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IMMUNOPHARMACOLOGY
Presented By –Janhavi Yashwant Burade
Vidyabharti College of Pharmacy Amravati
M.Pharm 2nd sem
( Pharmacology )
Content
■ Introduction
■ Immunostimulants
■ Immunosuppressants
■ Cellular and biochemical mediators of inflammation & immune
response
■ Allergic or hypersensitivity reactions
■ Recent advances in immunopharmacology
Introduction
■ Immunopharmacology is the study of the effects of the drugs
modifying immune mechanism in body.
■ It includes not only inoculation but also autoimmune disorders,
allergic reactions, and cancer.
■ A significant development has new approach to control the
immunological mechanism by drugs. Eg. Immunosuppressant.
Immune System
Immunity
■ The resistance offered by the host
to the harmful effects of
pathogenic micobial infection is
called ‘immunity ‘.
■ The study of immunity is called
'immunology’ & the preparation
used to produce immunity are
called 'immunological
preparations’ .
Types of Immunity
Components of Immune System
Antigen Antibodies
Antigen
■ It is any substance that when introduced into the body, stimulates
the production of an antibody.
■ An antigen is an organic compound – protein, polysaccharide or
glycolipid. It has 2 parts
■ Hapten
■ Carrier
Antigens include
■ Toxins
■ Bacteria
■ Foreign blood cells
■ Microorganisms
■ Allergens
■ Viruses Etc.
Types of Antigen
1.Exogenous antigens
Exogenous antigens are antigens that have entered the body from the outside, for example by
inhalation, ingestion, or injection.
2.Endogenous antigens
Endogenous antigens are antigens that have been generated within previously normal cells as a
result of normal cell metabolism, or because of viral or intracellular bacterial infection.
3.Autoantigens
An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA)
that is recognized by the immune system of patients suffering from a specific autoimmune
disease.
4.Tumour antigens or neoantigens
Those antigens that are presented by MHC I or MHC II molecules on the surface of tumor cells.
These antigens can sometimes be presented by tumor cells and never by the normal ones. In this
case, they are called tumor-specific antigens (TSAs) and, in general, result from a tumor-specific
mutation.
Antibodies ( Immunoglobulin )
■ They are gamma globulins or
immunoglobulin's produced in the serum
on exposure to antigen.
■ Chemically they are glycoprotein's
containing two heavy chains and two light
chains joined together by disulfide bonds.
■ It has 2 parts
1) Fab 2) Fc
■ The entire antibody structure can be
cleaved by papain(a proteolytic enzyme)
■ There are 5 types of Antibodies: IgG ,IgM ,
IgA , IgE , IgD
Types of Antibody
Immunomodulators
■ Immunomodulators are drugs which either suppress the immune
system –Immunosuppressants
or
■ stimulate the immune system –Immunostimulants
Immunostimulants
Immunostimulants
■ Immunostimulants are biologic therapeutic agents designed to boost
the body’s natural defenses to fight the cancer and other diseases.
■ It uses materials either made by the body or in a laboratory to
improve, target, or restore immune system function.
■ Precisely, It is the use of medicines to stimulate a patient’s own
immune system to recognize and destroy cancer cells more
effectively.
■ Immunostimulatory drugs have been developed with applicability to
infection, immunodeficiency,
■ They works on cellular as well as humoral immune system or both
Classification of Immunostimulants
1. Specific immunostimulants:- Immunostimulants provide
antigenic specificity in immune response, such as vaccines or any
antigen.
2. Non- specific immunostimulants:-Immunostimulants act
irrespective of adjuvantan specificity to augment immune response
of other antigen or stimulate components of the immune system
without antigenic specificity, such as adjuvants and non-specific
immunostimulators.
LEVAMISOLE
■ It was descovered in 1966
■ Levamisole was synthesized originally as an anthelmintic/antiparasitic agent
■ But it restores the depressed immune function of B lymphocytes,T
lymphocytes, monocytes and macrophages
■ It taken Orally, metabolised in liver & and excreted in urine
■ t½ - 3-4hrs
■ Brand name :- ERGAMISOL
Uses:-
hodgkin’s lymphoma
RA
ADR:-
Flu-like symptoms, allergic manifestation, nausea and muscle pain
THALIDOMIDE:
■ Thalidomide was introduced in 1958 for morning sickness and was
found to be highly teratogenic and withdrawn in 1961.
■ But it has been reintroduce as immunomodulator , and angiogenesis
inhibitor antitumour drug.
■ Again it has anxiolytic , antiemetic , adjuvant analgesic /antipyretic
properties and has been found to counteract cancer associated
cachexia and retard tumour growth by inhibiting angiogenesis.
■ Thalidomide is also useful in erythema nodosum leprosum(ENL).
MOA:-
■ It result in suppression of excessive tumor necrosis factor-alpha (TNF-a) production and
down-modulation of selected cell surface adhesion molecules involved in leukocyte
migration.
■ For example, administration of thalidomide has been reported to decrease circulating levels
of TNF-a in patients with ENL, however, it has also been shown to increase plasma TNF-a
levels in HIV-seropositive patients. As a cancer treatment, the drug may act as a VEGF
inhibitor(vascular endothelial growth factor inhibitor).
Pharmacokinetics:-
■ Thalidomide in treatment of ENL admisterd orally (100-300mg OD at bed time )
■ Protein binding:-55% and 66% for the (+)R and (−)S enantiomers, respectively.
■ Metabolism:- Thalidomide itself does not appear to be hepatically metabolized to
any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to
multiple metabolites. Thalidomide may be metabolized hepatically by enzymes of
the cytochrome P450 enzyme system. The end product of metabolism, phthalic acid,
is excreted as a glycine conjugate.
■ Route of elimination:- Thalidomide itself has less than 0.7% of the
dose excreted in the urine as unchanged drug.
■ Half-life:- The mean half-life of elimination ranges from
approximately 5 to 7 hours following a single dose and is not altered
upon multiple dosing
Adverse effect:- Teratogenicity
Brand Name:- THAANGIO , THALODA 50, 100mg cap.
Immunization
A.Bacterial Vaccine:-
■ Bacterial vaccines contain killed or attenuated bacteria that activate
the immune system.
■ Antibodies are built against that particular bacteria & prevents
bacterial infection later
■ An example of a bacterial Vaccine is tha BCG Vaccine.
BACILLUS CALMETTE-GUERIN (BCG)
■ Live culture of Bacillus Calmette-Guerin strain of Mycobacterium
bovis.
■ Induces granulomatous reaction at the site of administration.
Therapeutic uses:-
■ Treatment and prophylaxis of carcinoma of urinary bladder,
■ Prophylaxis of primary and recurrent stage of papillary tumors
■ BCG Vaccine is used in many countries with a high prevalence of TB to
prevent childhood tuberculosis , meningitis & miliary disease.
Side Effects:-
■ Hypersensitivity
■ Shock
■ chills
■ fever,
■ malaise,
B. Viral Vaccine
■ Viral Vaccine contains either inactivated virus or attinuatade ( alive but not
capable of causing disease )viruses
■ Inactivated or killed viral vaccine contains viruses , which have lost their
ability to replicate & in order for it to bring about a response it contains
more antigen that live vaccines
■ Attenuated or live vaccines contain the live form of the virus. These viruses
are not pathogenic but are able to induce an immune response.
Side ffects:-
■ Blood in the urine or stool
■ Pneumoniae
■ Inflammation of the stomach or intestine
C. Vaccine Combination
■ Vaccine combination merge antigens that prevent different diseases or
thet protect against multiple strains of infectious agents causing the same
diseasesb, into a single product.
■ This reduces the no. of injections required to prevent some disease.
Some examples of common combination Vaccine for children :-
1. MMR :- Mesales + Mumps + Rubella
2. DTaP :- Diptheria + Tetanus + Pertussis
3. Comvax :- Hib + Hepatitis B
4. Tunrix :- Hepatitis A + Hepatitis B
5. Pediarix :- DTaP + Hepatitis B+ IPV ( Polio)
6. Kinrix :- DTaP + IPV ( Polio)
RECOMBINANT CYTOKINES
A. Interferons:-
■ Interferons are cytokines produced by host cells in response to viral
infections.These are of 3types :- alpha , beta and gamma.
