Immunity Exam 2 Flashcards
During antigen recognition naive B cells are stimulated by antigen binding to cell surface IgM or IgD and _______________ of several B cell receptors
cross-linking
Expression of co-stimulatory molecules and cytokine receptors act as ____ in B cell activation
APC
Polysaccharides, lipids, nucleic acids are T independent. What does that mean
they are not seen by T cells
Multivalent antigen (repeated epitope) cross-links surface Ig on what kind of cells
B cells
Most proteins antigens are ___ ___________ antigens which mean they need T cell help for maximal response
T dependent
T independent antigens are most what kind of Ig response?
IgM sometimes IgG
How do T cells activate B cells
B cells present antigen and co-stimulators
activated T cells express CD40 and secrete cytokines
B cells are then activated
Do T cells and B cells bind the same epitope
no
What are haptens
a molecule that can be recognized by an antibody, but that cannot by itself induce antibody production (or T cell response)
Haptens are important in the generation of what
drug allergies
When attached to a carrier haptens become what
immunogenic, they can only be immunogenic when covalently coupled to a carrier
B cells need to __________ surface antibody
cross-link
Hapten on peptides can bind ______ and stimulate T cells
MHC
(A hapten on a carrier can stimulate T cell help by carrier-specific T cells. T cell recognizes foreign or modified peptides presented by the B cell.)
Poison Ivy reaction is a hapten-carrier reaction because urushiol is what
reactive
What happens in primary sensitization of poison ivy
sensitized T cells are produced and give rise to memory cells
What happens during second contact of poison ivy
T memory cells become activated; precipitate and inflammatory reaction and dermatitis
What happens during a sulfonamide-antibiotic allergy
reactive molecules can couple to proteins
antibodies recognize 5-membered ring
generate antibodies to the drug and T cells recognize it
T cells help induces what
more antibody production
heavy chain class switching
affinity maturation (antibody structure changes to have higher affinity for antigen)
memory B cell production
What do Ig B cells first secrete, how does this class swtich, and what happens in the decient individual
IgM first
-CD40L on T cell binds to CD40 on B cell
–CD40L deficiency have hyper-IgM
T cell cytokines determine new isotypes. What does IFN gamma cause, IL-4 cause, and TGF beta cause
IFNgamma -> IgG
IL-4 -> IgE (sometimes IgG)
TGFbeta -> mucosal tissues IgA
Isotype switching puts same ____ on a different Fc region. How does this activate the pathway
VH
Fc region recognized by Fc receptors and complement
Fc conformation changes when Ab binds to antigen
Fc conformation changes when Ab binds to antigen, so antigen-antibody complexes activate what
complement
What is the principle effector function of IgM
complement activation
What is the principle effector function of IgG
Fc receptor dependent phagocyte responses, complement activation, neonatal immunity
Principle effector functions of IgE
immunity against helminths
mast cell degranulation
Principle effector functions of IgA
mucosal immunity
What is the neonatal Fcgamma receptor
FcRn
What is FcRn responsible for
recycling IgG antibodies in the circulation
(controls half-life of antibodies and drugs)
(important in design of biologic drugs)
Once recycling of endosome occurs in the monocyte what happens when it reaches physiological pH in the blood
IgG dissociates
Dividing B cells accumulate point mutations in the what regions. What does this cause
Ig V, causes affinity of the Ab for Ag
During affinity maturation at low antigen levels, only high affinity what kind of cells bind and recieve the survival signals once a point mutation occurs
B cells
During the decline of humoral response the response subsides because what dies off
B cells dies off from lack of antigen stimulation
What kind of receptors are binded with low-affinity to Ag-Ab complexes on B cells. What does this further inhibit
Fc gamma RII
inhibit B cell receptor signaling causing no more production of antibodies
Too much antibody may reduce response to vaccine by enhanced clearance or what kind of inhibition
feedback
During memory B cells IgG or other isotypes can replace what two Igs on the cells surface
IgM and IgD
Why does IgG replace other isotypes on the surface during memory B cells
more antigen-specific cells present causing less time needed for production of high-affinity IgG
What is type 1 (Immediate hypersensitivity) caused by
