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.
• 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

• 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.

• 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.

• 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.
• 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.
• 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

• 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

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