■ Interferon gamma-1b a recombinant polypeptide that activates
phagocytes induces the generation of oxygen metabolites that are
toxic to a number of microorganisms.
■ Interferon beta-1a : 166-amino acid recombinant glycoprotein
■ interferon beta-1b :165-amino acid recombinant glycoprotein
■ Both have antiviral and immunomodulatory
■ They inhibit the multiplication of many DNA & RNA viruses.
Adverse effects:- Myelosuppresion , hypertension , alopecia ,
headache , arrhythmia , Neurotoxicity resulting in confusion , sedation ,
rearly seizures.
Uses:-
■ Chronic hepatitis B&C
■ Kaposis sarcoma in AIDS patients
■ Genetic warts caused by papilloma virus
■ Hairy cell leukemia
■ Rhinovirus cold :- Interferon alpha is given intranasally for prophylaxis
B. Iterleukins:-
■ Interleukins are a group of Cytokines which are synthesized by
lymphocytes, monocytes , macrophages and certain other cells
■ They are mainly used in treatment of cancer therapy
C. Colony Stimulating Factors:-
■ Colony stimulating factors are glycoproteins that promote production of WBC
( mainly granulocytes such as neutrophils ) in response to infection.
■ An administration of exogenous colony stimulating factors stimulates the
stem cells in the bone marrow to produce more of the particular WBCs.
■ The new WBCs migrate into the blood & fight the infection
Uses:-
■ Colony Stimulating Factors are used in patients who are undergoing
cancer treatment that causes low WBC count ( neutropenia ) & puts
the patient at risk of infection. Colony Stimulating Factors tend to
reduce the time where patient are neutropenic .
Immunosuppressant
Immunosuppressant
■ Immunosuppressant drugs are a class of drugs that suppress or
reduce the strength of the body’s immune system. They are also
called anti-rejection drugs. One of the primary uses of
immunosuppressant drugs is to lower the body’s ability to reject
a transplanted organ, such as a liver, heart or kidney.
■ Almost everyone who receives an organ transplant has to take
immunosuppressant drugs. The body recognizes a transplanted
organ as a foreign mass. This triggers a response by the body’s
immune system to attack it.
■ By weakening the immune system, immunosuppressant drugs
decrease the body’s reaction to the foreign organ. The drugs
allow the transplanted organ to remain healthy and free from
damage
Continue…
■ Immunosuppressant drugs also are used to treat autoimmune diseases
such as lupus. An autoimmune disorder is a disease process in which the
body attacks its own tissue. Lupus results from just such a misdirected
activity of the body’s own immune system. By suppressing this reaction,
immunosuppressant drugs can help control the impact of the disease on
the body.
■ OTHER DISEASES TREATED WITH IMMUNOSUPPRESSANT DRUGS
INCLUDE:
•Psoriasis
•Rheumatoid arthritis
•Crohn’s disease, a chronic inflammation of the digestive tract
•Multiple sclerosis
•Alopecia areata (patchy hair loss)
Classification of Immunosuppressants
1 . Calcineurin inhibitors (SpecificT-cell inhibitors):-
Cyclosporine (Ciclosporin), Tacrolimus , Sirolimus
2. Antiproliferative drugs (Cytotoxic drugs):-
Azathioprine, Cyclophospharnide,Methotrexate,
Chlorambucil,Mycophenolate mofetil (MMF)
3. Glucocorticoids:-
Prednisolone and others
4. Antibodies:-
Muromonab CD3, Antithymocyte globulin(ATG),
Rho (D) immuneglobulin
1.Calcineurin inhibitors
A.Cyclosporine
MOA
■ Cyclosporine preferentially suppresses cell-mediated immune
reactions
■ After diffusing into the T cell, Cyclosporine binds to a cyclophilin
(more generally called an immunophilin) to form a complex that
binds to calcineurin.
■ The latter is responsible for dephosphorylating NFATc (cytosolic
Nuclear Factor of Activated T cells).
■ The CsA-calcineurin complex cannot perform this reaction; thus,
NFATc cannot enter the nucleus to promote the reactions that are
required for the synthesis of a number of cytokines, including IL-2.
■ The end result is a decrease in IL-2 the primary chemical stimulus for
increasing the number of T lymphocytes.
Route of administration:- Oral & IV
■ Metabolised in liver by CYP3A4 & excreted in bike
■ The plasma half life is biphasic 4 – 6 hrs & 12 – 18 hrs
Side effects:-
Nephrotoxic
Impair liver function
Rise in BP.
Precipitation of diabetes
Anorexia
Hyperkalemia
Hirautism
Gum hyperplasia
Tremor seizures
Uses:-
1. Most effective drug for prevention &
treatment of graft rejection reaction
2. Routinely used in renal , hepatic , cardiac ,
bone marrow transplantation
3. Second line drug in autoimmune disease
like rheumatoid arthritis , uveitis , bronchial
asthma , inflammatory bowel disease ,
dermatomyositis ,etc .
4. In psoriasis , especially to suppress acute
excerbation
B. Tacrolimus
MOA:-
■ This Immunosuppressants is chemically different from cyclosporine
but has the same MOA , and is ~100 times more potent
■ It bind to a different cytoplasmic immunophilin protein labelled ‘FK
506 binding protein ( FKBP ) , but subsequent steps are same as
cyclosporine
Route of administration:- Oral & i.v. infusion
■ Metabolised in liver by CYP3A4 & excreted in bile with a t1/2 of 12
hrs
Uses:- Used in fistulating Chron’s disease
C. Sirolimus
MOA
■ SIROLIMUS bind to the same cytoplasmic FK-
binding protein,but instead of forming a
complex with calcineurin, SRL binds to
molecular target of rapamycin interfering with
Signal.
■ The latter is a serine-threoninekinase Binding
of SIROLIMUS to molecular target of
rapamycin blocks the progression of activated
T cells from the G1 to the S phase of the cell
cycle and, consequently, the proliferation of
these cells.
■ Unlike Cyclosporine and Sirolimus and
Tacrolimus does not owe its effect to lowering
IL-2 production but, rather, to inhibiting the
cellular responses to IL-2.
■ Sirolimus is absorbed orally , but fatty meal reduce its absorption
■ It is extensively metabolised , mainly by CYP3A4 , so that systemic
bioavailability is only 15-20%
■ Elimination by biliary route
■ t1/2 is ~60 hrs
Use:- prophylaxis and therapy of graft rejection reaction
Side effects :-
1. Bone marrow suppression
2. Thrombocytopenia
3. Rise in serum lipid
4. Diarrhoea
5. Liver damage
6. Pneumonitis
RAPACAN 1 mg tab
2. Antiproliferative Drugs
A.Mycophenolate motife ( MMF)
MOA
■ Mycophenolate safety and efficacy in
prolonging graft survival.
■ It has been successfully used in heart, kidney,
and liver transplants.
■ As an ester, it is rapidly hydrolyzed in the
gastrointestinal tract to mycophenolic acid
(MPA), which is a potent, reversible,
uncompetitive inhibitor of inosine
monophosphate dehydrogenase, blocking the
de novo formation of guanosine phosphate.
■ Thus, like 6-MP, it deprives the rapidly
proliferating T and B cells of a key component
of nucleic acids.
■ t1/2 ~16hrs
Side effects:- Vomiting , diarrhoea , leucopenia
, g.i. bleeding
B. Azathioprine
MOA:-
■ It is a purine antimetabolite which has more marked immunosuppressant than
antitumour action.
■ The basis for this difference is not clear, but may be due its selective uptake into
immune cells and intracellular conversion to the active metabolite 6-
mercaptopurine, which then undergoes further transformations to inhibit de
novo purine synthesis and damage to DNA. It selectively affects differentiation
and function of T cells and inhibits cytolytic lymphocytes; CMI is primarily
depressed.