IgE bound to mast cells
-allergic reaction, favored by TH2 cells
In types II and III hypersensitivity what is it caused by
antibody or immune complexes, often autoimmune
-damage by innate components interacting with adaptive components, often TH1
In delayed type hypersensitivity (Type IV) what is it caused by
cell mediated, usually CD4 cells
Why does hypersensitivity occur during adaptive memory for antigens
-Usually first contact with antigen produces memory, no damage
-Second contact causes damage
What is sensitization of immediate hypersensitivity (type 1)
-priming encounter causes no allergic symptoms, not inflammatory
-T cells are shifted to TH2 and IgE is produced
During immediate hypersensitivity (Type I) allergic response to second encounter what happens
no lag time due to IgE pre-bound to Fc epsilon RI on mast cells
immediate release of allergic mediators (histamine)
What is IgE’s half life in serum and how many days is it bound to mast cells in tissues
serum - 2 days
mast cells - 10 days
IgE production is dependent on what
TH2 CD4 cells stimulating B cells
What interleukins promote TH2 cells
IL-4, IL-5, IL-13
What inhibits production of IgE
TH1 CD4 production
What interleukins promote TH1 cells
IL-2, IL-12, INF gamma
What do histamine and serotonin do during Type 1 mediation
-loosen endothelial cell tight junctions increasing vascular permeability, tissue edema, drop BP
-constriction of smooth muscle cells; airway, GI
What does proteases do during Type 1 mediation
activation of complement
-increase vascular permeability, chemoattractant
activation of kinin cascade
-increase vascular permeability
What does proteoglycans do during type 1 mediation
heparin, chondroitin
What increases late phase symptoms that triggers smooth muscle contraction in the lungs
Leukotrienes
What are basophils attracted to and what attracts them
attracted to: IgE and mast cell inflammation
attracts them: D4 and E4
Basophils produce large quantities of what
leukotriene C4
(C4 converted to D4 and E4)
Are basophils present in the immediate phase of a type 1 reaction
no, they are involved with symptomology in late phase response
What are the chemotactins of eosinophils
leukotriene D4 and E4
Eosinophils are involved with ADCC which is triggered by what
IgG and IgA
What kind of cytokines do eosinophils produce
inflammatory
wound healing
-TGF-β, TGF-α, VEGF (vascular endothelial GF) and PDGF (platelet derived GF)
Antibodies may cause tissue injury and disease by what two things
binding directly to their target antigens on the surface of cells in extracellular matrix (type II hypersensitivity) or by form in immune complexes that deposit mainly in blood vessels (type III hypersensitivity)
What cells produce more complement-fixing isotypes (often autoimmune)
TH1 helper cells
Injury caused by antitissue antibody causes complement and Fc receptor mediated recruitment and activation of inflammatory cells which causes what
tissue injury
(effector mechanism of tissue injury caused by neutrophils and macrophages)
Type II hypersensitivity transfusion reactions are caused by what
mismatched blood types
-IgG destroys foreign RBC by complement mediated lysis
—produced fever, clots, lower back pain, Hgb in urine
What are the 2 fates of free Hgb during type II hypersensitivity
passes to the kidneys - hemoglobinuria
breaks down to bilirubin - can be toxic
During type III immune complex-mediated tissue injury, complement and Fc receptor-mediated recruitment and activation of inflammatory cells cause what
vasculitis
What are the 4 steps of type III hypersensitivity
-intermediate-sized immune complexes deposited in the tissue
-complement activation
-neutrophil chemotaxis
-neutrophil adherence and degranulation
What are the immune processes involved in type III hypersensitivity
classical complement pathway
phagocytic cells
takes hours to days to develop
High titers of what are required for type III hypersensitivity reactions
soluble antigen/IgG or IgM
What do type 1 reactions require the presence of
IgE (specific for the allergen’s antigenic determinant)
What are the newly formed mediators in Type 1 reactions
leukotrienes
Prostaglandins
Thromboxane
platelet-activating factor
What is the onset of reaction for type 1 sensitivity reactions
within 1 hour
What type 1 mediators are in bronchospasm
histamine
prostaglandins
leukotrienes
bradykinin
PAF
What type 1 mediators are in mucosal edema
histamine
prostaglandins
leukotrienes
bradykinin
PAF
What type 1 mediators are in mucus secretion
histamine
