IMMUNOMODULATOR

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IMMUNOMODULATORS

• Prepared By
• Ms. Prexita Patel
• Dept. of Pharmacology
• Anand Pharmacy College, Anand

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The Immune Response - why and how ?

• Discriminate Self / Non self
• Destroy
• Infectious invaders
• Dysregulated self (cancers)
• Immunity
• Innate, Natural
• Adaptive, Learned

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Who are involved ?

• Innate
• Complement
• Granulocytes
• Monocytes/macrophages
• NK cells
• Mast cells
• Basophils

• Adaptive
• B and T lymphocytes
• B antibodies
• T helper, cytolytic, suppressor.

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Application of Immunomodulator

• Hypersensitivity reactions
• It is undesirable reactions produced by the
  normal immune system and may be damaging,
  uncomfortable, or occasionally fatal
• Type I (immediate ) e.g. Anaphylactic shock,
  Allergy
• Type II antibody-dependent (or cytotoxic)
  Self-cells are marked by antibodies for
  destruction. e.g. cytopenia (low number of blood
  cells)
• Type III Immune complexes (antigen-antibody
  reactions) deposited in various tissues. e.g.
  Allergy to a medicine
• Type IV Cell-mediated or delayed these
  reactions are mediated by T cells, monocytes, and
  macrophages. e.g. Contact dermatitis

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• B. Autoimmunity
• Autoimmune diseases arise when the body mounts
  an immune response against itself as a result of
  failure to distinguish self tissues and cells
  from foreign antigens.
• E.g. Rheumatoid Arthritis, Systemic lupus
  erythematosus, Multiple Sclerosis etc.
• C. Immunodeficiency Diseases
• Occur when one or more of the components of the
  immune system are inactive
• Congenital Severe combined immunodeficiency
  (SCID) E.g. Adenosine deaminase (ADA)
  deficiency. Deficiency of this enzyme results in
  an accumulation of deoxyadenosine, which in turn
  leads to
•  1- increase in S-adenosylhomocysteine affecting
  the differentiations of lymphocytes
• 2- prevents DNA synthesis, so affecting T and B
  cells division.
• Extrinsic Cancer and HIV causing AIDS.

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D. Organ Transplants/Rejections Types of
Organ Transplants Autograft tissue graft from
one body site to another (same person) Isograft
graft received from a genetically identical donor
(identical twin) Allograft graft received from
genetically non-identical donor (same
species) Xenograft graft received from another
species of animal Transplant rejection mediated
by the immune system (especially T cells, NK,
antibodies) For e.g. Organ transplantation of
kidney, liver, Heart etc, Bone marrow etc.
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• E. Cytokines
• Cytokines are a category of signaling molecules
  used extensively in intercellular communication.
• They are regulators of host responses to
  infection, immune responses, inflammation, and
  trauma
• Cytokines can be classified as proteins,
  peptides, or glycoproteins
• Cytokines include
• Interleukins / lymphokines
• Interferons (IFNs),
• Tumor Necrosis Factors (TNFs) (causing the
  apoptosis),
• Transforming Growth Factors (TGFs)
• Colony-stimulating factors (CSFs) (causing cells
  to proliferate and differentiate).

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Immune Response
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MAJOR STEPS IN IMMUNE RESPONSES
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IMMUNOMODULATORS
Immunomodulator are drugs which either suppress
the immune system Immunosuppressant or stimulate
the immune system Immunostimulant
Immunosuppressant
Classification - Glucocorticoids-
Prednisolone, Methylprednisolone, Prednisone.
Calcineurin inhibitors - Cyclosporine,
Tacrolimus,
mTOR inhibitors - Sirolimus and
everolimus
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Antiproliferative / antimetabolic agents
- Azathioprine , Mycophenolate Mofetil. Others
Methotrexate, Cyclophosphamide, Thalidomide and
Chlorambucil
Biological agents - (a) TNFa inhibitors
Etanercept, Infliximab, Adalimumab. (b) IL-1
receptor antagonist Anakinra (c) IL-2 receptor
antagonists Daclizumab, Basiliximab. (d) Anti
CD-3 antibody Muromonab CD3 (e) Polyclonal
antibodies Antithymocyte antibody (ATG),
Rho immune
globulin.
MISCELLANEOUS
Campath-1H (Alemtuzumab) , ECULIZUMAB NATALIZUMAB
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Inhibitors of Immune Response (site of action)