Pharmacokinetics :-
■ It is administered orally or sometimes by means of intravenously
■ It metabolised mainly in liver , it is activated non-enzymatically, deactivated
mainly by xanthine oxidase
■ Bioavability :- 60+-31%
■ Protein binding :- 20 – 30%
■ T1/2 :- 26–80 minutes
■ Excreted by kidney
Uses:-
It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn’s
disease, ulcerative colitis, and systemic lupus erythematosus, and in kidney
transplants to prevent rejection.
Side Effect:-
■ Common side effects include bone-marrow suppression and vomiting.Bone-
marrow suppression is especially common in people with a genetic deficiency
of the enzyme thiopurine S-methyltransferase.
■ Other serious risk factors include an increased risk of certain cancers.
■ Use during pregnancy may result in harm to the baby.
3. Glucocorticoids inhibit MHC expression and IL-I. IL –II. IL-6
production so that Helper T cells are not activated.
4. Antibodies like muromonab CD-3 , antithymocyte
globulyne specifically bind to helper Tcells and prevent their response and
deplete them
Cellular & Biochemical
Mediators of Inflammation
& Immune Response
Inflammation
■ It is defined as the local response of living tissues to injury due to any
agent
■ Inflammation, a process by which the body’s immune system
malfunction.( Failure to function normally )
■ E.g. disease like arthritis , mysthenia gravis
■ There are two types of inflammation i.e acute inflammation and
chronic inflammation
Causes of Inflammation
1. Infective Agents :- Bacteria , viruses & their toxins , fungi ,
parasites
2. Immunological Agents :- Cell – mediated & antigen
antibody reactions
3. Physical Agents :- Heat , cold , radiation , mechanical
trauma
4. Chemical Agents :- Organic acid , inorganic poisons
5. Inert Materials :- such as foreign bodies
Cellular & Biochemical Mediators of
Inflammation & Immune Response
■ Definition: Any messenger that acts on blood vessels, inflammatory
cells, or other cells to contribute to an inflammatory response.
Classification
Cell derived
mediators
Plasma derived
mediators
1. Cell derived mediators
a) vasoactive amines (serotonin,histamine)
b) arachidonic acid metabolites
■ cycloxygenase pathway
■ lipoxygenase pathway
c) Lysosomal components
d) Platelet activating factor
e) Cytokines (IL-1,TNF-α,TNF-β,IF-γ,Chemokines)
f) Nitric oxide and oxygen metabolites
a) Vasoactive amines
Histamine :-
■ Stored in granuls of mast cells, basophiles and platelets.
■ Released by the stimuli of various agents like Heat, Cold, Irradiation,
Irritant chemicals, Anaphilatoxins, Interleukins,.. Etc.
■ Actions ; VasodilationVascular permeability Itching and pain
Serotonin/5-hydroxy tryptamine :-
■ Present in chromafin cells of GIT, Spleen, Nervous tissue, Mast cells,
Platelets.
■ Actions :- Similar to Histamine, but less potent
Vasodilation
Vascular permeabilityatoxins
b) Arachidonic acid Metabolites
c) Lysosomal comonents
■ Source :- Neutrophiles and monocytes
■ Potent mediators
■ Degredation of bacterial and extracellular components
■ Chemotaxis
■ Realease of acid proteases, collagenase, elastase, plasminogen
activator
D) Platelet activating factor
■ Phospholipid derived mediator
Released from :- Platelets, basophil, mast cells, neutrophils
macrophages, endothelial cells
Actions :-
1. Vascular permeability
2. Vasoconstriction
3. Vasodilatation
4. Bronchoconstriction
5. Adhesion of leukocytes to endothelium
6. Chemotaxis, degranulation
e) Cytokines
■ “Cytokines are a diverse group of small protein molecules with
potent biological activity whose main function is in the regulation of
immune responses.”
■ Main Cytokines are :-
Interleukins
Interferons
Tumor necrosis factor
Chemokines
Transforming growth factor-beta
Adipokines- leptin & adiponectin
Actions :-
■ Increase adhesion of leucocytes to endothelium
■ Increase synthesis of Prostacyclin, which is a vasodilator
and anti aggregator of platelets
■ Increase Synthesis of PAF and thrombogenic effect on
endothelial surface
2.Plasma derived mediators
■ a) The kinin system
■ b) The clotting system
■ c) The fibrinolytic system
■ d) The complement system
• 4 interlinked systems
• Hageman factor(factor
XII)
• End product of clotting
,fibrinolytic ,kinin
system will activate
complement system.
a) The kinin system
• Actions :-
•
• Smooth muscle
contraction
• Vasodilation
• Increase vascular
permeability
b) Clotting system
Actions :-
Increase vascular
permeability
Chemotaxis for leucocytes
Anticoagulant activity
C) Fibrinolytic system
Actions :-
■ Activation of factor XII to form prekallikrein activator that stimulates
kinin system to generate bradykinin
■ Splits off complement c3 to form c3a,which is permeability factor
■ Degrades fibrin to split products, they increase vascular permeability
D) Complement system
■ It consists plasma proteins
■ Product of complement system is anaphylatoxins c3a and c5a.
■ Potency is c3a>c5a>c4a
Actions:- release histamine from mast cells and basophils
■ C5a is chemotactic for leucocytes.
■ Membrane attack complex cause pores in cell of invading microbes.
Allergic Or Hypersensitivity
Reactions
Allergy
■ A disorder of the immune system often also referred to as atopy.
■ Strictly, allergy is one of four forms of hypersensitivity and is called
type I (or immediate) hypersensitivity.
■ Allergic reactions occur to normally harmless environmental
substances known as allergens.
■ Reactions are acquired, predictable, and rapid Include eczema,
hives, hay fever, asthma attacks, food allergy, and reactions to
drugs and the venom of stinging insect such as wasp and bees
Hypersensitivity Reactions
■ Hypersensitivity is an abnormal immune response which produces
physiological or histopathological damage in the host.
■ Hypersensitivity reactions have been classified into 'immediate’ &
'delayed’ types , based on the time required for a sensitised host to
develop clinical reactions on re-exposure to the antigen.
■ Coombs & Gell (1963) classified hypersensitivity reactions into five
types based on the different mechanisms of pathogenesis :-Type I ,
Type II , Type III , Type IV , Type V.
Types of Hypersensitivity Reactions
■ Type I :- Anaphylactic, immediate ,IgE or reagin dependent :- eg .
Anaphylaxis, Atopy etc
■ Type II:- Cytotoxic or cell stimulating :- e.g. thrombocytopenia ,
hemolytic anemia etc
■ Type III :- Immuno complex or toxic complex :- e.g. Arthus reaction ,
serum sickness etc
■ Type IV :- Delayed or T-cell mediated :- e.g.tuberculin type , contact
dermatitis etc
■ Type V:- Stimulatory or antireceptor:- e.g.autoimmune orchitis in
guinea pig
Type I Hypersensitivity
■ Type I hypersensitivity is also known as immediate or anaphylactic
hypersensitivity.
■ The reaction may involve skin (urticariaand eczema), eyes (conjunctivitis),
nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and
gastrointestinal tract (gastroenteritis).
■ The reaction may cause a range of symptoms from minor inconvenience to
death.
■ The reaction usually takes 15 – 30 minutes from the time of exposure to the
antigen, although sometimes it may have a delayed onset (10 – 12 hours).
■ Mediated by IgE antibody to specific antigens
■ The primary cellular component in this hypersensitivity is the mast cell or
basophil.
■ The reaction is amplified and/or modified by platelets, neutrophils and
eosinophils.
Causes of type I Hypersensitivity
■ ALLERGEN:Allergens are nonparasite antigens that can stimulate a type
I hypersensitivity response.
Common
Allergen
Associated
with Type I
Hypersensitivit
y
Atopy
■ Atopy is the term for the genetic trait to have a predisposition for
localized anaphylaxis.
■ Atopic individuals have higher levels of IgE and eosinophils.