prostaglandins
leukotrienes
What type 1 mediators are in airway inflammation
PAF
ECF-A (eosinophil)
leukotrienes
What are types of allergic disease
food allergies
drug allergies
What are types of atopic disease
asthma
indoor/seasonal allergies
atopic dermatitis
What is a pseudoallergic reaction
immediate systemic reactions that mimic anaphylaxis but are NOT caused by IgE-mediated immune responses
What is the treatment for anaphylaxis
epi pen
inhaled beta agonist
antihistamine (second line, not monotherapy)
corticosteroid
What is the dose of an epi pen and what is the special counseling point for it
0.3 dose
always carry 2 pens
What is the treatment algorithm for allergic rhinitis
antihistamines
decogestants
intranasal steroids (only one to help with nasal congestion)
montelukast
What is the important counseling point of taking medicine for allergic rhinitis
start a week before allergy season or exposure and continue throughout
What mediators do corticosteroids help with
decreases leukotrienes, prostaglandins, thromboxans
Adverse effects of oral antihistamines
sedation (1st gen)
dry mouth/eyes
dizziness
blurred vision
confusion
hypotension
Adverse effects of intranasal products
nasal irritation
throat irritation
headaches
nosebleed
What is atopic dermatitis
kind of eczema (dry skin, rash)
can be from weather or stress
How to treat atopic dermatitis
skin hydration
topical steroids
topical calcineurin inhibitors (tacrolimus, pimecrolimus)
monoclonal antibodies (dupilumab, tralokinumab)
What is the end goal of navigating drug allergies
de-label patients who are not truly allergic
What can be used to assess reactive risk to drugs
Skin testing followed by an optional oral challenge can be used to assess reactive risk to some drugs
A negative ____ result indicates that the risk of life-threatening immediate reactions is extremely low with the administration of penicillin or other β-lactams
PST (penicillin skin testing is only available commercial product IgE mediated)
When is drug desensitization used
when no other viable treatment options exist, and the patient has a type I hypersensitivity reaction to the medication needed
What is the MOA of desensitization, end goal, and how long does it take
process in which mast cells are rendered less responsive
goal to increase IgG antibodies by preventing binding of allergen to mast cell associated IgE
can be rapid or completed over hours (meds) or years (enviornmental allergies)
IgG4 can be produced in response to an allergen but does not do what
generate an allergic response
IL-10 is key to production of IgG4 versus what
IgE
(IgG4 and IgE are TH2 responses to allergens)
A rapid 12-step desensitization protocol has been described and tested in patients with both IgE and non IgE mediated reactions to what
antibiotics
platimum-containing chemotherapeutic agents
taxane chemotherapy agents
monoclonal antibodies
does successful desensitization remove the allergy long term
no, successful desensitization does not remove the allergy long-term from the medical record, but only allows for administration of the agent at that time.
During desensitization what happens if a dose is missed
therapy has to be started again
(Desensitization lasts only for as long as the patient is continuously exposed to the drug
Self reactive B and T cells can generate reactivity causing what diease
autoimmune
Where are self-reactive B and T cells deleted
bone marrow
thymus
Why are some self-reactive CD4 T cells not deleted in the thymus and what regulates them
they exit as regulatory T cells (Tregs) and then Tregs control anti-self responses in the peripheral immune organs
What are the 2 ways that self-reactive T cells are controlled
Tregs
Regulatory T cells by inhibiting effector T cell funciton
How do Tregs regulate
IL-10, TGF beta
Secrete adenosine which is inhibitory
Use IL-2
Induce APC inhibitory functions
Some T cells that see antigen w/out co-stimulators are made nonresponsive “anergy,” how can this be reversed
high IL-2 or inflammation
(this is why some autoimmune disease appear after viral infection)
Sometimes B or T cells escape tolerance and encounter the antigen in the body. What does this cause
tissue injury, inflammation
spread to other antigens
excess cytokines (IFN gamma, TNF)
complement activation
What could stimulate autoimmune disease
an infection may induce co-stimulatory molecules on a cell presenting self-antigen and overcome anergy
What is molecular mimicry
microbial peptide or proteins may be recognized by self-antigen reactive T or B cell
