IMMUNOMODULATORS

Dr. Manjunath
The Immune Response - why and how ?

 Discriminate: Self / Non self

 Destroy:
 Infectious invaders
 Dysregulated self (cancers)
 Immunity:
 Innate, Natural
 Adaptive, Learned
 Who are involved ?
 Innate  Adaptive:
 Complement  B and T
 Granulocytes lymphocytes
 Monocytes/macrophages  B: antibodies
 NK cells  T : helper,
 Mast cells cytolytic,
suppressor.
 Basophils
 IMMUNE MODIFIERS

Immunosuppressants Immunostimulants

? Immune tolerance
 Immunosuppressants
 Glucocorticoids
 Calcineurin inhibitors
 Cyclosporine
 Tacrolimus
 Antiproliferative / antimetabolic agents
 Sirolimus
 Everolimus
 Azathioprine
 Mycophenolate Mofetil
 Others – methotrexate, cyclophosphamide,
thalidomide and chlorambucil
 Antibodies
 Antithymocyte globulin
 Anti CD3 monoclonal antibody
 Muromonab
 Anti IL-2 receptor antibody –
 Daclizumab, basiliximab
 Anti TNF alpha – infliximab, etanercept
Immunostimulants
 Levamisole
 Thalidomide
 BCG
 Recombinant Cytokines
 Interferons
 Interleukin-2
 Immunosuppressants
 Organ transplantation
Problem
 Autoimmune diseases

 Life long use

 Infection, cancers
 Nephrotoxicity
 Diabetogenic
Glucocorticoids
 Induce redistribution of lymphocytes –
decrease in peripheral blood lymphocyte
counts
 Intracellular receptors – regulate gene
transcription
 Down regulation of IL-1, IL-6
 Inhibition of T cell proliferation
 Neutrophils, Monocytes display poor
chemotaxis
 Broad anti-inflammatory effects on multiple
components of cellular immunity
USES - Glucocorticoids
 Transplant rejection
 GVH – BM transplantation
 Autoimmune diseases – RA, SLE,
Hematological conditions
 Psoriasis
 Inflammatory Bowel Disease, Eye
conditions
Toxicity
 Growth retardation
 Avascular Necrosis of Bone
 Risk of Infection
 Poor wound healing
 Cataract
 Hyperglycemia
 Hypertension
Calcineurin inhibitors
 Cyclosporine
 Tacrolimus
 Most effective immunosuppressive
drugs
 Target intracellular signaling
pathways
 Blocks Induction of cytokine genes
Cyclosporine
 More effective against T-cell dependent
immune mechanisms – transplant rejection,
autoimmunity
 IV, Oral

Uses
 Organ transplantation: Kidney, Liver, Heart
 Rheumatoid arthritis, IBD, uveitis
 Psoriasis
 Aplastic anemia
 Skin Conditions- Atopic dermatitis, Alopecia
Areata, Pemphigus vulgaris, Lichen planus,
Pyoderma gangrenosum
Toxicity : Cyclosporine
 Renal dysfunction
 Tremor
 Hirsuitism
 Hypertension
 Hyperlipidemia
 Gum hyperplasia
 Hyperuricemia – worsens gout
 Calcineurin inhibitors + Glucocorticoids =
Diabetogenic
Drug Interaction : Cyclosporine
 CYP 3A4
 Inhibitors: CCB, Antifungals,
Antibiotics, HIV PI, Grape juice
 Inducers: Rifampicin, Phenytoin
 Additive nephrotoxicity: NSAIDs
Tacrolimus
 Inhibits T-cell activation by
inhibiting calcineurin
 Use
 Prophylaxis of solid-organ allograft
rejection
Toxicity - Tacrolimus
 Nephrotoxicity
 Neurotoxicity-Tremor, headache, motor
disturbances, seizures
 GI Complaints
 Hypertension
 Hyperglycemia
 Risk of tumors, infections

