Transcript Document

ALLERGY AND
HYPERSENSITIVITY
IMMUNE RESPONSE IN WHICH THE ANTIGEN IS AN
ENVIRONMENTAL AGENT, FOOD OR DRUG THAT IS NOT
INTRINSICALLY HARMFUL.
MOST WIDESPREAD IMMUNOLOGICAL DISORDER IN
HUMANS; RAPIDLY INCREASING – 27% INCIDENCE;
INDIVIDUAL SUSCEPTABILITY ??
WIDE RANGE OF SERVERITY
MOST EFFECTIVE THERAPY: ALLERGEN AVOIDANCE
HYGIENE HYPOTHESIS OF
ALLERGY
RECOGNIZED IN 1989, LACK OF INFECTION FAVORS THE
DEVELOPMENT OF ALLERGIC DISEASE.
MYCOBACTERIA AND HELMINTHS ARE IMPORTANT IN
THIS HYPOTHESIS AS INFECTIONS CAUSED BY THESE
AGENTS GENERATE REGULATORY MECHANISMS
THAT CAN RESTORE IMMUNE BALANCE.
MULTIPLE AND REPETITIVE INFECTIOUS FACTORS
DURING CERTAIN PERIODS OF IMMUNE SYSTEM
DEVELOPMENT INFLUENCE ALLERGY AND ASTHMA
DEVELOPMENT.
TYPE I ALLERGIC RESPONSES –
IMMEDIATE HYPERSENSITIVITY. MEDIATED BY IgE
AND CAUSES THE RELEASE OF HISTAMINE,
LEUKOTRIENES AND PROSTAGLANDINS FROM MAST
CELLS AND BASOPHILS. USUALLY ATOPIC (FAMILIAL
DISPOSITION.
1. IgE BINDS TO MAST CELLS
2. ANTIGEN CROSS BRIDGING
3. HISTAMINE RELEASE (MAST CELL DEGRANULATION)
EFFECTS OF MAST CELL
DEGRANULATION
EFFECTS OF MAST CELL
DEGRANULATION
HISTAMINE – INCREASES VASCULAR PERMEABILITY
EOSINOPHIL CHEMOTACTIC FACTOR – ATTRACTS EOSINOPHILS
TO THE AREA, EOSINOPHILS RELEASE:
1. MAJOR BASIC PROTEIN –CAUSES BRONCHIAL CONSTRICTION
AND HYPERRESPONSIVENESS, INHIBITS CILIAL FUNCTION,
TOXIC FOR RESPIRATORY EPITHELIAL CELLS AND
PNEUMOCYTES.
2. EOSINOPHIL PEROXIDASE – TOXIC FOR RESPIRATORY
EPITHELIAL CELLS AND PNEUMOCYTES.
LEUKOTRIENES – SLOW REACTING SUBSTANCE OF ANAPHYLAXIS,
CONSTRICTION OF SMOOTH MUSCLE
PLATELET ACTIVATING FACTOR – PLATELET AGGREGATION
AND LYSIS, MACROPHAGE AND NEUTROPHIL ACTIVATION
EXAMPLES: ACUTE ANAPHYLAXIS, HAY FEVER, FOOD ALLERGIES
MEDIATORS OF ALLERGY
A. IgE – ANTIBODY PRODUCED BY B CELLS, SENSITIZES
MAST CELLS FOR MEDIATOR RELEASE, USUALLY IN
VERY LOW AMOUNTS IN SERUM.
B. HISTAMINE - SECRETED BY MAST CELLS, CAUSES
VASODILATION, INC. VASCULAR
PERMEABILITY OF VENULES AND
MUCUS PRODUCTION, CONTRICTS
BRONCHIAL AIRWAYS, STIMULATES
NERVE ENDINGS. H1 RECEPTORS
RESPONSIBLE FOR MOST
ALLERGIC RESPONSES, H4 RECEPTORS
MAY PLAY A ROLE
C. PLATELET ACTIVATING FACTOR - LIPID MEDIATOR,
SECRETED BY BASOPHILS, NEUTROPHILS,
MONOCYTES, MACROPHAGES, ENDOTHELIAL CELLS,
CAUSES RELEASE OF MEDIATORS FROM PLATELETS,
NEUTROPHIL AGGREGATION, NEUTROPHIL
SECRETION AND SUPEROXIDE ANION PRODUCTION,
INCREASES VASCULAR PERMEABILITY, CONSTRICTS
BRONCHIAL AIRWAYS.