Mechanism of Type I Hypersensitivity
Mediators of Type I Hypersensitivity
1. Histamine
2. Cytokines TNF- , IL-1, IL-6.
3. Chemoattractants for Neutrophils and Eosinophils.
4. Enzymes tryptase, chymase, cathepsin.
5. Changes in connective tissue matrix, tissue breakdown
6. Leukotrienes
7. Prostaglandins
Treatment of Type I Hypersensitivity
■ Drugs.
1. Non-steroidal anti-inflammatories
2. Antihistamines block histamine receptors.
3. Steroids
4. Theophylline OR epinephrine –prolongs or increases cAMP levels in
mast cells which inhibits degranulation.
■ Immunotherapy
1. Desensitization (hyposensitization) also known as allergy shots.
2. Repeated injections of allergen to reduce the IgE on Mast cells and
produce IgG.
Type II Hypersensitivity
■ Type II hypersensitivity is also known as cytotoxic hypersensitivity and may
affect a variety of organs and tissues.
■ The antigens are normally endogenous, although exogenous chemicals
(haptens) which can attach to cell membranes can also lead to type II
hypersensitivity.
■ Drug-induced hemolytic anemia, granulocytopenia and thrombocytopeniaare
such examples. Pencillin allergy also belong to this class.
■ The reaction time is minutes to hours.
■ Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG
classes and complement .
■ Phagocytes may also play a role.
■ The lesion contains antibody, complement and neutrophils.
Type II Hypersensitivity Reaction
Type III Hypersensitivity
■ Antigen antibody immune complexes. IgG mediated
■ Large amount of antigen and antibodies form complexes in blood.
■ If not eliminated can deposit in capillaries or joints and trigger inflammation.
■ The reaction may be general (e.g.,serum sickness) or may involve individual
organs including skin (e.g., systemic lupus erythematosus, Arthus reaction),
kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), joints
(e.g.,rheumatoid arthritis) or other organs.
■ This reaction may be the pathogenic mechanism of diseases caused by
many microorganisms.
Continue…
■ The reaction may take 3 – 10 hours after exposure to the antigen .
■ It is mediated by soluble immune complexes.
■ They are mostly of the IgG class, although IgM may also be involved.
■ The antigen may be exogenous (chronic bacterial, viral or parasitic
infections), or endogenous (non-organ specific autoimmunity: e.g.,
systemic lupus erythematosus, SLE).
■ The antigen is soluble and not attached to the organ involved
Type III Hypersensitivity Reaction
Type IV Hypersensitivity
■ Reaction involves sensitized T cellsand release of its lymphokines as
mediators and amplifiers
■ Mediated by cells rather than antibodies
■ Clinical states: Contact dermatitis, Transplant rejection, Granuloma
■ Th1 cells release cytokines to activate macrophages causing
inflammation and tissue damage.
■ Continued macrophage activation can cause chronic inflammation
resulting in tissue lesions, scarring, and granuloma formation.
■ Response starts after 48 -72 hrs
Type IV Hypersensitivity Reaction
Type V Or Stimulatory Hypersensitivity
■ It is an antibody mediated Hypersensitivity
■ In this case, an antibody reacts with a key surface component such
as a hormone receptor & switch on or stimulates the cell.
■ E.g. thyroid Hypersensitivity in Grave’s disease due to thyroid
stimulating autoantibody.
Recent Advances In
Immunopharmacology
Recent Therapeutic Advances
A.Metastatic Melanoma
PHASE Zero
1 . IMIQUIMOD (ZYCLARA)
■ A drug in the form of cream which stimulates a local immune response against skin cancer cells
in sensitive areas on the face.some doctors may use imiquimod if surgery might be disfiguring.
2 . Cytokines
■ Cytokines such as INTERFERON-ALFA AND INTERLEUKIN-2 (IL-2), are proteins in the body that
boost the immune system.
■ They are given as intravenous (IV) infusions, at least at first.
■ Interferon-alfa can be used as an added (adjuvant) therapy after surgery to try to prevent the
thicker cells from spreading and growing. This may delay the recurrence of melanoma
3 . BACILLE CALMETTE-GUERIN (BCG) VACCINE
■ BCG activate the immune system.
■ The BCG vaccine works like a cytokine by enhancing the entire immune system.
■ It is sometimes used to help treat stage III melanomas by injecting it directly into tumors.
Later Phase
CTLA-4 INHIBITOR
DRUG USED
•Ipilimumab (Yervoy)
■ It is another drug that boosts
the immune response, but it
has a different target.
■ It blocks CTLA-4, another
protein on T cells that
normally helps keep them in
check.
■ Used in melanomas which
can’t be removed by surgery.
■ It helps in prolonging the life
span of the patient
PD-1 INHIBITORS
DRUGS USED
•Pembrolizumab (Keytruda)
•Nivolumab (Opdivo)
■ These are drugs that target PD-1, a
protein on immune system cells called T
cells that normally help keep these cells
from attacking other cells in the body.
■ By blocking PD-1, these drugs boost the
immune response against melanoma
cells, which can often shrink tumors and
help people live longer
B. FLAMMATORY BOWEL
DISEASE (IBD)
■ i.e. Crohn’s disease (CD) and
ulcerative colitis (UC)
AZATHIOPRINE (AZA),
6-MERCAPTOPURINE (6-MP),
METHOTREXATE (MTX)
C. NON-SMALL CELL
LUNG CANCER
Ipilimumab
D. ANCREATIC CANCER
Urelumab
E. LERGIC DISEASES
Peptides
Recent Technology
1. Oncolytic Virus Therapies
■ Oncolytic virus therapy use a modified virus that can cause tumor cells to destruct
& generate a greater immune response against the cancer
■ In May 2015, based on results from a large completed phase III trial , the oncolytic
virus therapy TALIMOGENE LAHERPAREPVEC (T-VEC) made by Amgen, was
recommended for marketing approval by an independent advisory panel to the
FDA .
■ The T-VEC used in the treatment of melanoma. By injecting locally into cutaneous,
subcutaneous or nodar melanoma.
■ Side effects :- flu like symptoms , pain at the site of injection
■ Contraindication :- Pregnancy
■ Trade Name :- T-Vec , IMIYGIC , ONCOVEX
2. Adoptive T Cell Therapy
■ Another major avenue of immunotherapy for melanoma is
ADOPTIVE T CELL TRANSFER. In this approach, T cells are
removed from a patient, genetically modified or treated
with chemicals to enhance their activity or numbers, and
then re-introduced into the patient with the goal of
improving the immune system’s anti-cancer response.
3.Therapeutic Vaccines
■ Cancer vaccines are designed to elicit an immune response against
tumor-specific or tumor-associated antigens, encouraging the immune
system to attack cancer cells bearing these antigens.
■ In 2010, the FDA approved Sipuleucel-T (Provenge) for people with
metastatic prostate cancer, which is prostate cancer that has spread.
■ Developed by Dendreon Pharmaceuticals,
■ Sipuleucel-T is tailored to each person through a series of steps:
1.White blood cells are removed from the person’s blood. White blood cells
help the body fight infection and disease.
2. The white blood cells are altered in a laboratory to target prostate cancer
cells.
3. Next, the doctor puts the altered cells back into the person through a
vein. This is similar to a blood transfusion. These modified cells teach the
immune system to find and destroy prostate cancer cells.
■ Route of Administration :- Intravenous
■ Uses :- prostate cancer ( only in men’s )
■ Trade Name :- PROVENGE
4 . Immunomodulatory effects of
Fluroquinolones
■ Immune response are indirectly modulated by FQs through
suppressing pro –inflammatory cytokines , such as interleukin 1 (IL-
1) ,IL-6, tumor necrosis factor-alpha (TNF-alpha), & super-inducing IL-
2, which tend to increase both the growth & activity of T & B
lymphocytes. In addition, they affect the development of immune
response by influencing of expression of both Cytokines & mediators.
References
■ Tripathi K.D. , Essentials of Medical Pharmacology , Jaypee Brothers Medical
Publishers (P) Ltd , 7th Edition 2015 , By , Page No.159 – 210 & 878 – 885.
