IMMUNOMODULATORS

Definition

• An immunomodulator is a substance(eg. a drug)

which has an effect on the immune system.

2 types

• Immunosuppressants

• Immunostimulants

The Immune Response - why and how ?

• Discriminate: Self / Non self• Destroy:– Infectious invaders– Dysregulated self (cancers)

• Immunity:– Innate, Natural– Adaptive, Learned

Mechanisms of immunomodulation

• Drugs may modulate immune mechanism by either

suppressing or by stimulating one or more of the

following steps:

– Antigen recognition and phagocytosis

– Lymphocyte proliferation/differentiation

– Synthesis of antibodies

– Ag –Ab interaction

– Release of mediators due to immune response

– Modification of target tissue response

• The importance of immune system in protecting

the body against harmful molecules is well

recognized

• However, in some instances, this protection can

result in serious problems

• E.g, the introduction of allograft can elicit a

damaging immune response causing rejection of

the transplanted tissue

Immunosuppressants

IMMUNOSUPPRESSANT DRUGS

• These categorized according to their MOA:

– Some agents interfere with cytokine production or

action (Calcineurin inhibitors/specific T-cell inhibitors)

– Others disrupt cell metabolism, preventing

lymphocyte proliferation (cytotoxic drugs)

– Mono, and polyclonal antibodies block T cell surface

molecules (antibodies)

1. Calcineurin inhibitors (specific T –cell inhibitors):– Cyclosporine, Tacrolimus and Sirolimus

2. Antiproliferative drugs (cytotoxic drugs)– Azathioprine, cyclophosphamide, methotrexate,

chlorambucil, mycophenolate mofetil (MMF)

3. Glucocorticoids– Prednisolone and others

4. Antibodies – Muromonab CD3,antithymocyte globulin (ATG), Rho

(D) immunoglobulin

IMMUNOSUPPRESSANT DRUGS Cont…

Immunosuppressants

• Organ transplantation• Autoimmune diseases

• Life long use• Infection, cancers• Nephrotoxicity• Diabetogenic

Problem

CYCLOSPORINE

• Cyclic peptide composed of 11 aa

• Extracted from a soil fungus

• Selectively (-) T lymphocyte proliferation, IL-2&

other cytokine production & response of inducer T

cells to IL-1, without any effect on suppressor T

cells

• Lymphocytes are arrested at G0 or G1 phase

Mechanism of action

• It’s bind to the cytosolic protein cyclophilin (immunophilin)

of immunocompetent lymphocytes, especially T-

lymphocytes.

• This complex of cyclosporine and cyclophilin (-) calcineurin,

which, under normal circumstances, is responsible for

activating the transcription of IL 2.

• It also (-) lymphokine production and IL release, leads to a

reduced function of effector T-cells. It does not affect

cytostatic activity.

• to prevent rejection of kidney, liver, cardiac, BM and other allogeneic transplants

• Can be used alone• More effective when glucocorticoids are also admini• Most active when admini before antigen exposure• Useful in autoimmune disease as well• Alternative to methotrexate for the treatment of

severe, active RA• 2nd line drug for uveitis, bronchial asthma, etc.• Selectively suppresses CMI

CYCLOSPORINE Cont…

• Prevents graft rejection and yet leaves the recipient with enough immune activity

• Humoral immunity remains intact• Free of toxic effects on BM and RE system• For induction it is started orally 12 hrs before the

transplant and continued for as long as needed• When graft rejection has started, it can be given i.v• Concentrated in RBCs and WBCs• Metabolized in liver excreted in bile• Biphasic t1/2: 4 -6hrs and 12 -18hrs

CYCLOSPORINE Cont…

Toxicity : Cyclosporine

• Renal dysfunction• Tremor• Hirsuitism• Hypertension• Hyperlipidemia• Gum hyperplasia• Hyperuricemia – worsens gout• Calcineurin inhibitors + Glucocorticoids =

Diabetogenic

Drug interactions:• All nephrotoxic drugs like AGs, vancomycin,

amphotericin B, and NSAIDs ↑ss its toxicity• By depressing renal function can reduce

excretion of many drugs• Enzyme inducers ↓ their levels –transplant

rejection• Erythromycin, ketaconozole and related drugs ↑ their levels –toxicity

CYCLOSPORINE Cont…

Tacrolimus (FK506)

• Chemically different from cyclosporine, newer immunosuppressant

• Macrolide that is isolated from soil fungus• Same MOA, 100 times more potent• orally as well as i.v infusion• Metabolized by CYP3A4 and excreted in bile

and plasma t1/2 is 12hrs• Clinical efficacy as well as toxicity profile are

similar to cyclosporine

Antiproliferative drugs

Azathioprine:• Purine antimetabolite, which has more

marked immunosuppressant than anti tumor action

• The basis for this difference is not clear• It selectively affects differentiation and

function of T –cells and (-) cytolytic lymphocytes

• The most important application is prevention of renal and other graft rejection

