1 – Anaphylactic shockType 2 – mismatched blood transfusionType 3 – Serum Sickness,

glomerulonephritis and arthritis.Type 4 – TB, leishmaniasis.

Autoimmunity – Autoimmune diseases arisewhen the body mounts an immune responseagainst itself as a result of failure to

distinguish self tissues and cells from foreign antigens.

Rheumatoid Arthritis, S.L.E, Type 1 Diabetes Mellitus, Multiple Sclerosis etc….

• Immunodeficiency Diseasesa) Congenital – Di George’s syndrome, SCID

due to ADA deficiency.b) Extrinsic – HIV causing AIDS.

DEFINITIONImmunomodulators are drugs whicheither suppress the immune system – Immunosuppressants

orstimulate the immune system – Immunostimulants

ImmunosuppressantsGlucocorticoids - Prednisolone.Calcineurin inhibitors

CyclosporineTacrolimus

Antiproliferative / antimetabolic agentsSirolimusEverolimusAzathioprineMycophenolate MofetilOthers – methotrexate, cyclophosphamide,

thalidomide and chlorambucil , Interferon

AntibodiesAntithymocyte globulinAnti CD3 monoclonal antibody

Muromonab Anti IL-2 receptor antibody –

Daclizumab, basiliximabAnti TNF alpha – infliximab, etanercept

ImmunosuppressantsOrgan transplantationAutoimmune diseases Problem Life long use Infection, cancers Nephrotoxicity Diabetogenic

GlucocorticoidsInduce 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 - GlucocorticoidsTransplant rejection GVH – BM transplantationAutoimmune diseases – RA, SLE,

Hematological conditionsPsoriasisInflammatory Bowel Disease, Eye

conditions

ToxicityGrowth retardationAvascular Necrosis of BoneRisk of InfectionPoor wound healingCataractHyperglycemiaHypertension

CALCINEURIN INHIBITORS• Calcineurin (CN) is a protein phosphatase

activates the T cells of the immune system and can be blocked by drugs.

Cyclosporine –

– bind to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophilin inhibits the phosphatase calcineurin, which under normal circumstances induces the transcription of interleukin-2.

The drug also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.

UsesOrgan transplantation: Kidney, Liver, Heart

Rheumatoid arthritis, IBD, uveitis

PsoriasisAplastic anemiaSkin Conditions- Atopic dermatitis, Alopecia Areata, Pemphigus vulgaris, Lichen planus, Pyoderma gangrenosum

Toxicity : CyclosporineRenal dysfunctionTremorHirsuitismHypertensionHyperlipidemiaGum hyperplasiaHyperuricemia – worsens goutCalcineurin inhibitors +

Glucocorticoids = Diabetogenic

Tacrolimus ( FK 506, Prograf )– It binds to the immunophilin FKBP1A,

followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than ciclosporin and has less pronounced side-effects.

Use-Prophylaxis of solid-organ allograft

rejection –Topical preparation available for use in

atopic dermatitis and psoriasis.

Toxicity - TacrolimusNephrotoxicityNeurotoxicity-Tremor, headache,

motor disturbances, seizuresGI ComplaintsHypertensionHyperglycemiaRisk of tumors, infections

Sirolimus (rapamycin, trade name Rapamune) Contrary to ciclosporin and tacrolimus,

drugs that affect the first phase of T lymphocyte activation, sirolimus affects the second one( namely signal transduction and lymphocyte clonal proliferation).

It binds to FKBP1A like tacrolimus, however the complex does not inhibit calcineurin but another protein, mTOR (mammalian target of rapamycin ).

It indirectly inhibits several T lymphocyte-specific kinases and phosphatases, hence preventing their transition from G1 to S phase of the cell cycle.

Sirolimus prevents B cell differentiation into plasma cells,

reducing production of IgM, IgG, and IgA antibodies.

CELL CYCLE

SirolimusUsesProphylaxis of organ transplant

rejection with other drugs

ToxicityIncrease in serum cholesterol,

TriglyceridesAnemiaThrombocytopeniaHypokalemiaFeverGI effects Risk of infection, tumors

Azathioprine (Imuran )the main immunosuppressive cytotoxic

substance. It is nonenzymatically cleaved to mercaptopurine, that acts as a purine analogue and an inhibitor of DNA synthesis.