■ Prof. Kokare Chandrakant , Pharmaceutical Microbiology Principles & Applications
, Nirali Prakashan , 9th Edition January 2013 , Page No. 20.1 – 24.10
■ Goodman & Gilman’s ,The Pharmacological Basis of Therapeutics, 13th Edition
,Page no. 619 – 637
■ Ananthnarayan R. , Paniker C.K.J., Textbook of Microbiology, Orient Longman
Private Limited , 7th Edition 2005 , Page no. 71 – 168
■ Shokrollah Assar et al, A Review of Immunomodulatory Effects of
Fluoroquinolones, A Journal of Molecular and Cellular Immunology, 2020
Immunopharmacology

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Immunopharmacology

  • 1. IMMUNOPHARMACOLOGY Presented By –Janhavi Yashwant Burade Vidyabharti College of Pharmacy Amravati M.Pharm 2nd sem ( Pharmacology )
  • 2. Content ■ Introduction ■ Immunostimulants ■ Immunosuppressants ■ Cellular and biochemical mediators of inflammation & immune response ■ Allergic or hypersensitivity reactions ■ Recent advances in immunopharmacology
  • 3. Introduction ■ Immunopharmacology is the study of the effects of the drugs modifying immune mechanism in body. ■ It includes not only inoculation but also autoimmune disorders, allergic reactions, and cancer. ■ A significant development has new approach to control the immunological mechanism by drugs. Eg. Immunosuppressant.
  • 4. Immune System Immunity ■ The resistance offered by the host to the harmful effects of pathogenic micobial infection is called ‘immunity ‘. ■ The study of immunity is called 'immunology’ & the preparation used to produce immunity are called 'immunological preparations’ .
  • 6. Components of Immune System Antigen Antibodies
  • 7. Antigen ■ It is any substance that when introduced into the body, stimulates the production of an antibody. ■ An antigen is an organic compound – protein, polysaccharide or glycolipid. It has 2 parts ■ Hapten ■ Carrier Antigens include ■ Toxins ■ Bacteria ■ Foreign blood cells ■ Microorganisms ■ Allergens ■ Viruses Etc.
  • 8. Types of Antigen 1.Exogenous antigens Exogenous antigens are antigens that have entered the body from the outside, for example by inhalation, ingestion, or injection. 2.Endogenous antigens Endogenous antigens are antigens that have been generated within previously normal cells as a result of normal cell metabolism, or because of viral or intracellular bacterial infection. 3.Autoantigens An autoantigen is usually a normal protein or complex of proteins (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease. 4.Tumour antigens or neoantigens Those antigens that are presented by MHC I or MHC II molecules on the surface of tumor cells. These antigens can sometimes be presented by tumor cells and never by the normal ones. In this case, they are called tumor-specific antigens (TSAs) and, in general, result from a tumor-specific mutation.
  • 9. Antibodies ( Immunoglobulin ) ■ They are gamma globulins or immunoglobulin's produced in the serum on exposure to antigen. ■ Chemically they are glycoprotein's containing two heavy chains and two light chains joined together by disulfide bonds. ■ It has 2 parts 1) Fab 2) Fc ■ The entire antibody structure can be cleaved by papain(a proteolytic enzyme) ■ There are 5 types of Antibodies: IgG ,IgM , IgA , IgE , IgD
  • 11. Immunomodulators ■ Immunomodulators are drugs which either suppress the immune system –Immunosuppressants or ■ stimulate the immune system –Immunostimulants
  • 13. Immunostimulants ■ Immunostimulants are biologic therapeutic agents designed to boost the body’s natural defenses to fight the cancer and other diseases. ■ It uses materials either made by the body or in a laboratory to improve, target, or restore immune system function. ■ Precisely, It is the use of medicines to stimulate a patient’s own immune system to recognize and destroy cancer cells more effectively. ■ Immunostimulatory drugs have been developed with applicability to infection, immunodeficiency, ■ They works on cellular as well as humoral immune system or both
  • 14. Classification of Immunostimulants 1. Specific immunostimulants:- Immunostimulants provide antigenic specificity in immune response, such as vaccines or any antigen. 2. Non- specific immunostimulants:-Immunostimulants act irrespective of adjuvantan specificity to augment immune response of other antigen or stimulate components of the immune system without antigenic specificity, such as adjuvants and non-specific immunostimulators.
  • 15.
  • 16. LEVAMISOLE ■ It was descovered in 1966 ■ Levamisole was synthesized originally as an anthelmintic/antiparasitic agent ■ But it restores the depressed immune function of B lymphocytes,T lymphocytes, monocytes and macrophages ■ It taken Orally, metabolised in liver & and excreted in urine ■ t½ - 3-4hrs ■ Brand name :- ERGAMISOL Uses:- hodgkin’s lymphoma RA ADR:- Flu-like symptoms, allergic manifestation, nausea and muscle pain
  • 17. THALIDOMIDE: ■ Thalidomide was introduced in 1958 for morning sickness and was found to be highly teratogenic and withdrawn in 1961. ■ But it has been reintroduce as immunomodulator , and angiogenesis inhibitor antitumour drug. ■ Again it has anxiolytic , antiemetic , adjuvant analgesic /antipyretic properties and has been found to counteract cancer associated cachexia and retard tumour growth by inhibiting angiogenesis. ■ Thalidomide is also useful in erythema nodosum leprosum(ENL).
  • 18. MOA:- ■ It result in suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. ■ For example, administration of thalidomide has been reported to decrease circulating levels of TNF-a in patients with ENL, however, it has also been shown to increase plasma TNF-a levels in HIV-seropositive patients. As a cancer treatment, the drug may act as a VEGF inhibitor(vascular endothelial growth factor inhibitor). Pharmacokinetics:- ■ Thalidomide in treatment of ENL admisterd orally (100-300mg OD at bed time ) ■ Protein binding:-55% and 66% for the (+)R and (−)S enantiomers, respectively. ■ Metabolism:- Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. Thalidomide may be metabolized hepatically by enzymes of the cytochrome P450 enzyme system. The end product of metabolism, phthalic acid, is excreted as a glycine conjugate.
  • 19. ■ Route of elimination:- Thalidomide itself has less than 0.7% of the dose excreted in the urine as unchanged drug. ■ Half-life:- The mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing Adverse effect:- Teratogenicity Brand Name:- THAANGIO , THALODA 50, 100mg cap.
  • 20. Immunization A.Bacterial Vaccine:- ■ Bacterial vaccines contain killed or attenuated bacteria that activate the immune system. ■ Antibodies are built against that particular bacteria & prevents bacterial infection later ■ An example of a bacterial Vaccine is tha BCG Vaccine. BACILLUS CALMETTE-GUERIN (BCG) ■ Live culture of Bacillus Calmette-Guerin strain of Mycobacterium bovis. ■ Induces granulomatous reaction at the site of administration.
  • 21. Therapeutic uses:- ■ Treatment and prophylaxis of carcinoma of urinary bladder, ■ Prophylaxis of primary and recurrent stage of papillary tumors ■ BCG Vaccine is used in many countries with a high prevalence of TB to prevent childhood tuberculosis , meningitis & miliary disease. Side Effects:- ■ Hypersensitivity ■ Shock ■ chills ■ fever, ■ malaise,
  • 22. B. Viral Vaccine ■ Viral Vaccine contains either inactivated virus or attinuatade ( alive but not capable of causing disease )viruses ■ Inactivated or killed viral vaccine contains viruses , which have lost their ability to replicate & in order for it to bring about a response it contains more antigen that live vaccines ■ Attenuated or live vaccines contain the live form of the virus. These viruses are not pathogenic but are able to induce an immune response. Side ffects:- ■ Blood in the urine or stool ■ Pneumoniae ■ Inflammation of the stomach or intestine
  • 23. C. Vaccine Combination ■ Vaccine combination merge antigens that prevent different diseases or thet protect against multiple strains of infectious agents causing the same diseasesb, into a single product. ■ This reduces the no. of injections required to prevent some disease. Some examples of common combination Vaccine for children :- 1. MMR :- Mesales + Mumps + Rubella 2. DTaP :- Diptheria + Tetanus + Pertussis 3. Comvax :- Hib + Hepatitis B 4. Tunrix :- Hepatitis A + Hepatitis B 5. Pediarix :- DTaP + Hepatitis B+ IPV ( Polio) 6. Kinrix :- DTaP + IPV ( Polio)
  • 24. RECOMBINANT CYTOKINES A. Interferons:- ■ Interferons are cytokines produced by host cells in response to viral infections.These are of 3types :- alpha , beta and gamma. ■ Interferon gamma-1b a recombinant polypeptide that activates phagocytes induces the generation of oxygen metabolites that are toxic to a number of microorganisms. ■ Interferon beta-1a : 166-amino acid recombinant glycoprotein ■ interferon beta-1b :165-amino acid recombinant glycoprotein ■ Both have antiviral and immunomodulatory ■ They inhibit the multiplication of many DNA & RNA viruses.