Autoreactive antibodies can cause tissue cytotoxicity. What kind of hypersensitivity reaction is that
Type II
Defects in what can cause autoimmune disease
MHC alleles that present peptides and dont delete anti-self T cells
regulatory cytokine defects
Complement C2 and C4 defects
Defects in complement C2 and C4 cause what
lupus-like disease
anti-DNA antibody (DNA complexes cause kidney damage)
What does a defect in HLA-DR4 cause
associated w/ increased risk of RA and insulin-dependent diabetes
Risk-Associated Genes for Systemic Lupus Erythematosus (SLE) is caused by defects in what
phagocytosis
complement and opsonization
too much IFN type 1
regulation of cytokines and cells
Antigens are often what molecules
dsDNA
small nuclear rebonucleoproteins
histones
phospholipids
Source of DNA for ANA (anti-nuclear antibodies) cause a defect in clearance of what
dying cells
antigen-antibody complexes
What is autoimmune psoriasis
inflammatory skin disease
uncontrolled growth of keratinocytes and dermal vascular endothelial cells
T cell, DC, neutrophil, and macrophage infiltration
genetics
How is triggering of auto-antigens caused
source unknown
could be minicry or microbiota
Inflammation recruits what 2 molecules
neutrophils
macrophages
What disease is caused by uncontrolled inflammatory cytokines leading to joint destruction, what is it mainly caused by
Autoimmune
-mainly TNF alpha and IL-1
-genetics
In RA antibodies created by autoantibody production cause the antibodies to go to what
citrullinated proteins
What are the cells involved with RA
TH1
TH17
B cells
innate cells
synovial cells
osteoclasts
What are the 3 stages of RA
induction
inflammation
destruction
Predominant genetic risk factors in MHC for RA
HLA-DR4
HLA-DR14
-inflammatory cytokine regulation
-B cell stimulation and antibody production
-T cell stimulation and regulation
What are citrullinated peptides
lose postive charge
unfold protein
recognized by B cells as foreign
When does citrullinated peptides happen
defective clearance of apoptosis and inflammation
B cells recognize them and create anti-citrullinated (CPP) peptide antibodies (aka ACPA)
Inflammation alters what kind of glycosylation
Fc
(Ab galactosylation is reduced w/ proinflammatory activity, galactosylation and sialylation results in anti-inflammation)
What type of Ig molecule is RA
mainly IgM but could be any isotype
Defective glycosylation of IgG can lead to Fc regions that are recognized by what
anti-Fc antibodies
Where can the generation of self-reactive B cells and T cells occur
happen in the lymph nodes or peripheral lymphoid organs (immune complexes can enter the joints or be formed there)
Inflammatory innate cytokines lead to infiltration of leukocytes into the ________. What cytokine is important in this process
synovium
TNF
What cells favor production of inflammatory cytokines and favor complement-activating IgG Anti-CCP antibodies and rheumatoid factor (RF)
TH1
What 2 cells favor osteoclast development and bone degradation
TH1 and TH17
What cells activate synoviocytes
TH17
Defective shutdown of the T cell response is caused by what
CTLA4
What is pannus
abnormal tissue growth, thickening of the synovium
T cells activate chondrocytes to degrade ________
cartilage
T cells promote osteoclasts to degrade ____
bone
______ from macrophages and other cells continues inflammation in destructive RA
TNF alpha
Epidemiology of Lupus
women (15-45)
more severe in men and children
non-whites
Etiology of Lupus
genetics
enviornment (smoking, UV, air pollution)
Hormones (estrogen and progesterone)
What are the drugs associated with drug induced lupus
Methyldopa
Hydralazine
Anti-TNF agents
What organs are affected with lupus
almost any organ
What are the clinical criteria for lupus
rash
ulcers
alopecia
arthritis
serositis
renal
neurologic symptoms
hemolyic anemia
leukopenia
thrombocytopenia
What are the immunologic criteria for lupus
ANA
anti-dsDNA
anti-SM
antiphospholipid
low complement (C3, C4, CH50)
Coombs test
What is the criteria for lupus
4 criteria w/ at least one from each category; or biopsy proven nephritis w/ ANA or Anti-dsDNA
What are the cutaneous signs of lupus
Malar rash (butterfly rash)
Discoid rash
Other rashes: maculopapular, urticarial, bullous
Photosensitivity
Oral ulcers
Alopecia
What are the systemic signs of lupus
Fatigue
Malaise
Fever
Nausea
Anorexia
Weight loss
What are the musculoskeletal signs of lupus
Arthralgias/myalgias
Nonerosive polyarthritis
Hand deformities
Myopathy
Ischemic necrosis of the bone
What are the renal signs of lupus