By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity.

UsesPrevention of organ transplant rejectionRheumatoid arthritis

Toxicity - Azathioprine Bone marrow suppression-

leukopenia, thrombocytopenia, anemiaIncreased susceptibility to infectionHepatotoxicityAlopeciaGI toxicity

Drug interaction: Allopurinol

Mycophenolate MofetilProdrug Mycophenolic acid Inhibits IMPDH – enzyme in guanine

synthesis (Inosine monophosphate dehydrogenase (IMPDH) is a major target for both antitumor and immunosuppresive drug design.)

T, B cells are highly dependent on this pathway for cell proliferation

Selectively inhibits lymphocyte proliferation, function , Antibody formation, cellular adhesion, migration

Uses - Mycophenolate MofetilProphylaxis of transplant rejectionCombination: Glucocorticoids

Calcineurin Inhibitors

ToxicityGI, Hematological

Diarrhea, Leucopenia Risk of Infection

Drug InteractionDecreased absorption when co-administered with antacids

Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion

AntibodiesAgainst

lymphocyte cell-surface antigens

Polyclonal / Monoclonal

AntibodiesAntithymocyte GlobulinMonoclonal antibodies

Anti-CD3 Monoclonal antibody (Muromonab-CD3)

Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab)

Campath-1H (Alemtuzumab) Anti-TNF Agents

InfliximabEtanerceptAdalimumab

LFA-1 Inhibitor (lymphocyte function associated)Efalizumab

Anti-thymocyte GlobulinPurified gamma globulin from serum

of rabbits immunized with human thymocytes

Cytotoxic to lymphocytes & block lymphocyte function

UsesInduction of immunosuppression –

transplantationTreatment of acute transplant

rejection

ToxicityHypersensitivity Risk of infection, Malignancy

Anti-CD3 Monoclonal Antibody(Muromonab-CD3 )Binds to CD3, a component of T-cell receptor complex involved inantigen recognitioncell signaling & proliferation

UsesTreatment of acute organ transplant rejection

Toxicity“Cytokine release syndrome” High fever, Chills, Headache, Tremor, myalgia, arthralgia, weakness

Prevention: Steroids

Cytokine release syndromeis a common immediate complication

occurring with the use of anti-T cell antibody infusions such as ATG, OKT3

The pathogenesis is that the antibodies bind to the T cell receptor, activating the T cells before they are destroyed. The cytokines released by the activated T cells produce a type of systemic inflammatory response similar to that found in severe infection characterised by hypotension, pyrexia and rigors.

the cytokine release syndrome is effectively a type of non-infective fever.

Anti-IL-2 Receptor Antibodies (Daclizumab and Basiliximab )

Bind 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

Anti-TNF AgentsTNF – Cytokine at site of inflammation

InfliximabEtanerceptAdalimumab

InfliximabUsesRheumatoid arthritisChron’s disease – fistulaePsoriasisPsoriatic arthritis Ankylosing spondylosis

ToxicityInfusion reaction – fever, urticaria,

hypotension, dyspnoeaOpportunistic infections – TB, RTI, UTI

EtanerceptFusion protein produced through

expression of recombinant DNA.Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1

UsesRheumatoid arthritis

Uses :moderate to severely active crohn’s disease

Adalimumab Adalimumab

Recombinant human anti-TNF mAbRecombinant human anti-TNF mAb

LFA-1 Inhibitor - EfalizumabMonoclonal Ab Targeting Lymphocyte Function Associated Antigen

Blocks T-cell Adhesion, Activation, Trafficking

UsesOrgan transplantationPsoriasis

Glucocorticoids – Lympholytic activity,

antiinflammatory property.• Used as 1st line immunosuppressive

therapy in solid and heamatopoietic stem cell transplant, ITP, RA etc….

• Sirolimus – inhibits protein kinase and inhibits T

cell response to IL-2.– Blocks cell cycle progression

SUMMARY

Thalidomide – inhibits angiogenesis, reducesphagocytosis, enhances cell mediated

immunity

– Increases levels of IL-10.