  • 25. Adverse effects:- Myelosuppresion , hypertension , alopecia , headache , arrhythmia , Neurotoxicity resulting in confusion , sedation , rearly seizures. Uses:- ■ Chronic hepatitis B&C ■ Kaposis sarcoma in AIDS patients ■ Genetic warts caused by papilloma virus ■ Hairy cell leukemia ■ Rhinovirus cold :- Interferon alpha is given intranasally for prophylaxis
  • 26. B. Iterleukins:- ■ Interleukins are a group of Cytokines which are synthesized by lymphocytes, monocytes , macrophages and certain other cells ■ They are mainly used in treatment of cancer therapy C. Colony Stimulating Factors:- ■ Colony stimulating factors are glycoproteins that promote production of WBC ( mainly granulocytes such as neutrophils ) in response to infection. ■ An administration of exogenous colony stimulating factors stimulates the stem cells in the bone marrow to produce more of the particular WBCs. ■ The new WBCs migrate into the blood & fight the infection
  • 27. Uses:- ■ Colony Stimulating Factors are used in patients who are undergoing cancer treatment that causes low WBC count ( neutropenia ) & puts the patient at risk of infection. Colony Stimulating Factors tend to reduce the time where patient are neutropenic .
  • 29. Immunosuppressant ■ Immunosuppressant drugs are a class of drugs that suppress or reduce the strength of the body’s immune system. They are also called anti-rejection drugs. One of the primary uses of immunosuppressant drugs is to lower the body’s ability to reject a transplanted organ, such as a liver, heart or kidney. ■ Almost everyone who receives an organ transplant has to take immunosuppressant drugs. The body recognizes a transplanted organ as a foreign mass. This triggers a response by the body’s immune system to attack it. ■ By weakening the immune system, immunosuppressant drugs decrease the body’s reaction to the foreign organ. The drugs allow the transplanted organ to remain healthy and free from damage
  • 30. Continue… ■ Immunosuppressant drugs also are used to treat autoimmune diseases such as lupus. An autoimmune disorder is a disease process in which the body attacks its own tissue. Lupus results from just such a misdirected activity of the body’s own immune system. By suppressing this reaction, immunosuppressant drugs can help control the impact of the disease on the body. ■ OTHER DISEASES TREATED WITH IMMUNOSUPPRESSANT DRUGS INCLUDE: •Psoriasis •Rheumatoid arthritis •Crohn’s disease, a chronic inflammation of the digestive tract •Multiple sclerosis •Alopecia areata (patchy hair loss)
  • 31. Classification of Immunosuppressants 1 . Calcineurin inhibitors (SpecificT-cell inhibitors):- Cyclosporine (Ciclosporin), Tacrolimus , Sirolimus 2. Antiproliferative drugs (Cytotoxic drugs):- Azathioprine, Cyclophospharnide,Methotrexate, Chlorambucil,Mycophenolate mofetil (MMF) 3. Glucocorticoids:- Prednisolone and others 4. Antibodies:- Muromonab CD3, Antithymocyte globulin(ATG), Rho (D) immuneglobulin
  • 32. 1.Calcineurin inhibitors A.Cyclosporine MOA ■ Cyclosporine preferentially suppresses cell-mediated immune reactions ■ After diffusing into the T cell, Cyclosporine binds to a cyclophilin (more generally called an immunophilin) to form a complex that binds to calcineurin. ■ The latter is responsible for dephosphorylating NFATc (cytosolic Nuclear Factor of Activated T cells). ■ The CsA-calcineurin complex cannot perform this reaction; thus, NFATc cannot enter the nucleus to promote the reactions that are required for the synthesis of a number of cytokines, including IL-2. ■ The end result is a decrease in IL-2 the primary chemical stimulus for increasing the number of T lymphocytes.
  • 33. Route of administration:- Oral & IV ■ Metabolised in liver by CYP3A4 & excreted in bike ■ The plasma half life is biphasic 4 – 6 hrs & 12 – 18 hrs Side effects:- Nephrotoxic Impair liver function Rise in BP. Precipitation of diabetes Anorexia Hyperkalemia Hirautism Gum hyperplasia Tremor seizures Uses:- 1. Most effective drug for prevention & treatment of graft rejection reaction 2. Routinely used in renal , hepatic , cardiac , bone marrow transplantation 3. Second line drug in autoimmune disease like rheumatoid arthritis , uveitis , bronchial asthma , inflammatory bowel disease , dermatomyositis ,etc . 4. In psoriasis , especially to suppress acute excerbation
  • 34. B. Tacrolimus MOA:- ■ This Immunosuppressants is chemically different from cyclosporine but has the same MOA , and is ~100 times more potent ■ It bind to a different cytoplasmic immunophilin protein labelled ‘FK 506 binding protein ( FKBP ) , but subsequent steps are same as cyclosporine Route of administration:- Oral & i.v. infusion ■ Metabolised in liver by CYP3A4 & excreted in bile with a t1/2 of 12 hrs Uses:- Used in fistulating Chron’s disease
  • 35. C. Sirolimus MOA ■ SIROLIMUS bind to the same cytoplasmic FK- binding protein,but instead of forming a complex with calcineurin, SRL binds to molecular target of rapamycin interfering with Signal. ■ The latter is a serine-threoninekinase Binding of SIROLIMUS to molecular target of rapamycin blocks the progression of activated T cells from the G1 to the S phase of the cell cycle and, consequently, the proliferation of these cells. ■ Unlike Cyclosporine and Sirolimus and Tacrolimus does not owe its effect to lowering IL-2 production but, rather, to inhibiting the cellular responses to IL-2.
  • 36. ■ Sirolimus is absorbed orally , but fatty meal reduce its absorption ■ It is extensively metabolised , mainly by CYP3A4 , so that systemic bioavailability is only 15-20% ■ Elimination by biliary route ■ t1/2 is ~60 hrs Use:- prophylaxis and therapy of graft rejection reaction Side effects :- 1. Bone marrow suppression 2. Thrombocytopenia 3. Rise in serum lipid 4. Diarrhoea 5. Liver damage 6. Pneumonitis RAPACAN 1 mg tab
  • 37. 2. Antiproliferative Drugs A.Mycophenolate motife ( MMF) MOA ■ Mycophenolate safety and efficacy in prolonging graft survival. ■ It has been successfully used in heart, kidney, and liver transplants. ■ As an ester, it is rapidly hydrolyzed in the gastrointestinal tract to mycophenolic acid (MPA), which is a potent, reversible, uncompetitive inhibitor of inosine monophosphate dehydrogenase, blocking the de novo formation of guanosine phosphate. ■ Thus, like 6-MP, it deprives the rapidly proliferating T and B cells of a key component of nucleic acids. ■ t1/2 ~16hrs Side effects:- Vomiting , diarrhoea , leucopenia , g.i. bleeding
  • 38. B. Azathioprine MOA:- ■ It is a purine antimetabolite which has more marked immunosuppressant than antitumour action. ■ The basis for this difference is not clear, but may be due its selective uptake into immune cells and intracellular conversion to the active metabolite 6- mercaptopurine, which then undergoes further transformations to inhibit de novo purine synthesis and damage to DNA. It selectively affects differentiation and function of T cells and inhibits cytolytic lymphocytes; CMI is primarily depressed. Pharmacokinetics :- ■ It is administered orally or sometimes by means of intravenously ■ It metabolised mainly in liver , it is activated non-enzymatically, deactivated mainly by xanthine oxidase ■ Bioavability :- 60+-31%
  • 39. ■ Protein binding :- 20 – 30% ■ T1/2 :- 26–80 minutes ■ Excreted by kidney Uses:- It is used in rheumatoid arthritis, granulomatosis with polyangiitis, Crohn’s disease, ulcerative colitis, and systemic lupus erythematosus, and in kidney transplants to prevent rejection. Side Effect:- ■ Common side effects include bone-marrow suppression and vomiting.Bone- marrow suppression is especially common in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase. ■ Other serious risk factors include an increased risk of certain cancers. ■ Use during pregnancy may result in harm to the baby.
