Immunopharma Flashcards
rapid first line of defense that can mobilize in minutes to hours
innate immunity
include antimicrobial peptides, and proteins, complement, enzymes interferons, acid pH and free radicals
biochemical components
c3a and c5a is responsible for?
chemotaxis attracts phagocytes
c3b is responsible for?
opsonization
c5b, c6,c7,c8,c9 or MAC is responsible for?
bacterial lysis
complement system is composed of how many proteins
9
complement may lyse host cell, what disease?
paroxysmal nocturnal hemoglobinuria
blocks cleavage of C5
eculizumab
in barrier injury, dendritic cells are fully activated? yes or no?
Yes
in homeostatic condition, dendritic cells react to infection? yes or no
No
mobilized by cues to innate response activation of t lymphocytes
adaptive immunity
induction of specific adaptive immunity requires ?
APCs, (dendritic cells, macrophages, lymphocyets)
induction needs atleast how many signals?
2
TCR engagement to peptide bound MHC Molecules
1st signal in induction of innate immunity
in the absence of 2nd signal in induction T cells become?
unresponsive/anergic or undergo apoptosis
involves binding of co stimulatory molecules cd40,cd80,cd86(b72) to respective ligands
2nd signal
causes proliferation and activation of cytotoxic T lymphocytes
interleukin 2
produces IFN Gamma and TNF beta
TH1
triggered when B lymphocytes bind antigen via surface immunoglobulin
humoral immunity
what are the 3 abnormal immune response?
hypersensitivity autoimmunity immunodeficiency
condition of exaggerated or augmented immune response
hypersensitivity
occurs upon initial encounter with an antigen
sensitization phase of hypersensitivity
involves immunologic memory and results in tissue pathology upon a subsequent encounter with that antigen
effector phase of hypersensitivity
immediate hypersensitivity, IgE mediated, with symptoms occuring within minutes following the patient’s re encounter to antigen
type 1 hypersensitivity
results from cross linking of membrane-bound IgE on blood basophils or tissue mast cell antigen ANAPHYLAXIS, ASTHMA, HAY FEVER, URTICARIA
type I hypersensitivity
results from formation of antigen-antibody complexes between foreign antigen and IgM or IgG immunoglobulins blood transfusion reactions
type II hypersensitivity
can also be a drug-induced and may occur during the administration of penicillin
type II hypersensitivity
due to presence of elevated levels of antigen-antibody complexes in the circulation that deposit on the basement membrane
type III hypersensitivity
immune complex complement to produce components with anaphylatoxic and chemotactic activities (c3a,c5a,c4a) SKIN RASHES, GLOMERULONEPHRITIS AND ARTHRITIS
type III hypersensitivity
delayed type hypersensitivity, cell mediated, occur 2-3 days after exposure
type IV hypersensitivity
caused by antigen-specific DTH Th1 cells and induces a local inflammatory response influx of antigen-non specific inflammatory cells specially macrophages
type IV Hypersensitivity
in this phase the processed allergen is presented to the CD4 TH1 cells by antigen-presenting cells in association with class II MHC, T cells are induced to express IL-2 receptors and are stimulated to proliferate and differentiate into memory TDTH cells
type IV -sensitization phase
memory TDTH cells release cytokines that attract and activate nonspecific inflammatory macrophages and neutrophils
type IV-effector phase
effects: chemotaxis of macrophages in type IV hypersensitivity
IL8 MIF MCP
effects: activation of macrophages in type IV hypersensitivity
IFN-y TNF-B
effects: induction of myelopoiesis of macrophage and neutrophil precursors in type IV hypersensitivity
IL3 GM-CSF
effects: chemotaxis and extravasation of macrophage in type IV hypersensitivity
IL8 TNF-A MIP
arises when the body mounts an immune response against itself due to failure to distinguish self tissues and cells from foreign (non-self ) antigens or loss of tolerance to self.