– Used in multiple myeloma, graft versus hostdisease, myelodysplastic syndrome, colon and prostrate Cancer.• Mycophenolate Mofetil – mycophenolic acid– Inhibits inosine monophosphatedehydrogenase which is a key enzyme inguanine nucleotide synthesis.– Used in steroid refractory GVHD, RA, SLE.

Leflunomide – it inhibits pyrimidine synthesis.Used in RA.• Cyclophosphamide – alkylating agent whichdestroys proliferating lymphoid cells. Used in

SLE, autoimmune haemolytic anaemia, multiple sclerosis, Wegener’s granulomatosis.

• Muromonab CD3 – T cell receptor complex( blocks Ag recognition ).– Used in steroid resistant rejection.• Daclizumab, Basiliximab – IL-2 receptor

(blocks IL-2 mediated T cell activation ).– Used in acute organ rejection in renal

transplant patients.

Azathioprine ( Mercaptopurine )– interferes with purine nucleic acid

metabolism and incorporates false nucleotide.

–Used in Renal allograft, RA, SLE, ITP, Crohn’s disease, glomerulonephritis

Interferons - IFN alpha- immune enhancing action

- melanoma.– IFN beta - multiple sclerosis– IFN gamma - chronic granulomatous

disease.

Immunostimulants

USES:

immunodeficiency disorders

Chronic infections cancer

specific ImmunostimulantsLevamisoleThalidomideBCGRecombinant Cytokines

Interferons Interleukin-2

Other drugs – inosiplex, azimexon, imexon, thymosin, methylinosine monophosphateImmunization Vaccines , Immune Globulin , Rho (D) Immune

Globulin

LevamisoleAntihelminthicRestores depressed immune function of

B, T cells, Monocytes, Macrophages USES:Adjuvant therapy with 5FU in colon

cancer Used to treat immunodeficiency

associated with Hodgkins disease.Toxicity

Agranulocytosis

ThalidomideBirth defectContraindicated in women with

childbearing potentialEnhanced T-cell production of

cytokines – IL-2, IFN-γ NK cell-mediated cytotoxicity

against tumor cells

USE:Multiple myeloma

Bacillus Calmette-GuerinLive, attenuated culture of BCG strain

of Mycobacterium BovisIt causes activation of macrophages to

make them more effective killer cells.used as intravesical therapy for

superficial bladder cancer.Adverse Effects HypersensitivityShockChills

InterferonsAntiviralImmunomodulatory activityBind to cell surface receptors –

initiate intracellular eventsEnzyme inductionInhibition of cell proliferationEnhancement of immune activitiesIncreased Phagocytosis

Interferon alfa-2bHairy 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 carcinomaMelanoma ToxicityCardiovascular: capillary leak

syndrome, Hypotension

Capillary leak syndrome(systemic capillary leak syndrome or

Clarkson syndrome) A rare medical condition where the

number and size of the pores in the capillaries are increased which leads to a leakage of fluid from the blood to the interstitial fluid, resulting in dangerously low blood pressure (hypotension), edema and multiple organ failure due to limited perfusion.

Immunization

Active – Stimulation with an Antigen

Passive – Preformed antibody

Active immunization

VaccinesAdministration of antigen as a whole,

killed organism, or a specific protein or peptide constituent of an organism

Booster dosesAnticancer vaccines: Vaccinating patients with autologous

antigen presenting cells (APC) expressing tumor-associated antigens (TAA)

Immune GlobulinIndicationsIndividual is deficient in antibodies –

immunodeficiencyIndividual is exposed to an agent,

inadequate time for active immunizationRabiesHepatitis B

Nonspecific immunoglobulinsAntibody-deficiency disorders

Specific immune globulinsHigh titers of desired antibody

Hepatitis B, Rabies, Tetanus

Rho (D) Immune GlobulinAntibodies against Rh(D)

antigen on the surface of RBC

prevent the immunological condition known as Rhesus disease (or hemolytic disease of newborn).

treating chronic idiopathic thrombocytopenic purpura in Rh-positive patients who have not been splenectomized