  • 40. 3. Glucocorticoids inhibit MHC expression and IL-I. IL –II. IL-6 production so that Helper T cells are not activated. 4. Antibodies like muromonab CD-3 , antithymocyte globulyne specifically bind to helper Tcells and prevent their response and deplete them
  • 41. Cellular & Biochemical Mediators of Inflammation & Immune Response
  • 42. Inflammation ■ It is defined as the local response of living tissues to injury due to any agent ■ Inflammation, a process by which the body’s immune system malfunction.( Failure to function normally ) ■ E.g. disease like arthritis , mysthenia gravis ■ There are two types of inflammation i.e acute inflammation and chronic inflammation
  • 43. Causes of Inflammation 1. Infective Agents :- Bacteria , viruses & their toxins , fungi , parasites 2. Immunological Agents :- Cell – mediated & antigen antibody reactions 3. Physical Agents :- Heat , cold , radiation , mechanical trauma 4. Chemical Agents :- Organic acid , inorganic poisons 5. Inert Materials :- such as foreign bodies
  • 44. Cellular & Biochemical Mediators of Inflammation & Immune Response ■ Definition: Any messenger that acts on blood vessels, inflammatory cells, or other cells to contribute to an inflammatory response. Classification Cell derived mediators Plasma derived mediators
  • 45.
  • 46. 1. Cell derived mediators a) vasoactive amines (serotonin,histamine) b) arachidonic acid metabolites ■ cycloxygenase pathway ■ lipoxygenase pathway c) Lysosomal components d) Platelet activating factor e) Cytokines (IL-1,TNF-α,TNF-β,IF-γ,Chemokines) f) Nitric oxide and oxygen metabolites
  • 47. a) Vasoactive amines Histamine :- ■ Stored in granuls of mast cells, basophiles and platelets. ■ Released by the stimuli of various agents like Heat, Cold, Irradiation, Irritant chemicals, Anaphilatoxins, Interleukins,.. Etc. ■ Actions ; VasodilationVascular permeability Itching and pain Serotonin/5-hydroxy tryptamine :- ■ Present in chromafin cells of GIT, Spleen, Nervous tissue, Mast cells, Platelets. ■ Actions :- Similar to Histamine, but less potent Vasodilation Vascular permeabilityatoxins
  • 48. b) Arachidonic acid Metabolites
  • 49. c) Lysosomal comonents ■ Source :- Neutrophiles and monocytes ■ Potent mediators ■ Degredation of bacterial and extracellular components ■ Chemotaxis ■ Realease of acid proteases, collagenase, elastase, plasminogen activator
  • 50. D) Platelet activating factor ■ Phospholipid derived mediator Released from :- Platelets, basophil, mast cells, neutrophils macrophages, endothelial cells Actions :- 1. Vascular permeability 2. Vasoconstriction 3. Vasodilatation 4. Bronchoconstriction 5. Adhesion of leukocytes to endothelium 6. Chemotaxis, degranulation
  • 51. e) Cytokines ■ “Cytokines are a diverse group of small protein molecules with potent biological activity whose main function is in the regulation of immune responses.” ■ Main Cytokines are :- Interleukins Interferons Tumor necrosis factor Chemokines Transforming growth factor-beta Adipokines- leptin & adiponectin
  • 52. Actions :- ■ Increase adhesion of leucocytes to endothelium ■ Increase synthesis of Prostacyclin, which is a vasodilator and anti aggregator of platelets ■ Increase Synthesis of PAF and thrombogenic effect on endothelial surface
  • 53. 2.Plasma derived mediators ■ a) The kinin system ■ b) The clotting system ■ c) The fibrinolytic system ■ d) The complement system • 4 interlinked systems • Hageman factor(factor XII) • End product of clotting ,fibrinolytic ,kinin system will activate complement system.
  • 54. a) The kinin system • Actions :- • • Smooth muscle contraction • Vasodilation • Increase vascular permeability
  • 55. b) Clotting system Actions :- Increase vascular permeability Chemotaxis for leucocytes Anticoagulant activity
  • 56. C) Fibrinolytic system Actions :- ■ Activation of factor XII to form prekallikrein activator that stimulates kinin system to generate bradykinin ■ Splits off complement c3 to form c3a,which is permeability factor ■ Degrades fibrin to split products, they increase vascular permeability
  • 57. D) Complement system ■ It consists plasma proteins ■ Product of complement system is anaphylatoxins c3a and c5a. ■ Potency is c3a>c5a>c4a Actions:- release histamine from mast cells and basophils ■ C5a is chemotactic for leucocytes. ■ Membrane attack complex cause pores in cell of invading microbes.
  • 59. Allergy ■ A disorder of the immune system often also referred to as atopy. ■ Strictly, allergy is one of four forms of hypersensitivity and is called type I (or immediate) hypersensitivity. ■ Allergic reactions occur to normally harmless environmental substances known as allergens. ■ Reactions are acquired, predictable, and rapid Include eczema, hives, hay fever, asthma attacks, food allergy, and reactions to drugs and the venom of stinging insect such as wasp and bees
  • 60. Hypersensitivity Reactions ■ Hypersensitivity is an abnormal immune response which produces physiological or histopathological damage in the host. ■ Hypersensitivity reactions have been classified into 'immediate’ & 'delayed’ types , based on the time required for a sensitised host to develop clinical reactions on re-exposure to the antigen. ■ Coombs & Gell (1963) classified hypersensitivity reactions into five types based on the different mechanisms of pathogenesis :-Type I , Type II , Type III , Type IV , Type V.
  • 61. Types of Hypersensitivity Reactions ■ Type I :- Anaphylactic, immediate ,IgE or reagin dependent :- eg . Anaphylaxis, Atopy etc ■ Type II:- Cytotoxic or cell stimulating :- e.g. thrombocytopenia , hemolytic anemia etc ■ Type III :- Immuno complex or toxic complex :- e.g. Arthus reaction , serum sickness etc ■ Type IV :- Delayed or T-cell mediated :- e.g.tuberculin type , contact dermatitis etc ■ Type V:- Stimulatory or antireceptor:- e.g.autoimmune orchitis in guinea pig
  • 62. Type I Hypersensitivity ■ Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. ■ The reaction may involve skin (urticariaand eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). ■ The reaction may cause a range of symptoms from minor inconvenience to death. ■ The reaction usually takes 15 – 30 minutes from the time of exposure to the antigen, although sometimes it may have a delayed onset (10 – 12 hours). ■ Mediated by IgE antibody to specific antigens ■ The primary cellular component in this hypersensitivity is the mast cell or basophil. ■ The reaction is amplified and/or modified by platelets, neutrophils and eosinophils.
  • 63. Causes of type I Hypersensitivity ■ ALLERGEN:Allergens are nonparasite antigens that can stimulate a type I hypersensitivity response. Common Allergen Associated with Type I Hypersensitivit y
  • 64. Atopy ■ Atopy is the term for the genetic trait to have a predisposition for localized anaphylaxis. ■ Atopic individuals have higher levels of IgE and eosinophils.