D. PROSTAGLANDINS – DERIVED FROM ARACHIDONIC
ACID
PGD2 – CONSTRICTS
BRONCHIAL AIRWAYS
PGE2 – CAUSES VASODILATION,
POTENTIATES EFFECTS
OF HISTAMINE AND
LEUKOTRIENES.
E. LEUKOTRIENES – DERIVED FROM ARACHIDONIC
ACID VIA 5-LIPOXYGENASE PATHWAY, MOST
CONTRIBUTE TO INC. VASCULAR PERMEABILITY,
CAN INDUCE BRONCHOCONSTRICTION, “SLOW
REACTING SUBSTANCE OF ANAPHYLAXIS”.
LTB4 – CHEMOTACTIC FOR NEUTROPHILS, INC.
VASCULAR PERMEABILITY IN THE PRESENCE
OF PGE2.
LTC4 – INC. VASCULAR PERMEABILITY, INDUCES
BRONCHOCONSTRICTION.
LTD4 & LTE4 – INC. VASCULAR PERMEABILITY
LTC4, LTD4 & LTE4 – TOGETHER WERE CONSIDERED
SRSA
F. CYTOKINES –
1. INTERLEUKIN 3 – STIMULATES EOSINOPHILS, MAST
CELL GROWTH FACTOR.
2. INTERLEUKIN 4 – STIMULATES PRODUCTION OF IgE
BY B CELLS, INDUCES B & T CELL PROLIFERATION,
INDUCES T HELPER CELLS, HAS INHIBITORY
EFFECT ON MACROPHAGES, ACTIVATES MAST
CELLS, INC. MUCUS PRODUCTION, BASEMENT
MEMBRANE THICKNESS AND SMOOTH MUSCLE
HYPERTROPHY IN BRONCHIAL TISSUE.
3. INTERLEUKIN 5 – EOSINOPHIL GROWTH FACTOR,
INC. IL-4 INDUCED IgE PRODUCTION
4. INTERLEUKIN 13 – STIMULATES IgE SYNTHESIS BY B
CELLS, HAS INHIBITORY EFFECT ON
MACROPHAGES, SIGNIFICANTLY INC. MUCUS
PRODUCTION, BASEMENT MEMBRANE THICKNESS
AND SMOOTH MUSCLE HYPERTROPHY IN
BRONCHIAL TISSUE.
4. GRANULOCYTE-MONOCYTE COLONY STIMULATING
FACTOR – INC. GRANULOCYTE
(INCLUDING EOSINOPHIL) AND MONOCYTE
COLONY FORMATION, ACTIVATES
MACROPHAGES
5. TUMOR NECROSIS FACTOR-a – INCREASES
NEUTROPHIL PHAGOCYTOSIS & DEGRANULATION,
PRODUCTION OF REACTIVE OXYGEN SPECIES,
CHEMOTACTIC FOR BOTH MACROPHAGES AND
NEUTROPHILS, INC. PGE2 PRODUCTION BY
MACROPHAGES.
ALLERGY TREATMENTS
IMMUNOLOGIC APPROACHES
ALLERGIC DESENSITIZATION
- INDIVIDUAL VARIATION
- MULTIPLE ALLERGEN ISOFORMS
(ANTIGEN SPECIFIC PEPTIDE THERAPY)
ANTI-IgE THERAPY: OMALIZUMAB (XOLAIR), GOOD
FOR AEROALLERGINS AND ASTHMA TREATMENT,
EFFICACY NOT SHOWN IN OTHER ALLERGIC
CONDITIONS. HUMAN IgG1 BINDS TO IgE TO
REMOVE IT FROM CIRCULATION, INHIBITS BINDING
OF IgE TO HIGH AFFINITY RECEPTORS ON MAST
CELLS AND BASOPHILS.
ALLERGY TREATMENTS
IMMUNOLOGIC APPROACHES (CONT.)