• Antigen recognition Immune Globulin
• IL-1production, cell proliferation
  Corticosteroids
• T cell receptors/surface proteins
  Muromonab-CD3 (OKT3), Anti-thymocyte
  globulin (ATG) 
• IL-2 gene expression (Cyclosporine, Tacrolimus),
  and IL-2 signal transduction (Sirolimus )
• T cell proliferation differentiation
  Mycophenolate
• Azathioprine, Cyclophosphamide
• (all cell proliferation)

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SITES OF ACTION OF IMMUNOSUPPRESSIVE DRUGS
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Glucocorticoids

• Mechanism of Action -
• 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

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Uses -

• Transplant rejection
• GVH BM transplantation
• Autoimmune diseases RA, SLE, Hematological
  conditions
• Psoriasis
• Inflammatory Bowel Disease, Eye conditions

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Toxicity

• Hyperglycemia
• Hypertension
• Growth retardation
• Avascular Necrosis of Bone
• Risk of Infection
• Poor wound healing
• Cataract

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Calcineurin inhibitors

• Eg. Cyclosporine, Tacrolimus , Sirolimus.
• Most effective immunosuppressive drugs.
• Target intracellular signaling pathways.
• Blocks Induction of cytokine genes.

M/A - 1. Inhibits calcineurin by binding
cyclophilins . This prevents the transcription of
genes responsible for the production of
Interleukin. 2. Also causes a decrease in
expression of Interferon-gamma. Decreased
activity and decreased growth of T-Lymphocytes.
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CYCLOSPORIN
TACROLIMUS
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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.

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Toxicity Cyclosporine

• Renal dysfunction
• Tremor
• Hirsuitism
• Gum hyperplasia
• Hypertension
• Hyperlipidemia
• Hyperuricemia worsens gout
• Calcineurin inhibitors Glucocorticoids
  Diabetogenic

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Drug Interaction - Cyclosporine

• CYP 3A4 Inhibitors CCB, Antifungals,
  Antibiotics, HIV PI, Grape juice inhibit its
  metabolism to increase bioavailability and
  toxicity.
• Inducers Rifampicin, Phenytoin lower its blood
  levels so that transplant rejection may result.
• Additive nephrotoxicity NSAIDs, Aminoglycoside,
  AMB.

TACROLIMUS
M/A- It binds to FK binding proteins to inhibit
calcineurin. Prevents Interleukin 2 transcription
and blocking activation and growth of
T-cells. Uses - 1. transplant rejection
prophylaxis. 2. Autoimmune diseases
e.g ulcerative colitis and vitiligo. Adverse
effects Similar to Cyclosporine with the
Nephrotoxicity and Neurotoxicity. Can increase
risk of diabetes. It does not cause any hirsutism
and gingival hyperplasia.
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Drug interaction of Tacrolimus CYP3A4 inhibitor
increses its concentration and leads to toxicity
while inducer decreses its concentration and lead
to failure of theray. SIROLIMUS(RAPAMYCIN)
M/A - Contrary to cyclosporine and tacrolimus,
drugs that affect the first phase of T lymphocyte
activation, sirolimus affects the second one (
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-cell growth and activation by
preventing their transition from G1 to S phase of
the cell cycle. It prevents B cell
differentiation into plasma cells, reducing
production of IgM, IgG, and IgA antibodies.
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Uses -
Anti-rejection drug that is used most commonly in
kidney transplant recipients. Preferred over
cyclosporine and tacrolimus for kidney transplant
patients due to the latter drugs nephrotoxicity.
Sirolimus does not cause nephrotoxicity. It is
also used as a coating on cardiac stents to
prevent restenosis following ballon
angioplasty. Adverse effects Can cause
Interstitial Pneumonitis, Anemia,
Thrombocytopenia, Leukopenia, Insulin resistance
and hyperlipidemia.
Drug Interactions of sirolimus Inhibitors and
inducers of CYP3A4 significantly alter its blood
level, which needs to be monitored. Cyclosporine
shares the same isozyme and raises the blood
level of sirolimus.
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EVEROLIMUS It is similar to sirolimus in
mechanism, clinicalefficacy, doses, toxicity and
drug interactions, but is better absorbed orally
and more bioavailability. The t½ is shorter (40
hours) so that steady state levels can be reached
earlier.
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Antiproliferative and Antimetabolic drugs

• Azathioprine
• Mycophenolate Mofetil
• Others
• Methotrexate
• Cyclophosphamide
• Chlorambucil

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Azathioprine (Imuran )

• M/A -
• An imidazolyl derivative of 6-MP
• The main immunosuppressive cytotoxic substance.
  It is non-enzymatically 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.
• Uses
• Prevention of organ transplant rejection
• Rheumatoid arthritis, systemic lupus
  erythematosus.