Autoimmune disease/Autoimmunity
This phenomenon derives from the activation of self-reactive T and B lymphocytes that generate cell-mediated or humoral immune responses directed against self antigens
Autoimmune disease/Autoimmunity
Triggers for autoimmune disease/autoimmunity
infections hormones pathogens food antigens heavy metals drugs stress
in this disease, IgM antibodies (rheumatoid factors) are produced that react with the Fc portion of IgG and may form immune complexes that activate the complement cascade, causing chronic inflammation of the joints and kidneys
rheumatoid arthritis
in this disease, antibodies are made against DNA, histones, red blood cells, platelets, and other cellular components.
lupus erythematosus
in these diseases, cell-mediated autoimmune attack destroys myelin surrounding nerve cells and insulin-producing islet beta cells of the pancreas
multiple sclerosis and type 1 diabetes
in this disease, activated CD4 TDTH cells that infiltrate the islets of Langerhans and recognize self islet beta cell peptides are thought to produce cytokines that stimulate macrophages to produce lytic enzymes, which destroy islet beta cells
type 1 diabetes
-result from inadequate function in the immune system; the consequences include increased susceptibility to infections and prolonged duration and severity of disease. -either congenital or arise from extrinsic factors such as bacterial or viral infections or drug treatment.
Immunodeficiency diseases
also characterized
by an imbalance in Th1 and Th2 cells, and the ratios of cells
and their functions are skewed toward Th2.
AIDS
reduces the size and lymphoid content of the
lymph nodes and spleen, although it has no toxic effect on proliferating myeloid or erythroid stem cells in the bone marrow
Glucocorticoids
is an immunosuppressive agent with efficacy in human organ transplantation, in thetreatment of graft-versus-host (GVH) disease after hematopoietic stem cell transplantation, and in the treatment of selectedautoimmune disorders
-PEPTIDE ANTIBIOTIC
Cyclosporine (cyclosporin A, CSA)
is a peptide antibiotic thatappears to act at an early stage in the antigen receptor–induced differentiation of T cells and blocks their activation. It binds to cyclophilin, a member of a class of intracellular proteins called immunophilins. Cyclosporine and cyclophilin form a complex that inhibits the cytoplasmic phosphatase,calcineurin, which is necessary for the activation of a T cell–specific transcription factor. This transcription factor, NF-AT, is involved in the synthesis of interleukins (eg, IL-2) by activated T cells
Cyclosporine
- may be given intravenously or orally, though it is slowly and incompletely absorbed (20–50%)
- available for severe dry eye syndrome, as well as ocular GVH disease
Toxicities are numerous and include nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures, and hirsutism. Cyclosporine causes very little bone marrow toxicity.
Cyclosporine
is an immunosuppressant macrolide antibiotic produced by Streptomyces tsukubaensis. It is not chemically related to cyclosporine, but their mechanisms of action are similar.
Tacrolimus (FK 506)
While cyclosporine binds to cyclophilin, tacrolimus binds to the?
FK-binding
protein (FKBP).
- can be administered orally or intravenously. The half-life of the intravenous form is approximately 9–12 hours.
- currently used in the therapy of atopic dermatitis and psoriasis.
Tacrolimus
bind the circulating immunophilin FK506-binding protein 12, resulting in an active complex that blocks the molecular target of rapamycin (mTOR).
includes sirolimus (rapamycin) and its derivative everolimus,Tofacitinib (Xeljanz)
-toxicities include profound myelosuppression(especially thrombocytopenia), hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and headache
PROLIFERATION SIGNAL INHIBITORS
is a key component of a complex intracellular signaling pathway involved in cellular processes such as cell growth and proliferation, angiogenesis, and metabolism
mTOR
has been used effectively alone and in combination
with other immunosuppressants (corticosteroids, cyclosporine,tacrolimus, and mycophenolate mofetil) to prevent rejection of solid organ allografts. It is used as prophylaxis and as therapy for steroid-refractory acute and chronic GVH disease in hematopoietic stem cell transplant recipients. Topical ___ is also used in some dermatologic disorders and, in combination with cyclosporine, in the management of uveoretinitis.