SOLUBLE IL-4Ra: DEC. DEVELOPMENT OF T CELLS,
REMOVES CIRCULATING IL-4 BY TRAPPING
IL-4 MUTEIN: IL-4 VARIENT, CAN BIND TO CELL
SURFACE RECEPTOR BUT NOT TRIGGER RESPONSE
SOLUBLE IL-13Ra2: DEC. AIRWAY RESPONSIVENESS
IN MOUSE STUDIES, REMOVES CIRCULATING IL-13
CHEMICAL APPROACHES - ANTIHISTAMINES
ASTHMA
DISEASE CHARACTERIZED BY REVERSIBLE
OBSTRUCTION OF THE BRONCHI. ACCOMPANIED BY
NONSPECIFIC BRONCHIAL HYPERRESPONSIVENESS OR
“IRRITABILITY”, ASSOCIATED WITH ATOPY,
SPONTANEOUS RELEASE OF MEDIATORS FROM MAST
CELLS IS INCREASED
PATHOPHYSIOLOGY OF ASTHMA
PATHOGENESIS OF ASTHMA
PATHOLOGY
EARLY RESPONSES - RAPID RELEASE OF PREFORMED
INFLAMMATORY MEDIATORS BY MAST CELLS,
SYNTHESIS OF EICOSANOIDS, BRONCHOCONSTRICTION
LATE RESPONSE - SECOND ROUND OF
BRONCHOCONSTRICTION
ACUTE ATTACK CAN BE FATAL, ACUTE ASPHYXIATION,
MARKED CONSTRICTION AND OCCLUSION OF THE
BRONCHI.
ASTHMATIC AIRWAY
OBSTRUCTION
NORMAL
ASTHMA
AIRWAY OBSTRUCTION
MUCUS PLUGGING
MUCUS CAST OF BRONCHIAL
TREE
CHRONIC ASTHMA
MARKED THICKENING OF THE BASEMENT MEMBRANE
OF BRONCHIAL MUCOSA, HYPERTROPHY OF
BRONCHIAL SMOOTH MUSCLE, HYPERTROPHY OF
BRONCHIAL MUCOUS GLANDS, EOSINOPHILS AND
CHRONIC INFLAMMATORY CELLS IN THE BRONCHIAL
WALL, INC. NUMBER OF MAST CELLS, PRESENCE OF
MUCOUS IN BRONCHI CONTAINING LARGE NUMBERS
OF EOSINOPHILS.
TISSUE INJURY IN ASTHMA
EPITHELIAL INJURY IN ASTHMA
NORMAL TRACHEA
ASTHMATIC TRACHEA
EOSINOPHILIC
INFILTRATION
HYPERTROPHIED AIRWAY
MUSCLE
EXTRINSIC ASTHMA- TRIGGERED BY
EXPOSURE TO ALLERGENS, IgE MEDIATED
FACTORS PREDISPOSING TO
DEVELOPMENT OF EXTRINSIC ASTHMA
1. HEREDITY
2. PRENATAL EFFECTS - high cord blood IgE levels, prenatal
exposure to allergens
3. HIGH POSTNATAL IgE SERUM LEVEL
4. BIRTH DURING POLLEN SEASON
5. BIRTH IN URBAN ENVIRONMENT
6. STRESSFUL PERINATAL PERIOD
7. EARLY DIET - early exposure to eggs, wheat, bovine products
8. LOW SERUM IgA LEVELS AT 3 MONTHS OF AGE
9. LOW LEVELS OF T LYMPHOCYTES AT 3 MONTHS OF AGE
10. EARLY SURGERY OR HOSPITALIZATION
11. EXPOSURE TO ANIMALS, MOLDS, TOBACCO SMOKE,
AND POLLEN
12. FREQUENT INFECTIONS
INTRINSIC ASTHMA
NON-ATOPIC, ORIGINALLY THOUGHT TO BE NON-IgE
MEDIATED, MAY BE DUE TO LOCAL PRODUCTION OF
IgE WITHIN AIRWAYS
TRIGGER UNKNOWN BUT MAY DEVELOP FROM
SEASONAL ALLERGY, MAY BE DUE TO IMBALANCE OF
PHYSIOLOGICAL CONTROL OF SMOOTH MUSCLE TONE.
