Immunomodulators

Discriminate: Self / Non self

Destroy:

Infectious invaders

Dysregulated self (cancers)

Immunity:

Innate, Natural

Adaptive, Learned

Refer to undesirable reactions produced by the normal immune

system and may be damaging, uncomfortable, or occasionally fatal

Type I: Immediate hypersensitivity: Anaphylaxis, Allergy, Asthma.

E.g. Certain drugs (Penicillin)

Type II: Antibody-mediated (or cytotoxic): Self-cells are marked by

antibodies for destruction. E.g. Autoimmune diseases, hemolytic

reactions

Type III: Immune complex deposition: (aggregations of antigens,

complement proteins, antigen-antibody reactions) deposited in

various tissues. E.g. SLE

Type IV: Cell-mediated or delayed: Reactions mediated by T cells,

monocyte, and macrophages. E.g. Chronic transplant rejections

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.

1. Rheumatoid Arthritis (RA): Inflammation of the joints and

surrounding tissues. Occurs at any age, usually affects women more

than men

2. Systemic lupus erythematosus (SLE): Chronic inflammation

Chest pain, fatigue, fever, general discomfort, hair loss, mouth sores,

sensitivity to sunlight, skin rash, swollen lymph nodes, arrhythmias,

blood in urine, abdominal pain, coughing up blood.

3. Diabetes Mellitus,

4. Multiple Sclerosis etc.

Occur when one or more of the components of the immune

system are inactive

Congenital or primary – Severe Combined Immunodeficiency

(SCID) E.g. Adenosine deaminase (ADA) deficiency.

Acquired or secondary – Cancer and HIV causing AIDS.

Organ Transplant - 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 cells, antibodies)

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

• Interferon (IFNs),

• Tumor Necrosis Factors (TNFs),

• Transforming Growth Factors (TGFs)

• Colony-stimulating factors (CSFs).

IMMUNOMODULATORS

Immunomodulators are drugs which either suppress the

immune system –Immunosuppressants

or

stimulate the immune system –Immunostimulants

Immunosuppressant

Glucocorticoids: Prednisolone, Methylprednisolone, Prednisone.

Calcineurin inhibitors

Cyclosporine

Tacrolimus

Sirolimus

Antiproliferative / antimetabolic agents

Azathioprine

Mycophenolate Mofetil

Leflunomide

Others – methotrexate, cyclophosphamide, thalidomide and chlorambucil , Interferon, Everolimus

Antibodies

Antithymocyte globulin (ATG)

Anti CD3 monoclonal antibody: Muromonab-CD3 (OKT3)

Anti IL-2 receptor antibody: Daclizumab, basiliximab

Anti TNFα: Infliximab, Etanercept, Adalimumab

MAJOR STEPS IN IMMUNE RESPONSES

Antigen

Antigen Presenting

Cell (macrophage,

dendritic cell)

CD4

Helper T-Cell

Primed CD4 Helper T-Cell

CD8 T-Cell

Cytotoxic

T-Cells

Plasma cells

1

2 3

4

4

IL-1 IL-2

IL-2

IL-2 B cell

A. Antigen recognition: Immune Globulin

B. IL-1production, cell proliferation: Corticosteroids

C. T cell receptors/surface proteins: OKT3, ATG

D. IL-2 gene expression (Cyclosporine, Tacrolimus), and IL-2

signal transduction (Sirolimus )

E. T cell proliferation & differentiation: Rapamycin,

Mycophenolate

Azathioprine, Cyclophosphamide (all cell proliferation)

Antigen

antigen

presenting

cell

CD4

T helper

cell

Primed CD4 T helper cell

CD8 T cell

Cytotoxic T cells

Plasma cells

1

2 3

4

4

IL-1 IL-2

IL-2

X

X

X X

X A

B D D

E C

X

IL-2

SITES OF ACTION OF

IMMUNOSUPPRESSIVE DRUGS

Cyclosporine (Neoral)

Tacrolimus (FK506, Prograf)

Sirolimus (Rapamune)

Mycophenolate mofetil (Cellcept)

Prednisone, Methylprednisolone

Corticosteroids Prednisone

Prednisolone

Methylprednisolone

Dexamethasone

They have both anti-inflammatory action and immunosuppressant effects.

Usually co-administered with other suppressive agents

Broad anti-inflammatory effects on multiple components of

cellular immunity

Mechanism of Action:

Bind to glucocorticoid receptors and the complex interacts with

DNA to inhibit gene transcription of inflammatory genes.