Sirolimus
inhibits JAK enzymes that stimulate hematopoiesis and immune cell function in response to cytokine or growth factor signaling. it also reduces circulating NK cells, serum immunoglobulins, and C-reactive protein
Tofacitinib (Xeljanz)
is a semisynthetic derivative of mycophenolic acid, isolated from the mold Penicillium glaucus. Invitro, it inhibits T- and B-lymphocyte responses, including mitogen and mixed lymphocyte responses, probably by inhibition of de novo synthesis of purines
Mycophenolate mofetil (MMF)
-available in both oral and intravenous forms. The oral form is rapidly metabolized to mycophenolic acid
-
used in solid organ transplant patients for refractory rejection and, in combination with prednisone, as an alternative to cyclosporine or tacrolimus in patients who do not tolerate those drugs.
Mycophenolate mofetil
- Its antiproliferative properties make it the first-line drug for preventing or reducing chronic allograft vasculopathy in cardiac transplant recipients
- used as prophylaxis for and treatment of both
acute and chronic GVH disease in hematopoietic stem cell transplant patients
-Toxicities include gastrointestinal disturbances (nausea and vomiting, diarrhea, abdominal pain) headache, hypertension, and reversible myelosuppression (primarily neutropenia).
Mycophenolate mofetil
inhibits angiogenesis and has anti-inflammatory andimmunomodulatory effects.
-inhibits TNF-α, reduces phagocytosis by neutrophils, increases IL-10, alters adhesion molecule expression, and enhances cell-mediated immunity via interactions with T cells.
THALIDOMIDE
- current treatment of multiple myeloma at initial diagnosis and for relapsed-refractory disease
- has been used for the treatment of some manifestations of leprosy and has been reintroduced in the USA for erythema nodosum leprosum; it is also useful in management of the skin manifestations of lupus erythematosus
- The most important toxicity is teratogenesis
- peripheral neuropahy, constipation, rash, fatigue, hypothyroidism, and increased risk of deep-vein thrombosis
THALIDOMIDE
- is an oral IMiD that in animal and in vitro studies has been shown to be similar to thalidomide in action, but with less toxicity, especially teratogenicity.
- treatment of the myelodysplastic syndrome with the chromosome 5q31 deletion
Lenalidomide
is a newer oral IMiD that is FDA approved. Like the other IMiDs, it has myriad mechanisms of actions including antiangiogenic activity, inhibition of TNF-α, and stimulation of apoptosis and cytotoxic T-cell activity
Pomalidomide (originally called CC-4047)
is a prodrug of mercaptopurine and, like mercaptopurine, functions as an antimetabolite
MOA: destroys lymphoid cells
aids in conversion: xanthine oxidase
Azathioprine
-used in: acute CGN, SLE,RA, MS and Chron’s disease
-maintain renal allografts
toxic effects: renal marrow supression
Azathioprine
examples of pyrimidin synthesis inhibitors?
- Leflunomide
- Teriflunomide
- They both reversibly inhibit the mitochondrial enzyme dihydroorotate dehydrogenase, which is involved in pyrimidinesynthesis and ultimately results in decreased lymphocyte activation.
- They have anti-inflammatory activity in addition to immunomodulatory properties
Leflunomide and Teriflunomide
-is orally active, and the active metabolite has a long half-life of several weeks. Thus, the drug should be started with a loading dose
used in RA
-liver toxicity
Leflunomide
- treatment of relapsing remitting multiple sclerosis
- hypothesized to decrease the number of activated lymphocytes in the central nervous system.
- NO LOADING DOSE
- Contraindicated in pregnancy
Teriflunomide
an antimalarial agent with immunosuppressant properties. It is thought to suppress intracellular antigen processing and loading of peptides onto MHC class II molecules by increasing the pH of lysosomal and endosomal compartments, thereby decreasing T-cell activation
-treat and prevent GVH disease after allogeneic stem cell transplantation.
Hydroxychloroquine
other miscellaneous agents
Methotrexate - used extensively in rheumatoid
arthritis and in the treatment of GVH disease
vinblastine- prevent mast cell degranulation in vitro by
binding to microtubule units within the cell and to prevent releaseof histamine and other vasoactive compound
Pentostatin-used for steroid-resistant GVH disease after allogeneic stem cell transplantation, as well as in preparative regimens prior tto those transplants
is the methyl ester of fumaric acid. Its exact mechanism of action is unknown, but it appears to activate the nuclear factor (erythroid-derived 2)-like 2 (NRF-2) transcriptional pathway.