INTRINSIC ASTHMA
OCCUPATIONAL ASTHMA
EXPOSURE TO SMALL PROTEINS OR MOLECULAR
WEIGHT MOLECULES AT WORK
PRESENTATION OF OCCUPATIONAL ASTHMA
•
•
•
•
IMMEDIATE HYPERSENSITIVITY REACTION
IMMEDIATE BRONCHOSPASM
ISOLATED LATE RESPONSE (USUALLY SENSITIZR
INDUCED)
SLEEP DISORDER
TYPES OF OCCUPATIONAL ASTHMA
• NEW ONSET
• SENSITIZER-INDUCED
• IRRITANT INDUCED
• AGGRAVATION OF UNDERLYING ASTHMA
• REACTIVE AIRWAYS DYSFUNCTION SYNDROME
(RADS)
• COLD AIR- OR EXERCISE-INDUCED SYNDROME
• AIRWAYS REACTIVITY SECONDARY TO
HYPERSENSITIVITY PNEUMONITIS
INDUCERS OF OCCUPATIONAL
ASTHMA
SENSITIZER-INDUCED
• SPECIFIC ANTIGEN
• LOW MW, “HAPTEN”
• HIGH MW
• MINIMAL EXPOSURE
• < OCCUPATIONAL
EXPOSURE LIMITS
• IgE MEDIATED
• PRIOR HISTORY OF ATOPY
NOT PREDICTIVE
• PPE OFTEN INSUFFICIENT
TO CONTROL SYMPTOMS
• MEDICAL REMOVAL
USUALLY NECESSARY
IRRITANT-INDUCED
• ANY IRRITANT
• MODERATE TO HEAVY
EXPOSURE
• USUALLY HISTORY OF
INTOLERANCE TO SECOND
HAND TOBACCO SMOKE
• OFTEN VARIABLE
• PPE OFTEN EFFECTIVE IN
PREVENTING EPISODES
• MEDICAL REMOVAL THE
LAST RESORT
• MOST COMMON
COMMON SENSITIZERS
(INCOMPLETE LIST)
LOW MW
• ISOCYANATES
• ANHYDRIDES
• METAL SALTS
• EPOXY RESINS
• FLUXES
• PERSULFATE
• ALDEHYDES
HIGH MW
• PHARMACEUTICALS
• ANIMAL PROTEINS
• LATEX
• CEREALS
• SEAFOOD
• PROTEOLYTIC
ENZYMES
• WOOD
CONSTITUENTS
TREATMENT OF ASTHMA
I. CROMOLYN SODIUM
MAST CELL STABILIZER, PREVENTS ANTIGEN
INDUCED HISTAMINE RELEASE FROM MAST CELLS,
APPEARS TO PREVENT TRANSMEMBRANE FLUX OF
CALCIUM TRIGGERED BY IgE INTERACTION WITH
MAST CELL SURFACE. SPECIFIC FOR MAST CELLS,
BEST USED PROPHYLACTICALLY. INHIBITS
BRONCHOSPASM AND APPEARANCE OF IL-8
(NEUTROPHIL CHEMOTACTIC FACTOR)
TRADE NAMES:
INTAL - PULMONARY AEROSOL
NASALCROM - NASAL AEROSOL
GASTROCROM - ORAL
II. NEDOCROMIL SODIUM
TRADE NAME: TIDADE
SIMILAR TO CROMOLYN SODIUM IN STRUCTURE
AND ACTIVITY, INHIBITS MEDIATOR RELEASE FROM
INFLAMMATORY CELLS (MAST CELLS, EOSINOPHILS,
NEUTROPHILS & MACROPHAGES), USED
PROPHYLACTICALLY BY INHALATION. NOT USED FOR
ACUTE ATTACKS.
III. METHYLXANTHINE DRUGS
CAUSE BRONCHODILATION, SMOOTH MUSCLE
RELAXATION, INHIBITS PHOSPHODIESTERASES,
INHIBITION OF ADENOSINE RECEPTORS, DOWN
REGULATION OF ADENYL CYCLASE ACTIVITY, MAY
TRIGGER EOSINOPHIL APOPTOSIS.