  • 65. Mechanism of Type I Hypersensitivity
  • 66. Mediators of Type I Hypersensitivity 1. Histamine 2. Cytokines TNF- , IL-1, IL-6. 3. Chemoattractants for Neutrophils and Eosinophils. 4. Enzymes tryptase, chymase, cathepsin. 5. Changes in connective tissue matrix, tissue breakdown 6. Leukotrienes 7. Prostaglandins
  • 67. Treatment of Type I Hypersensitivity ■ Drugs. 1. Non-steroidal anti-inflammatories 2. Antihistamines block histamine receptors. 3. Steroids 4. Theophylline OR epinephrine –prolongs or increases cAMP levels in mast cells which inhibits degranulation. ■ Immunotherapy 1. Desensitization (hyposensitization) also known as allergy shots. 2. Repeated injections of allergen to reduce the IgE on Mast cells and produce IgG.
  • 68. Type II Hypersensitivity ■ Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. ■ The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity. ■ Drug-induced hemolytic anemia, granulocytopenia and thrombocytopeniaare such examples. Pencillin allergy also belong to this class. ■ The reaction time is minutes to hours. ■ Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement . ■ Phagocytes may also play a role. ■ The lesion contains antibody, complement and neutrophils.
  • 70. Type III Hypersensitivity ■ Antigen antibody immune complexes. IgG mediated ■ Large amount of antigen and antibodies form complexes in blood. ■ If not eliminated can deposit in capillaries or joints and trigger inflammation. ■ The reaction may be general (e.g.,serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), joints (e.g.,rheumatoid arthritis) or other organs. ■ This reaction may be the pathogenic mechanism of diseases caused by many microorganisms.
  • 71. Continue… ■ The reaction may take 3 – 10 hours after exposure to the antigen . ■ It is mediated by soluble immune complexes. ■ They are mostly of the IgG class, although IgM may also be involved. ■ The antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous (non-organ specific autoimmunity: e.g., systemic lupus erythematosus, SLE). ■ The antigen is soluble and not attached to the organ involved
  • 73. Type IV Hypersensitivity ■ Reaction involves sensitized T cellsand release of its lymphokines as mediators and amplifiers ■ Mediated by cells rather than antibodies ■ Clinical states: Contact dermatitis, Transplant rejection, Granuloma ■ Th1 cells release cytokines to activate macrophages causing inflammation and tissue damage. ■ Continued macrophage activation can cause chronic inflammation resulting in tissue lesions, scarring, and granuloma formation. ■ Response starts after 48 -72 hrs
  • 75. Type V Or Stimulatory Hypersensitivity ■ It is an antibody mediated Hypersensitivity ■ In this case, an antibody reacts with a key surface component such as a hormone receptor & switch on or stimulates the cell. ■ E.g. thyroid Hypersensitivity in Grave’s disease due to thyroid stimulating autoantibody.
  • 77. Recent Therapeutic Advances A.Metastatic Melanoma PHASE Zero 1 . IMIQUIMOD (ZYCLARA) ■ A drug in the form of cream which stimulates a local immune response against skin cancer cells in sensitive areas on the face.some doctors may use imiquimod if surgery might be disfiguring. 2 . Cytokines ■ Cytokines such as INTERFERON-ALFA AND INTERLEUKIN-2 (IL-2), are proteins in the body that boost the immune system. ■ They are given as intravenous (IV) infusions, at least at first. ■ Interferon-alfa can be used as an added (adjuvant) therapy after surgery to try to prevent the thicker cells from spreading and growing. This may delay the recurrence of melanoma 3 . BACILLE CALMETTE-GUERIN (BCG) VACCINE ■ BCG activate the immune system. ■ The BCG vaccine works like a cytokine by enhancing the entire immune system. ■ It is sometimes used to help treat stage III melanomas by injecting it directly into tumors.
  • 78. Later Phase CTLA-4 INHIBITOR DRUG USED •Ipilimumab (Yervoy) ■ It is another drug that boosts the immune response, but it has a different target. ■ It blocks CTLA-4, another protein on T cells that normally helps keep them in check. ■ Used in melanomas which can’t be removed by surgery. ■ It helps in prolonging the life span of the patient PD-1 INHIBITORS DRUGS USED •Pembrolizumab (Keytruda) •Nivolumab (Opdivo) ■ These are drugs that target PD-1, a protein on immune system cells called T cells that normally help keep these cells from attacking other cells in the body. ■ By blocking PD-1, these drugs boost the immune response against melanoma cells, which can often shrink tumors and help people live longer
  • 79. B. FLAMMATORY BOWEL DISEASE (IBD) ■ i.e. Crohn’s disease (CD) and ulcerative colitis (UC) AZATHIOPRINE (AZA), 6-MERCAPTOPURINE (6-MP), METHOTREXATE (MTX) C. NON-SMALL CELL LUNG CANCER Ipilimumab D. ANCREATIC CANCER Urelumab E. LERGIC DISEASES Peptides
  • 80. Recent Technology 1. Oncolytic Virus Therapies ■ Oncolytic virus therapy use a modified virus that can cause tumor cells to destruct & generate a greater immune response against the cancer ■ In May 2015, based on results from a large completed phase III trial , the oncolytic virus therapy TALIMOGENE LAHERPAREPVEC (T-VEC) made by Amgen, was recommended for marketing approval by an independent advisory panel to the FDA . ■ The T-VEC used in the treatment of melanoma. By injecting locally into cutaneous, subcutaneous or nodar melanoma. ■ Side effects :- flu like symptoms , pain at the site of injection ■ Contraindication :- Pregnancy ■ Trade Name :- T-Vec , IMIYGIC , ONCOVEX
  • 81. 2. Adoptive T Cell Therapy ■ Another major avenue of immunotherapy for melanoma is ADOPTIVE T CELL TRANSFER. In this approach, T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity or numbers, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response.
  • 82. 3.Therapeutic Vaccines ■ Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. ■ In 2010, the FDA approved Sipuleucel-T (Provenge) for people with metastatic prostate cancer, which is prostate cancer that has spread. ■ Developed by Dendreon Pharmaceuticals, ■ Sipuleucel-T is tailored to each person through a series of steps: 1.White blood cells are removed from the person’s blood. White blood cells help the body fight infection and disease. 2. The white blood cells are altered in a laboratory to target prostate cancer cells. 3. Next, the doctor puts the altered cells back into the person through a vein. This is similar to a blood transfusion. These modified cells teach the immune system to find and destroy prostate cancer cells.
  • 83. ■ Route of Administration :- Intravenous ■ Uses :- prostate cancer ( only in men’s ) ■ Trade Name :- PROVENGE
  • 84. 4 . Immunomodulatory effects of Fluroquinolones ■ Immune response are indirectly modulated by FQs through suppressing pro –inflammatory cytokines , such as interleukin 1 (IL- 1) ,IL-6, tumor necrosis factor-alpha (TNF-alpha), & super-inducing IL- 2, which tend to increase both the growth & activity of T & B lymphocytes. In addition, they affect the development of immune response by influencing of expression of both Cytokines & mediators.
  • 85. References ■ Tripathi K.D. , Essentials of Medical Pharmacology , Jaypee Brothers Medical Publishers (P) Ltd , 7th Edition 2015 , By , Page No.159 – 210 & 878 – 885. ■ Prof. Kokare Chandrakant , Pharmaceutical Microbiology Principles & Applications , Nirali Prakashan , 9th Edition January 2013 , Page No. 20.1 – 24.10 ■ Goodman & Gilman’s ,The Pharmacological Basis of Therapeutics, 13th Edition ,Page no. 619 – 637 ■ Ananthnarayan R. , Paniker C.K.J., Textbook of Microbiology, Orient Longman Private Limited , 7th Edition 2005 , Page no. 71 – 168 ■ Shokrollah Assar et al, A Review of Immunomodulatory Effects of Fluoroquinolones, A Journal of Molecular and Cellular Immunology, 2020