immunology and immunosuppressants

IMMUNOLOGY &

IMMUNOSUPPRES

SANTS

-BY

DR.S.RATNA DEEPIKA

MDS PART I

What does immunity mean?The ability of the human body to resist almost all

types of organisms or toxins that tend to damage the

tissues and organs. This capacity is called immunity.

Immunity is of two types

Innate Acquired

INNATE IMMUNITY:

• Is otherwise called as natural immunity.

• It is present from birth and it is inborn capacity of the

body to resist the entry of microorganisms into the body.

• By chance, if the organism enter the body, innate

immunity eliminates them before they cause any disease.

• This type of immunity represents the first line of defence

against any pathogen.

ACQUIRED IMMUNITY:

• Acquired immunity is the resistance developed in the body

against any specific foreign body like bacteria, viruses,

toxins, vaccines or transplanted tissues.

• So, this type of immunity is also known as specific

immunity.

• Acquired immunity developed by the entrance of any

foreign body or a vaccine is called active immunity.

• Acquired immunity developed by transferring antibodies,

serum or lymphocyte from an immune individual is called

passive immunity.

ACQUIRED IMMUNITY

CELLULAR HUMORAL

CELLULAR IMMUNITY:

• The cellular immunity is by activation of T lymphocytes,

which destroy the organisms, entering the body.

• This is also called cell mediated immunity or T cell

immunity.

• This is the major defence mechanism against infections.

• Cellular immunity is also responsible for delayed allergic

reactions and rejection of tissues transplanted from other’s

body.

HUMORAL IMMUNITY:

• Humoral immunity is by the activation of B

lymphocytes.

• This is also called B cell immunity.

• B lymphocytes fight against the invading

organisms by secreting antibodies into the blood

and lymph.

• This plays an important role in defence

mechanism against bacterial and viral infections.

DEVELOPMENT OF CELL MEDIATED

IMMUNITY:

• The cell mediated immunity is carried out by the T lymphocytes.

• It develops when an antigen or an antigenic material from the invading microbial or nonmicrobial cells is exposed to the T lymphocytes.

• The exposure or presentation of antigen to the lymphocytes is an important process during development of immunity.

• It is carried out by some special type of cells called antigen presenting cells.

ANTIGEN PRESENTING CELLS:

• Two types-Macrophages

Dendritic cells

Role of antigen presenting cells:

Foreign organisms invade the body

Antigen presenting cells kill them

by phagocytosis

Antigens from organisms is digested into polypeptides

Polypeptides are presented to T lymphocytes along

with human leukocyte antigen

Antigenic products activate the helper T cells and B

lymphocytes

Activated helper T cells are proliferated and

released into circulation from lymphoid tissues

ROLE OF HELPER T CELLS:

• -T helper- 1 cells

-T helper -2 cells

• TH1 cells are concerned with cellular immunity. These secrete

interleukin 2 and gamma interferon.

• Gamma interferon promotes phagocytic action of cytotoxic

cells, macrophages and natural killer cells.

• TH2 cells concerned with humoral immunity.

• These secrete interleukin 4 and interleukin 5.

ROLE OF CYTOTOXIC T CELLS:

• The activated cytotoxic T cells circulate through blood and

lymphatic tissues and destroy the invading organism by attacking

them directly.

• The outer membrane of cytotoxic T cells contain some receptor

proteins.

• These receptor proteins bind the antigens or organisms tightly

with cytotoxic T cells.

• Then, the T cells are enlarged and release cytotoxic substances

like the lysosomal enzymes.

• These substances destroy the invaded organisms.

• Other actions include destruction of cancer cells and transplanted

cells.

DEVELOPMENT OF HUMORAL IMMUNITY:

• Humoral immunity is developed by the antibodies, which are

circulating in the blood.

• The antibodies are the gamma globulins produced by B

lymphocytes.

• The humoral immunity is the major defence mechanism against

bacterial infections.

ROLE OF ANTIGEN PRESENTING CELLS:

Invasion of foreign bodies or organisms

Macrophages and antigen presenting

cells destroy them by phagocytosis

Antigen from the organisms is digested

into polypeptides

Polypeptide products are presented to B

lymphocytes along with human leukocyte

antigens

Antigenic products activate the helper T cells

and B lymphocytes

Macrophages secrete interleukin 1

This causes activation and proliferation of lymphocytes

ROLE OF PLASMA CELLS:

• The B lymphocytes are proliferated and transformed into two

types of cells

Plasma

cells

Memory

cells

• The plasma cells produce the antibodies, which are globulin in

nature and are called immunoglobulins.

• The rate of antibody production is very high i.e. each plasma

cell produces about 2000 molecules of antibodies per second.

• The antibodies are released into lymph and then transported

into the circulation.