Dimethyl fumarate (DMF)
downregulates the immune response to myelin antigensby induction and activation of suppressor T cells that migrate to the central nervous system.
Glatiramer acetate (GA)
- is an orally active sphingosine 1-phosphate (S1P) receptor modulator that is derived from the fungal metabolite myriocin
- FH can cause serious cardiac toxicity including bradycardia, prolongation of the QT interval, and other abnormalities. Because of these potential complications, the drug requires cardiac monitoring for 6 hours after the first dose is given.
- should not be given in pre existing conditions of cardiovascular system
Fingolimod hydrochloride (FH)
acts primarily on the small, long-lived peripheral lymphocytes that circulate between the blood and lymph. With continuedadministration, “thymus-dependent” (T) lymphocytes from lymphoid follicles also are depleted
ALG
are useful for suppressing certain major compartments (ie, T cells) of the immune system and play a definite role in the management of solid organ and bone marrow transplantation
ALG and ATG
prepare recipients for bone marrow transplantation
ALG + ATG+cyclosporine
is prepared from pools of thousands of healthy donors, and no single, specific antigen is the target of the “therapeutic antibody.” Rather, one expects that the pool of different antibodies will have a normalizing effect upon the patient’s immune networks.
Immune Globulin Intravenous (IGIV)
usual dose of Rho(D) immune globulin
2 mL intramuscularly, containing approximately 300 mcg anti-Rho(D) IgG
preparations made from pools of selected human or animal donors with high titers of antibodies against particular agents of interest such as viruses or toxins
-for treatment of respiratory syncytial virus, cytomegalovirus, varicella zoster, human herpesvirus 3, hepatitis B virus, rabies, tetanus, and digoxin overdose
Hyperimmune immunoglobulins /IGIV
used in the induction of immunosuppression, in the treatment of initial rejection,
and in the treatment of steroid-resistant rejection
ALG + Monoclonal antibodies
MOA:
- reduction of T helper cells
- increase of regulatory T cells
- decreased spontaneous immunoglobulin production
- Fc receptor blockade
- increased antibody catabolism
- idiotypic–anti-idiotypic interactions with pathologic antibodies
Concentrated (15%) solution of human IgG against RhO antigen
- based on the observation that a primary antibody response to a foreign antigen
can be blocked if specific antibody to that antigen is administered passively at the
time of exposure to antigen
• Sensitization of Rh-negative mothers to the D antigen occurs usually at the time of
birth of an RhO-positive or D-positive infant, when fetal red cells leak into the mother’s
bloodstream
D Immune Globulin
Given to the Rh-mother 24-72hrs after birth of an Rh+ offspring
- mother’s own antibody response to the foreign RhO(D)-positive cells is
suppressed because the infant’s red cells are cleared from circulation before the
mother can generate a B-cell response against RhO(D)
- no memory B cells that can activate upon subsequent pregnancies with an
RhO(D)- positive fetus
D Immune Globulin
IGIV from donors with high titers of antibodies against toxins or viruses
Hyperimmune Ig
D Immune Globulin dosage
Dose: 2ml IM (300mcg antiRh IgG)
- Adverse reactions are infrequent and consist of local discomfort at the injection
site or, rarely, a slight temperature elevation
Various hyperimmune IGIVs are available for treatment of:
- respiratory syncytial virus
- cytomegalovirus
- varicella zoster
- human herpesvirus 3
- hepatitis B virus
- rabies
- tetanus
- digoxin overdo
administrationof hyperimmune Ig is a ___ transfer of high-titer antibodies that either reduces risk or
reduces the severity of infection
Tetanus hyperimmune globulin route of administration?
administered intravenously when indicated for prophylaxis
Rabies hyperimmune globulin route of administration?