Proteinuria (> 500 mg/24 hours)
Cellular casts
Nephrotic syndrome
Renal failure
What are the cardio signs of lupus
Pericarditis
Myocarditis
Endocarditis
What are the hematologic signs of lupus
Anemia of chronic disease
Hemolytic anemia
Leukopenia
Thrombocytopenia
Lupus anticoagulant
Splenomegaly
What are the neurologic signs of lupus
Cognitive dysfunction
Headaches
Psychosis
Seizures
Depression and anxiety associated with being chronically ill
What are the ocular signs of lupus
Retinal vasculitis
Conjunctivitis
Sicca syndrome (aka Sjogren Syndrome)
Nonpharm therapy for lupus
aerobic exercise
photosensitivity
smoking cessation
What is the general approach to therapy of lupus
NSAIDs (for mild symptoms)
Antimalarials
Corticosteroids
If therapy for lupus is ineffective or major organs are involved what kind of drugs are added
immunosuppressive or immunomodulatory
FDA approved agents for lupus
aspirin
prednisone
hydroxycloroquine
belimumab
anifrolumab
voclosporin
Off label use of meds for lupus
NSAIDs
cyclophosphamide
MMF (mycophenolate mofetil)
azathioprine
methotrexate
rituximab
Use of NSAIDs in lupus
Used as first-line treatment for arthritis, musculoskeletal complaints, fever, and serositis
Patients with mild disease likely to benefit
Dose used should be adequate to provide anti-inflammatory effects
Non-disease modifying; used for symptom relief
What are the problems with NSAIDs in lupus
GI
renal
-hepatotoxicity
Hydroxychloroquine use for lupus
Anti-inflammatory, immunomodulatory, anti-thrombotic
response time is 3-6 months
Hydroxychloroquine high quality evidence
decrease disease activity and improves survival
Hydroxychloroquine moderate quality evidence
increase bone mineral density and protects against thrombosis and irreversible organ damage
Hydroxychloroquine low quality evidence
reduce severe flares, enhance response of other agents in patients w/ nephritis, benefit for lipids, protect against cancer
Problems w/ Hydroxychloroquine
ocular
-baseline eval and appointments every 6-12 months
Corticosteroid use in Lupus
Control flares and maintain low disease activity
doses should be kept as low as possible
corticosteroid therapy dose for lupus
1-2 mg/kg/d
low dose <10
medium 10-20
high >20
Cushing disease
develop when the adrenal gland produces too much cortisol, or if exogenous steroids are taken in doses higher than the normal amount of endogenous cortisol
Addisons disease
Addison’s disease can be thought of as the opposite
The adrenal gland is not making enough cortisol
If exogenous steroids are stopped suddenly, it can cause an Addisonian Crisis
Hallmark signs & symptoms: volume depletion hypotension
Cyclophosphamide dosing and ADR
1-3 mg/kg/d
-carcinogenic, nausea, alopecia, anemia, infection
Azathioprine dose and ADR
1-3 mg/kg/d
can be “steroid-sparing” therapy
leukopenia, infection, nausea, rash, alopeica, arthralgia
Belimumab dose and ADRs
for pts with autoantibody postitive, receiving standard therapy
10 mg/kf at 2 wk intervals for first 3 doses and 4 wk intervals after
bradycardia, mylagia, rash, anaphylaxis, nausea, pyrexia, insomnia, pain
Rituximab dose and ADRs
iv 1,000 mg twice 2 wks apart
methylprenisiolone 100 given 30 min prior
antihistame and APAP adr
Hydroxychloroquine dose
400 po d or bid
Monitoring for NSAIDs/salicylates
CBC
platelets
creatinine
AST/ALT
bp
Monitoring for glucoccorticoids
bp
serum glucose
lipids
bone density
ophthalmic exams
Monitoring for hydroxychloroquine
fundoscopic and visual field exam
CBC
AST/ALT
albumin
Monitoring for belimumab
infection
depression
mood change
suicidal thoughts
hypersensitivity
Monitoring for cyclophosphamide
CBC
platelets
creatine
AST/ALT
urinalysis
urine cytology
PAP
Monitoring for mycophenolate mofetil
CBC
platelets
creatine
AST/ALT
BMP
chest x ray
Monitoring for azathioprine
CBC
platelets
creatine
AST/ALT
BMP
albumin
PAP
Monitoring for methotrexate
CBC
platelets
creatine
AST/ALT
BMP
bilirubin
alkaline phosphate
Monitoring for rituximab
CBC
platelets
creatine
vital signs
human antichimeric Ab
Pregnancy risk for mothers with lupus
maternal mortality
cesarean delivery
preterm labor
lupus nephritis flares
gestational diabetes
preeclampsia
Hemolysis with Elevated Liver tests and Low Platelets (HELLP)
thrombotic, infectious, and hematologic complications are increased
Fetal risk for mothers with lupus
include fetal loss
preterm birth
preterm premature rupture of membranes
intrauterine growth restriction
What is RA
common, chronic, progressive autoimmune condition that primarily affects the joint and synovium (soft-tissue membrane that lines the joints)