ROLE OF MEMORY B CELLS:

• B lymphocytes activated by the antigen are transformed into

memory B cells which occupy the lymphoid tissues throughout

the body.

• The memory cells are in inactive condition until the body is

exposed to the same organisms for the second time.

• During the second exposure, the memory cells are

stimulated by the antigen and produce more quantity of

antibodies at a faster rate, than in the first exposure.

• The antibodies produced during the second exposure to the

foreign antigen are also more potent than those produced

during first exposure.

• This forms the basic principle of vaccination against the

infections.

ROLE OF HELPER T CELLS:

• Helper T cells are simultaneously activated by the antigen.

• The activated helper T cells secrete two substances called

interleukin 2 and B cell growth factor, which promote:

1.Activation of more number of B lymphocytes

2.Proliferation of plasma cells and

3.Production of antibodies

ANTIBODIES:

• Antibodies or immunoglobulins(Ig) are produced by plasma

cells in response to the presence of antigens.

• The immunoglobulins form 20% of the total plasma proteins.

Types of Antibodies:

IgA (Ig alpha)

IgD (Ig delta)

IgE (Ig epsilon)

IgG (Ig gamma)

IgM (Ig mu)

STRUCTURE OF ANTIBODIES:

• Antibodies are gamma globulins with a molecular weight of

1,50,000 to 9,00,000.

• The antibodies are formed by two pairs of chains

- Heavy chain(400 amino acids)

- Light chain(200 amino acids)

• Each chain of the antibody includes two regions

- Constant region

- Variable region

FUNCTIONS OF ANTIBODIES:

1.IgA takes part in localized defence mechanisms in external

secretions like tears.

2.IgD is involved in the recognition of the antigen by B

lymphocytes.

3.IgE involved in allergic reactions.

4.IgG is responsible for complement fixation.

5.IgM is also responsible for complement fixation.

What are immunosuppressive drugs?

These are drugs which inhibit cellular/humoral or

both immune response and have their major use in

organ transplantation and autoimmune diseases.

CLASSIFICATION OF AUTOIMMUNE

DISEASES:

Organ specific autoimmune diseases

• Pemphigus

• Behcet’s disease

• Sjogrens syndrome

• Type I Diabetes mellitus

• Thyrotoxicosis

• Hashimottos thyroiditis

• Pernicious anemia

• Primary myxedema

• Myasthenia gravis

Non Organ Specific:

• Rheumatoid arthritis

• Systemic sclerosis

• SLE

Autoimmune diseases affecting Orofacial region

predominantly:

• Sjogrens syndrome

• Mikulicz’s disease

• Apthous stomatitis

Systemic autoimmune diseases with oral manifestations:

• Pemphigus

• Bullous pemphigoid

• Cicatricial pemphigoid

• Epidermolysis bullosa

• SLE

• Myasthenia gravis

• Systemic sclerosis

CLASSIFICATION:

Calcineurin inhibitors(Specific T cell

inhibitors)

o Cyclosporine(Ciclosporin)

o Tacrolimus

Antiproliferative drugs(Cytotoxic drugs)

o Azathioprine

o Cyclophosphamide

o Methotrexate

o Chlorambucil

o Mycophenolate mofetil(MMF)

Glucocorticoids:

o Hydrocortisone

o Prednisolone

o Methyl-prednisolone

o Triamcinolone

o Dexamethasone

o Betamethasone

Antibodies:

o MuromonabCD3

o Antithymocyte globulin(ATG)

o Rho(D) immunoglobulin

CYCLOSPORINE

• Cyclosporine(cyclosporine A) is a cyclic polypeptide consisting of

11 amino acids, produced as a metabolite of the fungus species

Beauveria nivea( Borel et al., 1976) .

• Cyclosporine is lipophilic and highly hydrophobic, it must be

solubilized for clinical administration.

Mechanism of action:

• Cyclosporine suppresses some humoral immunity but is more

effective against T cell-dependant immune mechanisms such as

those underlying transplant rejection and some forms of

autoimmunity.

CALCINEURIN INHIBITORS

• It preferentially inhibits antigen-triggered signal transduction

in T lymphocytes, blunting expression of many lymphokines,

including IL-2, as well as expression of antiapoptotic proteins.

Cyclosporine forms a complex with cyclophilin

This complex binds to calcineurin, inhibiting Ca2+ stimulated dephosphorylation of the

cytosolic component of NFAT

v

It translocates to the nucleus, where t complexes with the nuclear components required for complete T cell activation, including transactivation of IL-2

and other lymphokines genes

T cell lymphocyte fails to respond to specific antigenic stimulation

v

v

Disposition and pharmacokinetics:

• Cyclosporine can be administered intravenously or orally.

• Intravenous preparation(SANDIMMUNE Injection) is provided as

a solution in an ethanol-polyoxyethylated castor oil vehicle which

must be further diluted in 0.9% sodium chloride solution or 5%

dextrose solution before injection.