Engineered antibodies directed against therapeutic targets
Monoclonal Antibodies
humanized IgG1 with a kappa chain that binds to CD52 found on:
- normal and malignant B and T lymphocytes
- NK cells
- monocytes
- macrophages
- small population of granulocytes
Alemtuzumab
• humanized IgG1 monoclonal antibody that binds to vascular endothelial growth
factor (VEGF) and inhibits VEGF from binding to its receptor
• non-small cell lung cancer and glioblastoma multiforme
• off label use: intravitreal injection to slow progression of neovascular macular
degeneration
Bevacizumab
• recombinant bi-specific trifunctional rat-mouse IgG hybrid monoclonal antibody
that targets the epithelial cell adhesion molecule (EpCAM) on tumor cells and the
CD3 protein on T cells
Catumaxomab
• human-mouse chimeric monoclonal antibody that targets epidermal growth factor
receptor (EGFR)
• Binding to EGFR inhibits tumor cell growth by causing a decrease in:
- kinase activity
- matrix metalloproteinase activity
- growth factor production
- increased apoptosis
Cetuximab: EGFR
• binds to CD38 which is over-expressed on myeloma cells
• Binding to CD38 on myeloma cells likely induces cell death by apoptosis,
complement-dependent cytotoxicity, or antibody-dependent cytotoxicity
Daratumumab:
• ganglioside D2 (GD2)-binding Mab approved for pediatric patients with highrisk
neuroblastoma in combination with granulocyte-macrophage colonystimulating
factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA)
Dinutuximab:
• binds to EGFR (similar to cetuximab), inhibiting epidermal growth factor from
binding to its receptor, and prevents ligand-induced receptor autophosphorylation
and activation of receptor-associated kinases
• fully human
• metastatic colorectal carcinoma
Panitumumab
• HER-2/neu
• approved for the treatment of metastatic or locally advanced HER-2/neu-positive
breast cancer in combination with trastuzumab and docetaxel as neoadjuvant
therapy.
Pertuzumab
• chimeric murine-human monoclonal IgG1 that binds to the CD20 molecule on
normal and malignant B lymphocytes
• approved for the therapy of patients with CD20-positive large-B-cell diffuse non-
Hodgkin’s lymphoma
Rituximab
• binds to the extracellular domain of HER-2/neu
• blocks the natural ligand from binding and downregulates the receptor
• Used in breast cancer and metastatic gastric carcinoma.
Mabs and Fusion Proteins Used as Immunomodulatory
Trastuzumab:
approved for use in rheumatoid and other forms of arthritis
Abatacept
approved to help prevent rejection in kidney transplants
• block the activation of T cells by binding CD80, blocking the CD28 activation signal
in T cell
Belatacept
• recombinant form of the naturally occurring IL-1 receptor antagonist that prevents
IL-1 from binding to its receptor, stemming the cascade of cytokines that would
otherwise be released
• approved for use in adult rheumatoid arthritis
Anakinra
• binds and neutralizes the biological activity of IL-5, thereby suppressing the
production and survival of eosinophils
• approved for adult patients with severe eosinophilic asth
Reslizumab
• binds to CD25, the IL-2 receptor α chain on activated lymphocytes
• indicated for prophylaxis of acute organ rejection in renal transplant patients
• either drug may be used as part of an immunosuppressive regimen that also
includes glucocorticoids and cyclosporine
Basiliximab/daclizumab
• anti-IgE recombinant humanized monoclonal antibody
• approved for the treatment of allergic asthma in adult and adolescent patients
whose symptoms are refractory to inhaled corticosteroids and chronic urticaria
Omalizumab
• Mab that inhibits B cell activating factor, also known as B lymphocyte
stimulator, preventing B cells from being stimulated
• approved for treatment of adults with active, autoantibody-positive systemic lupus
erythematosus (SLE)
Belimumab
• binds to the integrin GPIIb/IIIa receptor on activated platelets and inhibits
fibrinogen, von Willebrand factor, and other adhesion molecules from binding to
activated platelets, thus preventing their aggregation
• indicated as an adjunct to percutaneous coronary intervention in combination with
aspirin and heparin for the prevention of cardiac ischemic complications
Abcizimab
• anti-cholesterol mabs
• lower LDL levels by blocking proprotein convertase subtilisin/kexin type 9 (PCSK9)