epidemiology for RA
women
north america and northern europe
Joint involvement for RA
bilaterally
warmth and swelling w or w/out pain
Extra articular involvement for RA
rheumatoid nodules
vasculitis
pulmonary
ocular
cardiac
felty’s syndrome
renal
ACR/EULAR Rheumatoid Arthritis Classification Criteria
patients who have at least 1 joint w/ clinical synovitis and with the synovitis not better explained by another disease
(joint, ACPA +, abnormal CRP/ESR, over 6 wk)
Osteoarthritis
wear and tear
degradation of cartilage, decreased chondrocytes
risk factors: heredity, obesity, injury, overuse
pain, asymmetrical, stiffness, crepitus, radiology
Conventional DMARDs in RA
methotrexate
hydroxychloroquine
sulfasalazine
leflunomide
Biologic DMARDs in RA
anti TNF
-etanercept, infliximab, adalimumab
non TNF
-anakinra, abatacept, rituximab
Approach to therapy for RA
double or triple DMARD
Tofacitnib in combo w/ DMARD
low dose glucocorticoid for short duraiton if disease stays high
Methotrexate dose for RA
7.5-15 mg once weekly
combine with folic acid
ADRs of methotrexate
gi
pulmonary
hepatic
alcohol consumption
monitoring in methotrexate
AST
ALT
alkaline phosphate
albumin
bilirubin
hepatitis B and C
CBC w/ platelets
Scr
Leflunomide dose for RA
100 mg po for 3 days
maintenance of 20 mg po daily
ADR leflunomide
liver toxic
bone marrow toxic
teratogenic
GI
alopecia
Sulfasalazine dose for RA
500 mg po bid
increase to 1 g po bid
ADRs Sulfasalazine
nausea, diarrhea, rash, leukopenia, alopecia, discolor of skin
Hydroxychloroquine dose for RA
200-300 mg bid
after 1-2 months decrease to 200 bid or d
Recommended safety monitoring for Hydroxychloroquine, Sulfasalazine, Methotrexate, Leflunomide
CBC
liver transaminases
serum creatinine
Infliximab (Remicade) ADRs
infusion reactions
fever, chills, pruritus, rash
APAP, benadryl, corticosteroids
lupus-like symtoms
mylagia, arthralgia
fatigue
pericarditis, pleuritis
Adalimumab (Humira) ADRs
tuberculosis
other infection risk
Etanercept (Enbrel) ADRs
tuberculosis
other infection risk
Rituximab (Rituxin) ADRs
infection risk
antihistamine, APAP can help with infection risk along with methylprednisolone 30 minutes prior to infusion
Tofacitinib (Xeljanz) ADRs
infection
malignancy GI perforations
upper respiratory tract infections
headache, diarrhea
nasopharyngitis
What do Abs bind to that interfere with binding to host cells and infection
free microbes
What are neutralizing antibodies
antibodies that not only bind but also prevent infection
Abs bind to toxins and prevent them from killing what
host cells
What are the steps of opsonization of phagocytosis
opsonization of microbe by IgG
binding of opsonized microbes to phagocyte Fc receptors
Fc receptor signals activate phagocyte
phagocytosis of microbe
killing of ingested microbe
Where is IgA antibody produced
mucosal tissues
-high levels of TGF beta
-T independent B1 cells also make IgA
What moves IgA across the mucosal epithelium
a special transport molecule, this prevents colonization by microbes and blocks their entry to the body
Why do we need a different flu vaccine each year
different strains
change hemagglutinin and neuraminidase molecule each year
microbes can change their surface molecules to evade antibody production
What is antigenic drift
one or several mutations change a few epitopes
What is antigenic shift
a change in complement or gene leading to changes in many epitopes
What determines Type A or B
Type of M proteins of virus envelope and nucleoprotein
Type A has 15 antigenic forms in what? Type A has 9 antigenic forms in what?
15 - H = hemagglutinin
9 - N = neuraminidase
Type A both drift and shift while type B only does what
drift only
(annual changes are difts)
What are killed or subunit vaccines
less effective
cannot replicate host
multiple boosters
produce antibody response (not CD8 mediated)
What are live vaccines (natural, mild infection, attenuated)
replicate host for short time
long term protection
produce Ab and CD8 cell mediated protection
produce mucosal immunity
cause disease in immunocompromised host
What are adjuvants
substances that trigger the innate response to enhance adaptive immunity
What are freunds adjuvant’s for incomplete and complete
incomplete: mainly mineral oil
complete: mineral oil plus killed mycobacteria
What are alum adjuvants (mainly used in humans)
aluminum compound precipitate allows slow release
mainly TH2
What are synthetic cell components adjuvants
muramyl dipeptide - stimulate macrophage
What are toll-like receptor ligands adjuvant
