IMMUNOMODULATORS

The Immune Response - why and

how ?

• Discriminate: Self / Non self

• Destroy:

– Infectious invaders

–Dysregulated self (cancers)

• Immunity:

– Innate, Natural

–Adaptive, Learned

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

•defenses 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.

ABNORMAL IMMUNERESPONSE

• Hypersensitivity reactions

Type 1 – Anaphylactic shock

Type 2 –mismatched blood transfusion

Type 3 – Serum Sickness, glomerulonephritis

and arthritis.

Type 4 – TB

Autoimmunity

– Autoimmune diseases arise

when the body mounts an immune response

against itself as a result of failure to distinguishself tissues and cells from foreign antigens.

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

• Immunodeficiency Diseases

Extrinsic – HIV causing AIDS.

IMMUNOMODULATORS

DEFINITION

Immunomodulators are drugs which

either suppress the immune system –

Immunosuppressants

orstimulate the immune system –

Immunostimulants

Immunosuppressant

Immunosuppressants

• Glucocorticoids - Prednisolone.• Calcineurin inhibitors

– Cyclosporine– Tacrolimus

• Antiproliferative / antimetabolic agents

– Sirolimus– Everolimus– Azathioprine–Mycophenolate Mofetil– Others –methotrexate, cyclophosphamide,thalidomide and chlorambucil , Interferon

• Antibodies

– Antithymocyte globulin

– Anti CD3 monoclonal antibody

• Muromonab

– Anti IL-2 receptor antibody –

• Daclizumab, basiliximab

– Anti TNF alpha – infliximab, etanercept

Problem

Life long use

Infection, cancers

Nephrotoxicity

Diabetogenic

Sites of Action of Selected ImmunosuppressiveAgents on T-Cell Activation

DRUG SITE OF ACTIONGlucocorticoid response elements inDNA (regulate gene transcription)CD3T-cell receptor complex (blocksantigen recognition)Calcineurin (inhibits phosphataseactivity)Calcineurin (inhibits phosphataseactivity)Deoxyribonucleic acid (falsenucleotide incorporation)Inosine monophosphatedehydrogenase (inhibits activity)IL-2 receptor (block IL-2-mediatedT-cell activation)Protein kinase involved in cell-cycleprogression (inhibits activity)

• Glucocorticoids

• Muromonab-

• Cyclosporine

• Tacrolimus

• Azathioprine

• Mycophenolate Mofetil

• Daclizumab, Basiliximab

• Sirolimus

Glucocorticoids

• Induce redistribution of lymphocytes –decrease in peripheral blood lymphocytecounts

• Intracellular receptors – regulate genetranscription

• Inhibition of T cell proliferation• Neutrophils, Monocytes display poorchemotaxis

• Broad anti-inflammatory effects on multiplecomponents of cellular immunity

USES - Glucocorticoids

• Transplant rejection

• Autoimmune diseases – RA , Hematologicalconditions

• Psoriasis

• Inflammatory Bowel Disease, Eye conditions

Toxicity

• Growth retardation

• Avascular Necrosis of Bone

• Risk of Infection

• Poor wound healing

• Cataract

• Hyperglycemia

• Hypertension

• Sirolimus

– inhibits protein kinase and inhibits T cellresponse to IL-2.

– Blocks cell cycle progression

Thalidomide – inhibits angiogenesis, reduces

phagocytosis, enhances cell mediated immunity

– Increases levels of IL-10.– Used in multiple myeloma, graft versus host

disease, colon and prostrate Cancer.

Antibodies

• Against lymphocyte cell-surface antigens

• Polyclonal / Monoclonal

•Mycophenolate Mofetil –mycophenolic acid

– Inhibits inosine monophosphate

dehydrogenase which is a key enzyme in

guanine nucleotide synthesis.

– Used in steroid refractory diseases, RA.Leflunomide – it inhibits pyrimidine synthesis.

Used in RA.

• Cyclophosphamide – alkylating agent which

destroys proliferating lymphoid cells. Used inautoimmune haemolytic anaemia, multiplesclerosis.

•Muromonab CD3 – T cell receptorcomplex

( blocks Ag recognition ).

– Used in steroid resistant rejection.

• Daclizumab, Basiliximab – IL-2receptor (blocks IL-2 mediated T cellactivation ).

– Used in acute organ rejection inrenal transplant patients.

Azathioprine ( Mercaptopurine )– interferes with purine nucleic acidmetabolism and incorporates falsenucleotide.

–Used in Renal allograft, RA ,glomerulonephritis

Interferons

- IFN alpha- immune enhancing action -melanoma.

– IFN beta - multiple sclerosis

– IFN gamma - chronic granulomatousdisease.

Immunostimulants

Immunostimulants

USES:

• immunodeficiency disorders

• Chronic infections

• cancer

specific Immunostimulants

• Levamisole• Thalidomide• BCG• Recombinant Cytokines

InterferonsInterleukin-2

• Other drugs– inosiplex, azimexon, imexon, thymosin,methylinosine monophosphate

• ImmunizationVaccines , Immune Globulin , Rho (D) Immune Globulin

Levamisole

• Antihelminthic

• Restores depressed immune function of B, Tcells, Monocytes, Macrophages

USES:

• Adjuvant therapy in colon cancer

• Used to treat immunodeficiency associated withHodgkins disease.

Toxicity

• Agranulocytosis

Thalidomide

• Birth defect• Contraindicated in women with childbearingpotential

• Enhanced T-cell production of cytokines – IL-2

• Cell-mediated cytotoxicity against tumor cells

USE:• Multiple myeloma

Bacillus Calmette-Guerin

• Live, attenuated culture of BCG strain ofMycobacterium Bovis

• It causes activation of macrophages to make themmore effective killer cells.

• used as intravesical therapy for superficial bladdercancer.

Adverse Effects

– Hypersensitivity

– Shock

– Chills

Interferons

• Antiviral

• Immunomodulatory activity

• Bind to cell surface receptors – initiate intracellularevents

– Enzyme induction

– Inhibition of cell proliferation

– Enhancement of immune activities

– Increased Phagocytosis

Interferon

• Hairy cell leukemia• Malignant melanoma• sarcoma• Hepatitis B

Adverse reactions• Flu-like symptoms – fever, chills, headache• CVS- hypotension, Arrhythmia• CNS- depression, confusion

Interleukin-2 (aldesleukin)

• Proliferation of cellular immunity –Lymphocytosis, eosinophilia, release of multiplecytokines .

Uses• Metastatic renal cell carcinoma• MelanomaToxicity

• Cardiovascular: capillary leak syndrome,Hypotension

Capillary leak syndrome

• (systemic capillary leak syndrome or Clarksonsyndrome)

• A rare medical condition where the numberand size of the pores in the capillaries areincreased which leads to a leakage of fluidfrom the blood to the interstitial fluid,resulting in dangerously low blood pressure(hypotension), edema and multiple organfailure due to limited perfusion.

Immunization

• Active – Stimulation with an Antigen

• Passive – Preformed antibody

Active immunization

Vaccines• Administration of antigen as a whole, killedorganism, or a specific protein or peptideconstituent of an organism

• Booster doses

• Anticancer vaccines:

Vaccinating patients with autologous antigenpresenting cells (APC) expressing tumor-associated antigens (TAA)

Immune Globulin

Indications

• Individual is deficient in antibodies –immunodeficiency

• Individual is exposed to an agent, inadequate timefor active immunization

– Rabies

– Hepatitis B

• Nonspecific immunoglobulins

–Antibody-deficiency disorders

• Specific immune globulins

–Hepatitis B, Rabies, Tetanus