from binding to LDL receptors (LDRL) and causing LDL receptor degradation
• these Mabs have the effect of increasing LDLR on hepatocytes, which lowers LDL
levels in circulation
Alirocumab and evolocumab
Solid Organ and Bone Marrow Transplantation Categories of agents:
Induction agents
Maintenance agents
- Have mono- or polyclonal antibodies
- Given immediately following and sometimes even prior to surgery
Given to maintain immunosuppression for transplantations
Maintenance agents
- preformed antibodies against the donor organ, such as anti–blood group
antibodies - occurs within hours of transplant
- results in rapid necrosis and failure of the transplanted organ
- cannot be stopped by immunosuppressive dru
- Hyper acute
- type of rejection wherein mediated by both antibodies and T cells
- cannot be stopped by immunosuppressive drugs
Accelerated
type of rejection:occurs within days to months and involves mainly cellular immunity
- Reversal of acute rejection is usually possible with general
immunosuppressive drugs such as azathioprine, mycophenolate mofetil,
cyclosporine, tacrolimus, glucocorticoid
acute
- usually occurs months or even years after transplantation
- characterized by thickening and fibrosis of the vasculature of the
transplanted organ, involving both cellular and humoral immunity
Chronic
- potentially curative procedure for a variaty of malignant and nonmalignant
diseases - An HLA-matched donor, usually a family member, is located, patients are
conditioned with high-dose chemotherapy and/or radiation therapy
• Allogeneic hematopoietic stem cell transplantation (HCT/bone marrow transplant)
- common occurrence among recipients of allogeneic transplants
- occurs because donor T cells fail to recognize the patient’s skin, liver, and gut
(usually) as self and attack those tissues
GVH disease (graft vs host disease)
acute GVH manifestations?
manifest as a skin rash, severe diarrhea, or hepatotoxicity
‣ Additional medications are added, invariably starting with high-dose
corticosteroids
after 100 days
- Unlike solid-organ transplant patients, however, most stem cell transplant
patients are able to eventually discontinue immunosuppressive drugs as GVH
disease resolves (usually 1–2 years after their transplant)
chronic GVH
• agents that can modulate instead of suppress the immune response has been
developed in the hopes of increasing the immune responsiveness of patients
who have either selective or generalized immunodeficiency
- immunodeficiency disorders, chronic infectious diseases, and
IMMUNOMODULATION THERAPY
• group of proteins of which some are immunoregulatory proteins synthesized by
leukocytes and play numerous interacting roles in the function of the immune system
and in the control of hematopoiesis
• cytokines mediate their effects through receptors on relevant target cells and appear to
act in a manner similar to the mechanism of action of hormones
Cytokines
• proteins that are currently grouped into three families:
- IFN-α, IFN-β , and IFN-γ
INTERFERONS
constitute type I IFNs, ie, acid-stable proteins that bind to the
same receptor on target cells
IFN-α and IFN-β:
type II IFN, is acid-labile and binds to a separate receptor on target cells
IFN-γ,
are usually induced by virus infections, with leukocytes producing IFN-α
Type I IFNs
Fibroblasts and epithelial cells produce what type of interferons?
IFN-β
Interferon that is usually the product of activated T lymphocytes
-display immune-enhancing properties, which include increased antigen presentation and macrophage, NK cell, and cytotoxic T-lymphocyte
activation
IFN-γ
• has been used for malignant melanoma and soft tissue sarcoma of the extremities
• GM-CSF has been used in stimulating granulocyte production
• In case of febrile neutropenia, and especially those with absolute neutrophil counts
that are very low, WBC counts increase when giving GM-CSF
• Among all of the cytokines, erythropoietin is the most commonly used (given to
patients on end-stage renal disease and on regular hemodialysis as either epoietin
α or β)
TNF-α
• Used to stimulate production of platelets and in some instances like patients with
leukemias who have severe thrombocytopenia with severe bleeding episod
THROMBOPOIETIN
drug reactions are manifested as?