Decrease production of inflammatory mediators as

Prostaglandins, Leukotriene, Histamine, PAF, Bradykinin

Decrease production of cytokines IL-1, IL-2, Interferon, TNF.

Decrease generation of IgG.

Inhibit Antigen Presentation by macrophages.

Suppress Helper T-cell function.

Decrease T-Cell proliferation.

Neutrophils, Monocyte display poor chemotaxis

Uses:

Transplant rejection: Bone Marrow transplantation

Autoimmune diseases – RA, Systemic Lupus Erythematosus,

Asthma, Psoriasis

Inflammatory Bowel Disease, Eye conditions

Toxicity

Increased Risk of Infection

Growth retardation

Avascular Necrosis of Bone

Poor wound healing

Cataract

Hyperglycemia

Hypercholesterolemia

Hypertension

Osteoporosis

Calcineurin (CN) is a protein phosphatase which induces dephosphorylation of transcription factors, including NFAT (Nuclear factor of activated T cells) required for the synthesis of IL-2 and activates the T cells.

Calcineurin can be inhibit by drugs: Cyclosporine

Tacrolimus

Sirolimus

Fat soluble peptide antibiotic

Binds to the cytosolic protein cyclophilin (an immunophilin)

Cyclosporin - cyclophilin complex inhibits the calcineurin

Inhibits the gene transcription of IL-2, IL-3, IFN-γ, and other factors produced by antigen-stimulated T cells.

Acts by blocking activation of T cells by inhibiting IL-2 production.

Also decreases proliferation and differentiation of T- cells.

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

Cyclosporine: Uses Organ transplantation: Kidney, Liver, Heart

either alone or with other immunosuppressive agents (Corticosteroids).

Autoimmune diseases –RA, Psoriasis and other skin disease Aplastic anemia

Cyclosporine: Toxicity

Nephrotoxicity, Hepatotoxicity, Neurotoxicity

Tremor

Hirsuitism

Hypertension

Hyperlipidemia

Gum hyperplasia

Hyperuricemia – worsens gout

Calcineurin inhibitors + Glucocorticoids = Diabetogenic

CYT p450 inducers (Phenobarbitone, Phenytoin &

Rifampin ) enhanced clearance of cyclosporine

rejection of transplant.

Erythromycin or Ketoconazole, Grapefruit juice

decreased clearance of cyclosporine cyclosporine

toxicity.

Macrolide antibiotic.

It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity.

It prevents the cell from transitioning from the G0 into G1 phase of the cell cycle.

Tacrolimus is more potent than cyclosporine and has less pronounced side-effects.

Uses:

Prophylaxis of solid-organ allograft rejection

For liver, kidney, heart, pancreas, and bone marrow transplant applications (with glucocorticoids).

Topical preparation available for use in dermatitis and psoriasis.

Nephrotoxicity (more than Cyclosporin)

Neurotoxicity (more than Cyclosporin)

Tremor, headache, motor disturbances, seizures

GI Complaints

Hypertension

Hyperglycemia

Hypersensitivity,

Risk of tumors, infections

Increased risk of lymphomas,

NO hirsutism or gum hyperplasia

Tacrolimus is more favorable than Cyclosporin

due to:

Tacrolimus is 10 – 100 times more potent than

Cyclosporin in inhibiting immune responses.

Tacrolimus has decreased episodes of rejection.

Tacrolimus is combined with lower doses of

glucocorticoids.

But

Tacrolimus is more nephrotoxic and neurotoxic.

Macrolide antibiotic similiar to tacrolimus

Contrary to cyclosporine and tacrolimus, drugs that affect the first

phase of T lymphocyte activation, sirolimus affects the second phase

(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).

mTOR is serine-threonine kinase essential for cell cycle

progression, DNA repairs, protein translation.

It indirectly inhibits several T lymphocyte-specific kinases and

phosphatases, hence preventing their transition from G1 to S phase

of the cell cycle (Antiproliferative action).

Sirolimus inhibits B cell proliferation and prevents differentiation

into plasma cells, reducing production of antibodies.

Uses: Prophylaxis of organ transplant rejection with other

drugs

Toxicity: Hyperlipidaemia: Increase in serum cholesterol, Triglycerides

Anemia Thrombocytopenia Leukopenia Hypokalemia Fever GI effects Risk of infection, tumors

An imidazolyl derivative of mercaptopurine (6-MP)

The main immunosuppressive cytotoxic substance.