• The oral dosage forms include soft gelatin capsules and oral

solutions.

• A modified microemulsion formulation (NEORAL) was

developed to improve absorption.

• The elimination of cyclosporine from the blood is generally

biphasic, with a terminal half life of 5 to 18 hours.

• Following oral administration of cyclosporine(as

Neoral) the time to peak blood concentrations is 1.5 to

2.0 hours.

• Only 0.1% of cyclosporine is excreted unchanged in

urine.

• Cyclosporine is extensively metabolized in the liver by

the cytochrome-P450 3A enzyme system and to a

lesser degree by the gastrointestinal tract and kidney.

• In the presence of hepatic dysfunction, dosage

adjustments are required.

Therapeutic Uses:

• Clinical indications for cyclosporine are kidney, liver, heart

and other organ transplantation; rheumatoid arthritis; and

psoriasis.

• Cyclosporine usually is used in combination with other agents,

especially glucocorticoids and either azathioprine or

mycophenolate mofetil and most recently sirolimus.

Toxicity:

• Renal dysfunction

• Tremor

• Hirsutisim

• Hypertension, hyperlipidemia

• Gingival hyperplasia

Drug Interactions:

• Any drug that affects microsomal enzymes , especially the

CYP3A system may often affect cyclosporine blood

concentrations( Faulds et al., 1993).

• Calcium channel blockers( verapamil, nicardipine)

• Antifungal agents( fluconazole, ketoconazole)

• Antibiotics( Erythromycin)

• Glucocorticoids( methyl prednisolone)

• HIV- protease inhibitors (indinavir)

• Allopurinol

• Metoclopramide

TACROLIMUS:

• Tacrolimus( PROGRAF, FK506) is a macrolide antibiotic

produced by Streptomyces tsukubaensis (Goto et al., 1987)


• Like cyclosporine, tacrolimus inhibits T cell activation by

inhibiting calcineurin.

Disposition and Pharmacokinetics:

• Tacrolimus is available for oral administrations as capsules(0.,1,

and 5mg) and a sterile solution for injection(5mg/ml).

• Its half life is about 12 hours.

• It is extensively metabolized in the liver.

Therapeutic uses:

• Tacrolimus is indicated in prophylaxis of solid-organ allograft

rejection n a manner similar to cyclosporine and as rescue

therapy in patients with rejection episodes despite

“therapeutic” levels of cyclosporine.

• Recommended starting dose for tacrolimus injection is 0.03 to

0.05 mg/kg per day as a continuous infusion.

Toxicity:

• Nephrotoxicity

• Neurotoxicity

• Gastrointestinal complaints

• Hypertension

• Hyperkalemia

• Hyperglycemia

Drug interactions:

• Same as cyclosporine.

Antiproliferative and Antimetabolic Drugs

SIROLIMUS:• Sirolimus (rapamycin; RAPAMUNE) is a macrolide lactone

produced by Streptomyces hygroscopicus.


• Sirolimus inhibits T-lymphocyte activation and proliferation

downstream of the IL-2 and other T-cell growth factor

receptors.

• It also requires formation of a complex with the

immunophilin,FKBP-12.


• Following oral administration, sirolimus is absorbed rapidly and

reaches a peak blood concentration within 1hour after a single dose

in healthy subjects and within about 2 hours after multiple oral doses

in renal transplant patients.

Therapeutic uses:

• Indicated for prophylaxis of organ transplant rejection in

combination therapy with calcineurin inhibitors and glucocorticoids.

• Used with glucocorticoids and mycophenolate mofetil to avoid

permanent renal damage.

• Loading dose 3mg/m2 .Dose should be adjusted based on the age.

Toxicity:

• Anemia

• Leukopenia

• Thrombocytopenia

• Hypo or hyperkalemia

• Fever

• Gastrointestional effects

Drug interactions:

• Dose adjustment may be required with

coadministration of sirolimuus with

-cyclosporine

-diltiazem

-rifampin

AZATHIOPRINE:

• Azathioprine (IMURAN) is a purine antimetabolite.

• It is a an imidazolyl derivative of 6-mercaptopourine.


Exposure to nucleophiles, such as glutathione

Azathioprine is cleaved to 6-mercaptopurine

6-mercaptopurine is converted to additional metabolites that inhibit de novo purine

synthesis

• Cell proliferation is prevented, inhibiting a variety of

lymphocyte functions.


• Azathioprine is well absorbed orally

and reaches maximum blood levels

within 1 to 2 hours after administration.

• Half life is about 10 minutes.

• Both azathioprine and mercaptopurine

are rapidly removed from the blood by

oxidation or methylation in the liver

and/or erythrocytes.

Therapeutic uses:• It was introduced as immunosuppressive agents in 1961, helping to

make allogeneic kidney transplantation possible.