 Drug interaction
 Synergistic nephrotoxicity with cyclosporine
 CYP3A4
 Antiproliferative and Antimetabolic
drugs
 Sirolimus
 Everolimus
 Azathioprine
 Mycophenolate Mofetil
 Others:
 Methotrexate
 Cyclophosphamide
 Thalidomide
 Chlorambucil
Sirolimus
 Inhibits T-cell activation and
Proliferation
 Complexes with an immunophilin,
Inhibits a key enzyme in cell cycle
progression – mammalian target of
rapamycin (mTOR)
Sirolimus
Uses
 Prophylaxis of organ transplant rejection along
with other drugs
Toxicity
 Increase in serum cholesterol, Triglycerides
 Anemia
 Thrombocytopenia
 Hypokalemia
 Fever
 GI effects
 Risk of infection, tumors

 Drug Interactions: CYP 3A4

Everolimus
 Shorter half life compared to
sirolimus
 Shorter time taken to reach steady
state
 Similar toxicity, drug interactions
 Azathioprine
 Purine antimetabolite
 Incorporation of false nucleotide
6 Thio-IMP 6Thio-GMP 6Thio-GTP
 Inhibition of cell proliferation
 Impairment of lymphocyte function

Uses
 Prevention of organ transplant
rejection
 Rheumatoid arthritis
Toxicity - Azathioprine
 Bone marrow suppression- leukopenia,
thrombocytopenia, anemia
 Increased susceptibility to infection
 Hepatotoxicity
 Alopecia
 GI toxicity

 Drug interaction: Allopurinol

Mycophenolate Mofetil
 Prodrug  Mycophenolic acid
 Inhibits IMPDH – enzyme in guanine
synthesis
 T, B cells are highly dependent on this
pathway for cell proliferation
 Selectively inhibits lymphocyte
proliferation, function – Antibody
formation, cellular adhesion, migration
Uses - Mycophenolate Mofetil
 Prophylaxis of transplant rejection
 Combination: Glucocorticoids
Calcineurin Inhibitors

 Toxicity
 GI, Hematological
 Diarrhea, Leucopenia
 Risk of Infection
 Drug Interaction
 Decreased absorption when co-
administered with antacids
 Acyclovir, Gancyclovir compete with
mycophenolate for tubular secretion
FTY720
 S1P-R agonist – sphingosine 1 receptor
 Reduce recirculation of lymphocytes from
lymphatic system to blood and peripheral
tissues
 “Lymphocyte homing” – periphery into
lymph node
 Protects graft from T-cell-mediated attack
Uses
 Combination immunosuppression therapy
in prevention of acute graft rejection
Toxicity
 Lymphopenia
 Negative chronotropic effect
 S1P-receptor on human atrial myocytes
Antibodies
 Against
lymphocyte cell-
surface antigens
 Polyclonal /
Monoclonal
 Antibodies
 Antithymocyte Globulin
 Monoclonal antibodies
 Anti-CD3 Monoclonal antibody (Muromonab-CD3)
 Anti-IL-2 Receptor antibody (Daclizumab,
Basiliximab)
 Campath-1H (Alemtuzumab)
 Anti-TNF Agents
 Infliximab
 Etanercept
 Adalimumab
 LFA-1 Inhibitor (lymphocyte function associated)
 Efalizumab
 Anti-thymocyte Globulin
 Purified gamma globulin from serum of
rabbits immunized with human thymocytes
 Cytotoxic to lymphocytes & block lymphocyte
function

Uses
 Induction of immunosuppression –
transplantation
 Treatment of acute transplant rejection

Toxicity
 Hypersensitivity
 Risk of infection, Malignancy
Anti-CD3 Monoclonal Antibody
 Muromonab-CD3
 Binds to CD3, a component of T-cell
receptor complex involved in
 antigen recognition
 cell 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, weakness
 Prevention: Steroids
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
Uses
 Prophylaxis of Acute organ rejection