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• Toxicity
• Bone marrow suppression- leukopenia,
  thrombocytopenia, anemia.
• Increased susceptibility to infection
• Hepatotoxicity,
• Alopecia,
• GI toxicity
• Drug interaction
• With Allopurinol increases plasma level of
  6-MP.
• With alcohol - Nausea

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Mycophenolate Mofetil
M/A - 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 - Prophylaxis of transplant rejection In
Combination Glucocorticoids. It is superior to
azathioprine, MMF glucocorticoid sirolimus is
a non-nephrotoxic combination that is utilized in
patients developing renal toxicity with
cyclosporine/tacrolimus.
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• 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
Chlorambucil It has relatively weak
immunosuppressant action. Utilized in autoimmune
diseases and transplant maintenance regimens.
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Methotrexate This folate antagonist is a potent
immunosuppressant which markedly depresses
cytokine production and cellular immunity, and
has anti-inflammatory property. It has been
used as a first line drug in many autoimmune
diseases like rapidly progressing rheumatoid
arthritis ,severe, psoriasis, pemphigus,
myasthenia gravis, uveitis, chronic active
hepatitis. Low dose Mtx maintenance therapy is
relatively well tolerated.
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Cyclophosphamide This cytotoxic drug has more
marked effect on B cells and humoral immunity
compared to that on T cells and CMI. It has
been particularly utilized in bone marrow
transplantation in which a short course with high
dose is generally given. In other organ
transplants it is employed only as a reserve
drug. In rheumatoid arthritis, it is rarely
used, only when systemic manifestations are
marked. Low doses are occasionally employed for
maintenance therapy in pemphigus, systemic lupus
erythematosus and idiopathic thrombocytopenic
purpura.
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BIOLOGICAL AGENTS These are biotechnologically
produced recombinant proteins or
polyclonal/monoclonal antibodies directed to
cytokines or lymphocyte surface antigens which
play a key role in immune response. They are
important in refractory cases of autoimmune
diseases and graft versus host reaction. TNFa
inhibitors TNFa is secreted by activated
macrophages and other immune cells to act on TNF
receptors (TNFR1, TNFR2) which are located on the
surface of neutrophils, fibroblasts, endothelial
cells as well as found in free soluble form in
serum and serous fluids. TNFa amplifies immune
inflammation by releasing other cytokines and
enzymes like collagenases and metalloproteinase.
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Etanercept This fusion protein of human TNF
receptor and Fc portion of human IgG1 neutralizes
both TNFa and TNFb. It prevents activation of
macrophages and T-cells.
It is used rheumatoid arthritis,
severe/refractory ankylosing spondylitis,
idiopathic juvenile arthritis and psoriasis.
Infliximab It is monoclonal antibody against
TNFa which binds and inactivates TNFa. Used in
refractory rheumatoid arthritis, Crohns disease,
ulcerative colitis, psoriasis and ankylosing
spondylitis. Adalimumab It is fully human
recombinant anti-TNFa antibody indicated in the
same range of autoimmune diseases as infliximab,
and does not bind TNFß, but is less antigenic.
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IL-1 receptor antagonist Stimulated macrophages
and other mononuclear cells elaborate IL-1 which
activates helper T-cells and induces production
of other ILs, metalloproteinases, etc. An
endogenous IL-1 receptor antagonist has been
isolated and several of its recombinant variants
have been produced for clinical use. Anakinra
This recombinant human IL-1 receptor antagonist
prevents IL-1 binding to its receptor. Use in
refractory rheumatoid arthritis not controlled by
conventional DMARDs. Anakinra along with
continued Mtx has been used alone as well as
added to TNFa antagonists, because its clinical
efficacy as monotherapy appears to be lower.
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IL-2 receptor antagonist The CD-25 molecule is
expressed on the surface of immunologically
activated, but not resting T-cells. It acts as
a high affinity receptor for IL-2 through which
cell proliferation and differentiation are
promoted. Some anti CD-25 antibodies have been
developed as IL-2 receptor antagonist to
specifically arrest the activated
T-cells. Daclizumab and Basiliximab M/A - Bind
to IL-2 receptor on surface of activated T cells
? Block IL-2 mediated T-cell activation and
proliferation. Uses Prophylaxis of Acute organ
rejection Toxicity Anaphylaxis, Opportunistic
Infections
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Anti-CD3 Monoclonal Antibody