• But less effective than cyclosporine, generally combined or used in pts developing cyclosporine toxicity

• Used in progressive RA and some other auto immune diseases

Antiproliferative drugs: Azathioprine

Cyclophosphomide

• More marked effect on B cells and humoral immunity

• used in BM transplantation in which short course with high dose is given

• In other organ transplantations it is employed only as a reserve drug

• In RA, it is rarely used• Low doses are occasionally employed for

maintenance therapy in pemphigus, SLE and idiopathic thrombocytopenic purpura

Methotrexate

• Folate antagonist• Markedly depresses cytokine production and

cellular immunity and has anti-inflammatory property

• Used as 1st line drug in many autoimmune diseases like rapidly progressing RA, severe psoriasis, pemphigus, myasthenia gravis, uveitis, chronic active hepatitis

• Low dose as maintenance therapy is relatively well tolerated

Mycophenolate mofetil (MMF)

• Prodrug (mycophenelic acid)• New immunosuppressant• Selectively (-) inosine monophosphate dehydrogenase an

enzyme essential for denovo synthesis of guanosine nucleotides in the T&B cells

• Lymphocyte proliferation, ab production and CMI are inhibited• Add on drug to Cyclo+gluco in renal transplantation• It good or even superior to azathioprine, but should not be

combined with it• Can help to reduce the dose of cyclosporine and thus its toxicity• Vomiting, diarrhoea, leucopenia and predisposition to CMV

infection, g.i. bleeds are the prominent A/E

Glucocorticoids

• Potent immunosuppressant and antiinflammatory• Inhibits several components of the immune

response• They particularly (-) MHC expression and

proliferation of T lymphocytes• Expression of several IL and other cytokine genes

is regulated by corticosteroids• The short lived rapid lymphopenic effect of

steroids is due to sequestration of lymphocytes in tissues

• Widely employed as companion drug to

cyclosporine in various drug transplantations

• In case graft rejection sets in –large doses of

corticosteroids i.v. are employed for short

periods

Glucocorticoids Cont…

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

Immunosuppressant antibodiesMUROMONAB CD3

• Muromonab CD3 ,used as induction therapy together with cortico & azathioprine with delayed use of cyclosporine in sequential regimen for organ transplantation

• This serves to postpone potential nephro and hepatotoxicity of cyclosporine

• Initial doses of muromonab CD3 are associated with flu like symptoms: chills, rigor and wheezing

• Occasionally aseptic meningitis, intragraft thrombosis, pulmonary edema, seizures and a shock like state are produced

• High dose of corticosteroid pretreatment reduces the reaction

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

Antithymocyte globulin (ATG)• Polyclonal Ab purified from horse or rabbit

immunized with human thymic lymphocytes which binds to T lymphocytes and depletes them

• Potent immunosuppressant and has been used primarily to suppress acute allograft rejection episodes especially in steroid resistant cases or is combined with them

• It has the potential to produce serum sickness or anaphylaxis but is less expensive than muromonab CD3

Anti –D immuneglobulin

• Human Ig G having high titre of antibodies against Rh (D) antigen

• It binds the Rho Ag (-) antibody formation in Rh -ve individuals

• It is used for prevention of postpartum /post –abortion formation of antibodies in Rho-D negative, DU -ve women who delivered or aborted an Rho-D +ve, DU +ve baby/ foetus

• Administered within 72 hrs of delivery

/abortion, such treatment prevents Rh

hemolytic disease in future offspring

• It has also been given at 28th week of

pregnancy

• Never be given to Rh +ve /DU +ve individuals

Anti –D immuneglobulin Cont…

Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation

DRUG

• Glucocorticoids• Muromonab-• Cyclosporine • Tacrolimus• Azathioprine • Mycophenolate Mofetil • Daclizumab, Basiliximab • Sirolimus

SITE OF ACTION• Glucocorticoid response elements in DNA

(regulate gene transcription)• CD3T-cell receptor complex (blocks

antigen recognition)• Calcineurin (inhibits phosphatase activity)• Calcineurin (inhibits phosphatase

activity)• Deoxyribonucleic acid (false nucleotide

incorporation)• Inosine monophosphate dehydrogenase

(inhibits activity)• IL-2 receptor (block IL-2-mediated T-cell

activation)• Protein kinase involved in cell-cycle

progression (mTOR) (inhibits activity)

Immunostimulants

Cytokines

• INF• IL• TNF• Hemopoietic growth factors (G-CSF, M-CSF, GM-

CSF, etc)• These are now available for use by rDNA

technology• Applications in the treatment of viral infections,

autoimmune and neoplastic diseases

Levimazole

• An antihelminthic

• Appears to enhance the magnitude of T –cell

mediated immunity

• It has been tried in some immunodeficiency

diseases, RA and post surgery and colorectal

cancer

BCG and other adjuvants

• BCG and other microbial products (picibanil,

lentinan and pachymaran) are being tried as

adjuvants and probably act by activation of

macrophages

Thank you