want TH1 stimulating compounds
What are bacterial components adjuvant
pertussis toxin
What is AS01 Adjuvant
controls properties of liposome
activated inflammasome
(IFN pathway creating pro-inflammatory cytokines by attracting granulocytes and monocytes)
TLR ligand
What is the Lymph Node Response to AS01- Vaccine
antigen and AS01 drain from the injection site w/in 30 minutes
house later migratory DCs and monocytes follow
What are the different vaccine strategies
whole organism
DNA/mRNA
subunit
What are the whole organism vaccines
-natural
-live attenuated
-killed
-recombinant
What are the subunit vaccines
-viral or bacterial
-conjugate
What are the response expected for “Live” vaccines
intracellular and extracellular
CD8 and CD4, B cells (antibody)
What are the live vaccines
natural/attenuated virus
recombinant virus
DNA/RNA
What are the response expected for “dead” vaccines
extracellular only
CD4, B cells (antibody)
What are the dead vaccines
killed bacteria/virus
subunit - protein or carb
toxin
conjugate
What vaccines are natural virus vaccines
vaccinia
smallpox
What vaccines are live attenuated vaccines
viral
-sabin oral polio vaccine
-MMR: measles, mumps, rubella
FluMist
Varicella (chicken pox)
What vaccines are killed virus vaccines
Salk polio vaccine
Influenza vaccine
Hepatitis A
What are recombinant viral vectors
can generate live vaccine with a nonpathogenic virus
-vaccinia virus (attenuated virus)
-adenovirus (cold virus, SARS cov-2)
What is the Johnson & Johnson/ Janssen SARS-Cov-2 vaccine
gives antibodies and CD4 and CD8 T cells because people do not have antibodies to Ad26
What are DNA/RNA vaccines
DNA or stabilized mRNA ingested by host antigen-presenting cells
Intracellulat antigen generation produces cell-mediated response
What is the Pfizer-BioN Tech and Moderna SARS-CoV-2 Vaccines
stabilized mRNA
cell surface and cytoplasmic spike protein
generate antibodies CD4 and CD8 T cells
What are subunit vaccines
Portions of a bacteria or virus, usually an isolated protein or carbohydrate
-usually recombinant proteins
-often need adjuvant to get strong response
What are the viral subunit vaccines
Hepatitis B vaccine
Shingrix
AREXVY
Inflluenza
What are the bacterial subunit vaccines
Inactivated bacterial toxins
-Cholera, diphtheria, tetanus
-DTaP vaccine for children
What are the conjugate vaccines
Haemophilus influenzae type B
Streptococcus pneumoniae
What is the Pneumococcal conjugate vaccine (PCV)Prevnar
Pneumococcal polysaccharide vaccine (PPV) conjugated to inactive diphtheria toxin
Polysaccharides from multiple (13) strains in one vaccine protect against most strains
What is direct allorecognition
Recipient’s T cells recognize donor’s antigen presenting cells or tissue cells with foreign MHC and foreign peptides
Strong reaction
CD4 and CD8 T cells, B cells can be helped
What is indirect allorecognition
Recipient APC pick up donor peptides from graft and stimulate recipient T cells in lymph node
Recipient T cells move to graft and stimulated by recipient APC that have been picked up donor peptides
Usually CD4 T cells
T cells require what to proliferate making them a good target for inhibiting T cells
IL-2
How does cyclosporine A, CsA (Sandimmune) immunosuppress Drugs Targeting IL-2
CsA through formation of a complex with cyclophilin inhibits the phosphatase activity of CALCINEURIN, which REGULATES NUCLEAR TRANSLOCATION and subsequent activation of NFAT TRANSCRIPTION FACTORS. Also inhibits other signaling pathways in T cell activation.
What is cyclosporine A, CsA (Sandimmune)
Fungal cyclic, lipophilic polypeptide
Inhibits activation needed for IL-2 production
How does FK506 (Tacrolimus) immunosuppress IL-2
Fungal macrolide antibiotic
receptor of immunophilin (FK-binding protein, FKBP-12) inhibits calcineurin
Inhibits activation needed for IL-2 production
How does Sirolimus (Rapamune) immunosuppress IL-2R
The cellular target of sirolimus is FKBP12
binds to and inhibits mTOR
Sirolimus inhibits cell activation
-response to IL-2, cytokines, cell growth, metabolism, cytokine production
How does Anti-IL-2Rα (CD25) antibody (Basiliximab) immunosuppress IL-2
IL-2Rα expression upregulated on activated T cells
Prevents IL-2 binding/eliminates activated T cells
Does not block binding to intermediate or low affinity IL-2 receptors
Chimeric antibody
How does Alemtuzumab Target CD52 on T and B Cells
Innate cells express low or no CD52
CD52 expressed on mature T cells, B cells, monocytes, and some dendritic cells
eliminates most mature T cells, fewer B cells and monocytes