skin eruptions, edema, anaphylactoid
reactions, glomerulonephritis, fever, and eosinophilia
(immediate) sensitivity allergy to certain drugs occurs when the drug, not capable of
inducing an immune response by itself, covalently links to a host carrier protein
(hapten)
• immune system detects the drug-hapten conjugate as “modified self” and responds
by generating IgE antibodies specific for the drug-hapten
• Fixation of the IgE antibody to high-affinity Fc receptors on blood basophils or their
tissue equivalent (mast cells) sets the stage for an acute allergic reaction
Immediate (Type I)
Sites for mast cells:
- Skin
- Nasal epithelium
- Lung
- GIT
applying an extremely dilute solution of the drug to the skin and making a
scratch with the tip of a needle
- If allergy is present, an immediate (within 10–15 mins) wheal and flare will occur
- Should not be on steroids or antihistamines
scratch test
- often used in severe allergic reactions, is immunosuppressive
- blocks proliferation of the IgE-producing clones and inhibits IL-4 production
by T helper cells in the IgE response, since glucocorticoids are generally toxic
to lymphocytes
Prednisone
In the efferent limb of the allergic response, ___,___ and ___ reduce the release of mediators from mast cells and basophils and produce bronchodilation
isoproterenol, epinephrine, and
theophylline
- opposes histamine
- relaxes bronchiolar smooth muscle and contracts vascular muscle, relieving
both bronchospasm and hypotension - DOC for anaphylaxis
Epinephrine
Desensitization or hyposensitization
- In the face of life-threatening illness and absence of alternatives, desensitization
(also called hyposensitization) can sometimes be accomplished by starting with
very small doses of the drug and gradually increasing the dose over a period of
hours or days to the full therapeutic range - slow and progressive administration of the drug gradually binds all available IgE
on mast cells, triggering a gradual release of granules - Once all of the IgE on the mast cell surfaces has been bound and the cells have
been degranulated, therapeutic doses of the offending drug may be given with
minimal further immune reaction - Therefore, a patient is desensitized only during administration of the drug
• Drugs often modify host protein, thereby eliciting antibody response to the modified
protein
• These allergic responses involve IgG or IgM in which the antibody becomes fixed to a
host cell which is then subject to complement-dependent lysis or to antibodydependent
cytotoxicity
Autoimmune (Type II) reaction
Autoimmune (Type II) is seen in?
Seen in:
‣ systemic lupus erythematosus — hydralazine or procainamide therapy
‣ lupoid hepatitis — cathartic sensitivity
‣ autoimmune hemolytic anemia — methyldopa administration
‣ thrombocytopenic purpura — quinidine
‣ agranulocytosis — variety of drugs
Serum Sickness and Vasculitic Reaction (Type III)
• clinical features of serum sickness include urticarial and erythematous skin eruptions,
arthralgia or arthritis, lymphadenopathy, glomerulonephritis, peripheral edema, and
fever
• last 6–12 days and usually subside once the offending drug is eliminated
• mechanism of tissue injury is immune complex formation and deposition on
basement membranes (eg, lung, kidney), followed by complement activation and
infiltration of leukocytes, causing tissue destruction
• Immune vasculitis can also be induced by drugs
• sulfonamides, penicillin, thiouracil, anticonvulsants, and iodides
- initiation of hypersensitivity angiitis
• e.g. Erythema multiforme and Stevens-Johnson syndrome
Cell-Mediated (Type IV)
• 24-48hrs after exposure
• Delayed type
• Upon first exposure to the allergen (drug), antigen-presenting cells stimulate a T-cell
response specific for that allergen (takes 1–2 weeks)
• Upon second and all subsequent exposures, tissue-derived antigen-presenting cells
that come in contact with the new antigen secrete chemokines and cytokines that
attract memory T cells to the site of allergen re-exposure
• Contact hypersensitivity
- form of DTH
- occurs when an allergen elicits DTH on the skin, resulting in spongiosis such as
when an ointment containing an allergen is applied to skin