Toxicity
 Anaphylaxis, Opportunistic Infections
 Campath-1H (Alemtuzumab)
 Targets CD52 – expressed on
lymphocytes, monocytes, Macrophages
 Extensive lympholysis – Prolonged T &
B cell depletion

Uses
 Renal transplantation
 Anti-TNF Agents
 TNF – Cytokine at site of inflammation

 Infliximab
 Etanercept
 Adalimumab
 Infliximab
Uses
 Rheumatoid arthritis
 Chron’s disease – fistulae
 Psoriasis
 Psoriatic arthritis
 Ankylosing spondylosis

Toxicity
 Infusion reaction – fever, urticaria,
hypotension, dyspnoea
 Opportunistic infections – TB, RTI, UTI
 Etanercept
 Fusion protein
 Ligand binding portion of Human TNF-α
receptor fused to Fc portion of human
IgG1

Uses
 Rheumatoid arthritis
 Adalimumab
Recombinant human anti-TNF mAb

moderate to severely active crohn’s disease

LFA-1 Inhibitor - Efalizumab
 Monoclonal Ab Targeting
Lymphocyte Function Associated
Antigen
 Blocks T-cell Adhesion, Activation,
Trafficking

Uses
 Organ transplantation
 Psoriasis
 Sites of Action of Selected Immunosuppressive Agents on
T-Cell Activation

DRUG SITE OF ACTION

 Glucocorticoids 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
 Levamisole
 Thalidomide
 BCG
 Recombinant Cytokines
 Interferons
 Interleukin-2
Immunization
 Vaccines
 Immune Globulin
 Rho (D) Immune
Globulin
Levamisole
 Antihelminthic
 Restores depressed immune function
of B, T cells, Monocytes, Macrophages
 Adjuvant therapy with 5FU in colon
cancer

Toxicity
 Agranulocytosis
 Thalidomide

 Birth defect
 Contraindicated in women with
childbearing potential
 Enhanced T-cell production of
cytokines – IL-2, IFN-γ
 NK cell-mediated cytotoxicity against
tumor cells

USE:
 Multiple myeloma
Bacillus Calmette-Guerin
 Live, attenuated culture of BCG
strain of Mycobacterium Bovis
 Carcinoma Bladder

Adverse Effects
 Hypersensitivity
 Shock
 Chills
Interferons
 Antiviral
 Immunomodulatory activity
 Bind to cell surface receptors –
initiate intracellular events
 Enzyme induction
 Inhibition of cell proliferation
 Enhancement of immune activities
 Increased Phagocytosis
 Interferon alfa-2b
 Hairy cell leukemia
 Malignant melanoma
 Kaposi 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
multiple cytokines – TNF, IL-1, IFN-γ

Uses
 Metastatic renal cell carcinoma
 Melanoma
 Toxicity
 Cardiovascular: capillary leak syndrome,
Hypotension
Immunization
 Active – Stimulation with an Antigen
 Passive – Preformed antibody
Active immunization

Vaccines
 Administration of antigen as a whole,
killed organism, or a specific protein
or peptide constituent of an organism
 Booster doses

 Anticancer vaccines – immunizing

patients with APCs expressing tumor
antigen.
Immune Globulin

Indications
 Individual is deficient in antibodies
– immunodeficiency
 Individual is exposed to an agent,
inadequate time for active
immunization
 Rabies
 Hepatitis B
 Nonspecific immunoglobulins
 Antibody-deficiency disorders
 Specific immune globulins
 High titers of desired antibody
 Hepatitis B, Rabies, Tetanus
 Rho (D) Immune Globulin
 Antibodies against Rh(D)
antigen on the surface of
RBC
 Rh-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
Immune tolerance
 Induction and maintenance of
immunologic tolerance - active state
of antigenic specific
nonresponsiveness
 Still experimental
Summary
 Immunosuppresion
 Calcineurin inhibitors
 Glucocorticoids
 Antimetabolites
 Newer immunosuppresive agents
 Effective control of rejection
 Glucocorticoid withdrawal