• Muromonab-CD3
• M/A - Binds to CD3, a component of T-cell
  receptor involved in antigen recognition and
  cell signaling proliferation.

Uses Treatment of of acute rejection of renal
allografts as well as for corticosteroid-resistant
acute allograft rejection in cardiac and hepatic
transplant patients. Toxicity Cytokine release
syndrome High fever, Chills, Headache, Tremor,
myalgia, arthralgia, weakness
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Polyclonal antibodies Antithymocyte globulin
(ATG)
M/A- Purified gamma globulin from serum of
rabbits immunized with human thymocytes Cytotoxic
to lymphocytes block lymphocyte function.
Clinical uses Combine with immune suppressive
agents to prevent early allograft rejection, to
treat severe rejection episodes or
corticosteroid-resistant acute rejection. Adverse
effects include chills, fever, leukopenia and
thrombocytopenia.
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• Anti-D immune globulin (RHESUMAN, RHOGAM, IMOGAM)
• It is human IgG antibodies against Rh (D)
  antigen.
• It binds the Rho antigens and does not allow them
  to induce antibody formation in Rh negative
  individuals.
• Used for the prevention of postpartum/post-abortio
  n formation of antibodies in Rho-D negative, DU
  negative women who have delivered or aborted an
  Rho-D positive foetus.
• Administered within 72 hours of delivery/
  abortion, such treatment prevents Rh hemolytic
  disease in future offspring.
• It has been given at 28th week of pregnancy.
• Higher doses (10002000 µg) are needed for Rh
  negative recipients of which administered Rh
  positive blood.
• It should never be given to the infant or to
  Rho-D positive, DU positive individuals.

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Campath-1H (Alemtuzumab)
MISCELLANEOUS

• Targets CD52 expressed on lymphocytes,
  monocytes, Macrophages and prolonged T B cell
  depletion
• Use in Renal transplantation.
• ECULIZUMAB
• Antibody against complement protein C5.
• Used in the treatment of Paroxysmal Nocturnal
  Haemoglobinuria.
• NATALIZUMAB
• Antibody against Alpha4-integrin.
• Used in the treatment of Multiple sclerosis and
  Crohns disease.

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IMMUNOSTIMULANTS

• Levamisole
• Thalidomide
• Vaccines BCG
• Immune Globulin
• Rho (D) Immune Globulin
• Recombinant Cytokines
• Interferons
• Interleukin-2

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LEVAMISOLE

• Anthelminthic
• Restores depressed immune function of B, T cells,
  Monocytes, Macrophages
• Adjuvant therapy with 5FU in colon cancer
• Toxicity
• Agranulocytosis

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Thalidomide

• Birth defect
• Contraindicated in women with childbearing
  potential
• Enhanced T-cell production of cytokines IL-2,
  IFN-?
• NK cell-mediated cytotoxicity against tumor cells
• USE
• Multiple myeloma

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Bacillus Calmette-Guerin

• Live, attenuated culture of BCG strain of
  Mycobacterium Bovis.
• Carcinoma Bladder
• Adverse Effects
• Hypersensitivity
• Shock
• Chills

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Interferons

• Antiviral
• Immunomodulatory activity
• Bind to cell surface receptors initiate
  intracellular events
• Enzyme induction
• Inhibition of cell proliferation
• Enhancement of immune activities
• Increased Phagocytosis

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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

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Interleukin-2 (aldesleukin)

• Proliferation of cellular immunity
  Lymphocytosis, eosinophilia, release of multiple
  cytokines TNF, IL-1, IFN-?
• Uses
• Metastatic renal cell carcinoma
• Melanoma
• Toxicity
• Cardiovascular capillary leak syndrome,
  Hypotension

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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.

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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

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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 RBCs.
• Hemolytic disease of newborn.

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