• It is indicated as an adjunct for prevention of organ transplantation

rejection and in severe rheumatoid arthritis.

• 3 to 5mg/kg per day is the usual starting dose.

• Lower initial doses are used in treating rheumatoid arthritis(

1mg/kg per day)

• Bullous pemphigoid, Behcet disease. Toxicity:

• Bone marrow suppression with leukopenia, thrombocytopenia,

anemia.

• Increased susceptibility to infections.

• Hepatotoxicity, alopecia, pancreatitis, increased risk of neoplasia.

Drug interactions:

• Its best to avoid allopurinol and azathioprine

together.

• Adverse effects with other myelosuppressive

agents or angiotensin converting enzyme

inhibitors- leukopenia, thrombocytopenia,

anemia as a result of myelosuppression.

MYCOPHENOLATE MOFETIL:• Mycophenolate mofetil is the 2-morpholinoethyl ester of

mycophenolic acid.

• It is a new immunosuppressant.


• It is a prodrug that is rapidly hydrolysed to the active drug,

mycophenolic acid, a selective, uncompetitive and reversible

inhibitor of inosine monophosphate dehydrogenase, an

important enzyme in the de nevo pathway of guanine

nucleotide synthesis.

• B and T lymphocytes are highly dependant on this pathway

and therefore inhibits lymphocyte proliferation and functions

including antibody formation, cellular adhesion and migration.


• It undergoes rapid and complete metabolism to

MPA after oral or intravenous administration.

• T half is about 16 hours.

Therapeutic uses:

• Indicated for prophylaxis of transplant

rejection and is typically used in

combination with glucocorticoids and

calcineurin inhibitors, but not with

azathioprine.


• Dose: 1.gm BD oral; CELLMUNE,

MYCEPT, MYCOFIT 250, 500 mg tab/cap.

Toxicity:

• Leukopenia

• Diarrhoea

• Vomiting

• Increased incidence of infections, especially

sepsis with CMV.

Drug interactions:

• Cyclosporine

• Sulfamethoxazole/trimethoprim

• Oral contraceptives

METHOTREXATE

• This folate antagonist is a potent immunosuppressant

which markedly depresses cytokine production and cellular

immunity and has antinflammatory property.

• Used as first line of drug in many autoimmune diseases

like rapidly progressing rheumatoid arthritis, severe

psoriasis, pemphigus, myasthenia gravis.

GLUCOCORTICOIDS

• The introduction of glucocorticoids as immunosuppressant

drugs in the 1960s played a key role in making organ

transplantation possible.


• Steroids lyse and possibly induce the redistribution of

lymphocytes, causing a rapid, transient decrease in peripheral

blood smear count.

• Of central importance in this regard is the downregulation of

important proinflammatory cytokines, such as IL-1 and IL-6.

• T cells are inhibited from making IL-2

Therapeutic uses:

• Commonly used in combination with immunosuppressive

agents to both prevent and treat transplant rejection.

• High doses of methylprednisolone sodium succinate are used

to reverse acute transplant rejection and acute exacerbations

of selected autoimmune diseases.

• Graft versus host disease

• Rheumatoid and other arthritides

• SLE

• Oral lichen planus

• Oral lesions of lupus erythematosus

• Cicatricial pemphigoid


• Pemphigus

• Behcet disease

• Recurrent apthous stomatitis

• Limit allergic reactions that occur with

other immunosuppressive agents Toxicity:

• Growth retardation

• Osteopenia

• Avascular nrcrosis of bone

• Increased risk of infection

• Poor wound healing

• Cataracts, hyperglycemia and hypertension

ANTIBODIES

Muromonab CD3:

• It is a murine monoclonal antibody against the CD3

glycoprotein located near to T cell receptor on helper T

cells.

• Participation of T cells in the immune response is prevented

and T cells rapidly disappear from circulation leading to an

immune blocked state.

• It has an induction therapy together with corticosteroids and

azathioprine

• Serves to delay potential nephron- and hepatotoxicity.

Antithymocyte globulin:

• It is a polyclonal antibody purified from horse or rabbit

immunized with human thymic lymphocytes which binds to T

lymphocyte and depletes them.

• It is a potent immunosuppressant and has been used primarily

to suppress acute allograft rejection episodes.

• It has the potential to produce serum sickness or anaphylaxis.

• Dose: LYMPHOGLOBULIN 100mg/vial inj;10mg/kg/day i.v

ATG 100mg inj; 200mg i.v/day.

REFERENCES:

• Goodman and Gilman’s The pharmocological

basics of therapeutics

• Medical physiology – Guyton and Hall

• Pharmacology KD Tripathi.

• Essential of Medical Physiology – K Sembulingam

• Burket’s Oral Medicine Eleventh Edition

• Daniel M. Laskin Oral and Maxillofacial Surgery Volume 1

THANK YOU

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