ADVERSE EFFECTS:
A. CENTRAL NERVOUS SYSTEM – NERVOUSNESS,
TREMOR, INSOMNIA
B. CARDIOVASCULAR – IMPAIRMENT OF Ca++
SEQUESTRATION BY SARCOPLASMIC RETICULUM
C. GASTROINTESTINAL – STIMULATE SECRETION OF
GASTRIC AND DIGESTIVE ENZYMES
D. KIDNEY – WEAK DIURETICS
** E. SMOOTH MUSCLE - BRONCHODILATION, INHIBITION
OF HISTAMINE RELEASE
F. SKELETAL MUSCLE – REVERSES DIPHRAGM FATIGUE
AMINOPHYLLINE THEOPHYLLINE ETHYLENEDIAMINE,
79% THEOPHYLLINE
THEOPHYLLINE TRADE NAMES: ELIXOPHYLLIN, SLO-PHYLLIN
DYPHYLLINE
PENTXIFYLLINE
TRADE NAME: TRENTAL
IV. SYMPATHOMIMETIC DRUGS
ADENORECEPTOR AGONISTS, RELAX AIRWAY SMOOTH
MUSCLE, INHIBIT RELEASE OF BRONCHOCONSTRICTING
COMPOUNDS.
A. EPINEPHRINE - BRONCHODILATOR, RAPIDLY ACTING,
STIMULATES BOTH b1 & b2 RECEPTORS, CAN CAUSE
TACHYCARDIA, ARRHYTHMIAS AND ANGINA,
TRADE NAME: PRIMATINE MIST
B. EPHEDRINE - LONGER DURATION AND LOWER
POTENCY THAN EPINEPHRINE, USED INFREQUENTLY,
CAN BE USED WITH THEOPHYLLINE & A SEDATIVE.
C. ISOPROTERENOL – POTENT BRONCHODILATOR, CAN
CAUSE CARDIAC ARRHYTHMIAS,
TRADE NAME: ISUPREL
D. $2-SELECTIVE AGENTS - BRONCHODILATORS,
LONG LASTING, BRONCHODILATION WITHIN 30 MIN,
PERSISTS FOR 3-4 HR, MOST WIDELY USED
SYMPATHOMIMETICS.
1. METAPROTERENOL –
TRADE NAMES: ALUPENT, METAPREL
2. TERBUTALINE - TRADE NAME: BRETHINE, BRICANYL
3. ALBUTEROL - TRADE NAMES: PROVENTIL,
VENTOLIN
4. BITOLTEROL - TRADE NAME: TORNALATE
5. PIRBUTEROL ACETATE - TRADE NAME: MAXAIR
6. SALMETEROL - LONGER ACTING, HIGH LIPID
SOLUBILITY, MAY ALSO INHIBIT EOSINOPHILS,
TRADE NAME: SEREVENT
7. FORMOTEROL – LONG ACTING, HIGH LIPID
SOLUBILITY, TRADE NAME: FORADIL
V. MUSCARINIC ANTAGONISTS
INHIBIT EFFECT OF ACETYLCHOLINE AT
MUSCARINIC RECEPTORS, BLOCKS CONTRACTION
OF AIRWAY SMOOTH MUSCLE, BRONCHODILATORS,
INC. MUCUS SECRETION.