Prodrug: 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 mediated and humoral immunity.

Uses

Prevention of organ transplant rejection

Acute glomerulonephritis

Rheumatoid arthritis, systemic lupus erythematosus

Toxicity

Bone marrow suppression - leukopenia, thrombocytopenia, anemia

Increased susceptibility to infection

Hepatotoxicity,

Alopecia,

GI toxicity

Drug Interaction Co-administration with allopurinol may lead to

toxicity due to inhibition of xanthine oxidase by allopurinol.

Prodrug Mycophenolic acid

Inhibits IMPDH (Inosine monophosphate dehydrogenase – key enzyme for guanine synthesis, 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

Prophylaxis of transplant rejection

Combination: Glucocorticoids, Calcineurin Inhibitors

Toxicity

GI toxicity: Nausea, Vomiting, Diarrhea

Hematological: Leucopenia, neutropenia

Risk of Infection Increased incidence of lymphomas and other malignancies

Drug Interaction

Decreased absorption when co-administered with antacids

Acyclovir, Gancyclovir compete with mycophenolate for tubular secretion

A prodrug

Has long duration of action.

Can be given orally

Antimetabolite immunosuppressant

Pyrimidine synthesis inhibitor

Approved only for rheumatoid arthritis

Adverse effects

Elevation of liver enzymes

Renal impairment

Cardiovascular effects (tachycardia)

Against lymphocyte cell-surface antigens

Polyclonal / Monoclonal

Antibodies are used as a quick and potent immuno-suppression method to prevent the acute rejection reaction

Antithymocyte Globulin

Monoclonal antibodies

Anti-CD3 antibodies

E.g. Muromonab-CD3

Anti-IL-2 Receptor antibodies

E.g. Daclizumab, Basiliximab)

Purified gamma globulin from serum of rabbits immunized with human thymocytes

Cytotoxic to lymphocytes & block lymphocyte function. When a patient receives an organ transplant, the body's

WBCs try to reject the transplanted organ. Anti-thymocyte globulin (rabbit) works by preventing the

WBCs from doing this Uses Treatment of acute transplant rejection

Toxicity Hypersensitivity Risk of infection, Malignancy

More specifically, it is a purified murine (mouse) monoclonal antibody

Specific to CD3 T-cell lymphocyte antigens,

Binds to CD3 receptor on the surface of human T-cells, a component of T-cell receptor complex involved in:

antigen recognition

cell signaling & proliferation

MOA: It appears to kill CD-3 positive cells by inducing Fc mediated apoptosis and, antibody mediated cytotoxicity.

Uses: Treatment of acute organ transplant rejection

Toxicity

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

Prevention: Steroids

Obtained by replacing murine amino acid sequences with human ones.

Basiliximab is a human-mouse IgG (25% murine, 75% human protein).

Daclizumab is a humanized IgG (90% human protein). Basiliximab is more potent than Daclizumab. Bind to IL-2 receptor on surface of activated T cells

Block IL-2 mediated T-cell activation Uses Prophylaxis of Acute organ rejection (with cyclosporin)

Toxicity Anaphylaxis, Opportunistic Infections

E.g. Infliximab, Etanercept, Adalimumab

Infliximab Infliximab neutralizes the biological activity of TNF-α by binding

with high affinity to the soluble and transmembrane (located on the outer membranes of T cells and similar immune cells) forms of TNF-α, and inhibits or prevents the effective binding of TNF-α with its receptors.

Uses: Rheumatoid arthritis Psoriasis Psoriatic arthritis Ankylosing spondylitis

Toxicity: Infusion reaction – fever, urticaria, hypotension, dyspnoea Opportunistic infections – TB, RTI, UTI

Etanercept act as a TNF inhibitor and used to treat autoimmune diseases.

Dimeric Fusion protein produced

through expression of recombinant DNA.

Extracellular Ligand binding portion of Human TNF-α receptor fused to Fc portion of human IgG1

Uses: Rheumatoid arthritis

Recombinant human anti-TNF mAb Uses : moderate to severely active crohn’s disease

Monoclonal Ab Targeting Lymphocyte Function Associated Antigen

Blocks T-cell Adhesion, Activation, Trafficking

Uses

Organ transplantation

Psoriasis