1. ATROPINE
2. IPRATROPIUM BROMIDE - TRADE NAME: ATROVENT
VI. CORTICOSTEROIDS
POTENTIATE EFFECTS OF $-RECEPTOR AGONISTS,
REDUCE BRONCHIAL REACTIVITY, DECREASE NUMBER
& ACTIVATION OF INFLAMMATORY CELLS (MAY
TRIGGER EOSINOPHIL APOPTOSIS, INHIBIT
CYTOKINE SYNTHESIS. INHALED STEROIDS ARE LIPID
SOLUBLE SO LESS LIKELY TO HAVE SYSTEMIC EFFECTS
COMMONLY USED STEROIDS
1. PREDNISONE – ORAL
2. BECLOMETHASONE –
TRADE NAME: BECLOVENT, VANCERIL, AEROSOL
3. TRIAMCINOLONE - TRADE NAME: AZMACORT, AEROSOL
4. BUDESONIDE – TRADE NAME: PULMICORT, AEROSOL
5. FLUNISOLIDE - TRADE NAME: AEROBID, AEROSOL
6. FLUTICASONE PROPIONATE –
TRADE NAME: FLOVENT, AEROSOL
7. MOMETASONE – TRADE NAME: ASMANEX, AEROSOL
8. METHYLPREDNISONE - INTRAVENOUS
VII. CALCIUM INFLUX BLOCKING DRUGS
INHIBIT BRONCHOCONSTRICTION, NOT COMMONLY
USED
1. NIFEDIPINE – TRADE NAMES: PROCARDIA, ADALAT
2. VERAPAMIL
VIII. LEUKOTRIENE INHIBITORS
INHIBIT BRONCHOCONSTRICTION, MICROVASCULAR
LEAKAGE, EDEMA, MUCUS SECRETION, AND
LEUKOCYTE ACCUMULATION
A. BIOSYNTHESIS INHIBITORS - INHIBIT 5-LIPOXYGENASE
1. BENSOFURANS – DIRECT INHIBITION OF
5-LIPOXYGENASE
2. N-HYDROXYUREA DERIVATIVES – EFFECTIVE COLD,
EXERCISE INDUCED, ASPIRIN SENSITIVE &
CHRONIC ASTHMA, ZILEUTON, TRADE NAME: ZYFLO
3. INDAZOLINONES – INHIBIT CYSTEINYL-LEUKOTRIENE
(LTC4, D4, & E4) COMPONENT OF ANTIGEN-INDUCED
BRONCHOCONSTRICTION.
4. HYDROXAMATES - INHIBIT CYSTEINYL-LEUKOTRIENE
(LTC4, D4, & E4) COMPONENT OF AG-INDUCED
BRONCHOCONSTRICTION, INHIBIT LTB4 SYNTHESIS
5. METHYLOXYALKYL-THIAZOLES – SELECTIVE
INHIBITOR OF 5-LIPOXYGENASE
B. RECEPTOR ANTAGONISTS - BLOCKS RECEPTORS
FOR LEUKOTRIENE B4 (BLT RECEPTORS) AND/OR
LEUKOTRIENE C4, D4, AND E4 (CYS LT RECEPTORS).
1. ZAFIRLUKAST (ICI-204219) – INHIBITS LTD4-INDUCED
BRONCHOCONSTRICTION, INHIBITS EARLY & LATE
RESPONSES TO ALLERGEN, EFFECTIVE AGAINST
EXERCISE & COLD INDUCED, & CHRONIC ASTHMA,
TRADE NAME: ACCOLATE
2. MONTELUKAST SODIUM – INHIBITS LTD4-INDUCED
BRONCHOCONSTRICTION, INHIBITS EARLY & LATE
RESPONSES BUT IS MORE EFFECTIVE AGAINST
EARLY, TRADE NAME: SINGULAIR
3. QUINOLONES (MK-571) - INHIBITS LTD4-INDUCED
BRONCHOCONSTRICTION
4. PRANKULAST (ONO-1078) - INHIBITS LTD4-INDUCED
BRONCHOCONSTRICTION
RELATIVE POTENCIES OF ANTILEUKOTRIENE AGENTS
AS DETERMINED BY THEIR ABILITY TO BLOCK
LEUKOTRIENE D4-INDUCED BRONCHCONSTRICTION:
ZILEUTON<PRANKULAST<MK-571<ZAFIRLUKAST
IX. ANTI-IgE THERAPY
OMALIZUMAB (XOLAIR) - SUBCUTANEOUS INJECTION,
USED PREDOMINANTLY FOR ASTHMA TREATMENT,
USED PROPHYLACTICALLY, WILL NOT HAVE EFFECT ON
ACUTE ATTACKS
HUMAN IgG1 BINDS TO IgE TO REMOVE IT FROM
CIRCULATION, INHIBITS BINDING OF IgE TO HIGH
AFFINITY RECEPTORS ON MAST CELLS AND BASOPHILS.
POSSIBLE NEW TARGETS FOR ASTHMA
THERAPIES
T cell
Eosinophil
Recruitment
Chemotaxis
(eotaxin)
Eosinophil
survival
(IL-5)
Immumodulators
cyclosporins
Anti-IL-5
(Mepolizumab)
Adhesion blockers
Anti-VLA-4
Anti-selectins
CCR3 antagonists
(receptor responsible for Th2 recruitment)
Corticosteroids
Apoptosis-inducers