How is Mycophenolate Mofetil (CellCept) an Immunosuppressant
Prodrug form of mycophenolic acid
Inhibitor of de novo purine biosynthesis (GMP)
-T and B cell proliferation, apoptosis of T cells
Inhibits adhesion molecule function
-Inhibits NO biosynthesis
____ needed for nucleic acid biosynthesis, glycosylation of cell surface proteins, and cofactors used to make NO
GMP
(starts with Ribose-5-Phosphate and turns into nucleic acid synthesis)
What drugs are used in induction therapy
Basiliximab
Alemtuzumab
High dose steroids
What drugs are used in Maintenance immunosupporession
Tacrolimus
Sirolimus
Mycophenolate mofoetil
Roles of a pharmacist in transplant
patient counseling
increase adherence
recognizing and preventing potential drug interactions
be a resource for patients and providers
What is the role of CMS in transplant
individuals with the appropriate qualifications, training, and experience in the relevant areas of pharmacology
What is the role of OPTN (UNOS) in transplant
-at least one clinical transplant pharmacist on staff
-provision of pharmacological expertise to transplant r-recipients, families, and members of transplant team
-licensed pharmacist with experience in transplant pharmacotherapy
Pre transplant: CMS/OPTN
OPTN
Pre donation: CMS/OPTN
CMS
Peri transplant: CMS/OPTN
CMS and OPTN
Peri donation: CMS/OPTN
CMS
Post transplant: CMS/OPTN
OPTN
Post donation: CMS/OPTN
none
Induction: corticosteroids
methylprenisolone
Induction: IL-2 antagonist
basiliximab
Induction: Anti-CD52
alemtuzumab
Induction: polyclonal t-cell depleting agents
ATGAM
thymoglobulin
Corticosteroids adverse effects
hyperglycemia
fluid retention
HTN
mental changes
T cell sparing drug
basiliximab (simulect)
T cell depleting drug
thymoglobulin
atgam
alemtuzumab (campath)
Basiliximab (simulect) mechanism and side effects
IL-2 receptor antagonist
chills, fever, injection site reaction, anaphylaxis
Alemtuzumab (campath) mechanism and side effects
Anti-CD52 monoclonal antibody
rigor, fever, anemia, neutropenia
anti-lymphocyte antibodies ATGAM, thymoglobulin mechanism and side effects
T cell clearance from circulation
inhibition of proliferative response of T-cells
infusion site reaction, flu, cytokine release syndrome, hypersensitivity, bone marrow suppression
Maintenance Immunosuppression drugs
calcineurin inhibitor (tacrolimus)
antimetabolite (mycophenolate)
corticosteroid (prednisone)
combo of two or more agents w/ different mechanisms
Calcineurin inhibitors drugs MOA
tacrolimus (FK)
cyclosporine
block production of IL-2 and other cytokines by T-helper cells
Dose conversion astagraf XL
100% IR dose given daily
Dose conversion envarsus XR
70-80% IR dose given daily
Tacrolimus side effects
seizure, headache, tremor
alopecia
QT prolongation
diabetes
nephrotoxicity, hypomagnesemia, hyperkalemia
Cyclosporine side effects
gingival hyperplasia
HTN, HLD
hephrtoxicity
hirutism
Antimetabolite drugs
MMF (mycophenolate mofetil)
MPA (mycophenolic acid)
AZA (azathioprine)
mycophenolate MOA
IMPDH
inhibit de novo guanosine nucleotide synthesis
block DNA synthesis and inhibit leukocyte recruitment to sites of inflammation
mycophenolate side effects
GI***
leukopenia, thrombocytopenia
teratogenicity
MMF IV formulation dose change
1:1 conversion
MPA IV formulation dose change
1000 mg IV MMF = 720 mg oral MPA
Azathioprine Mechanism
azathiprine
6-MP
6-thioguanine nucleotide
inhibit DNA synthesis
Azathioprine side effects
alopecia
skin cancer
n/v
leukemia
mTOR drugs
sirolimus (rapamune)
everolimus (zortress)
mTOR side effects
mouth ulcers
elevated cholesterol and triglycerides
(lipid panel and urinalysis)*****
Belatacept (nulojix) MOA
bind to CD80-86 receptors on antigen presenting cells thereby preventing costimulation of the T cell, cytokine production and cell proliferation
Belatacept (nulojix) side effects
PTLD
increase CNS disease risk
EBV
PML
tuberculosis
Tacrolimus/Cyclosporine Interactions
Pgp bioavailability
Cyp 3A4
nephrotoxic meds (avoid NSAIDs)
mTOR inhibitor interactions
Pgp
CYP3A4
CNI and mTOR CYP3A4 interactions increase
protease inhibitor
azole antifungal
macrolides
verapamil, dilt
amiodarone
letermovir
grapefruit juice
CNI and mTOR CYP3A4 interactions decrease
CYP3A54 inducers
rifampin
anti-convulsants
st john wart
cyclosporine interactions increase
digoxin
colchine
statins***
sirolimus
Azathioprine interactions
xanthine oxidase inhibitor (allopurinol/febuxostat) not recommended****
cause bone marrow suppression
Mycophenolate interactions
antacids (2 hours after)
PPI (MMF only)
cyclosporine
antimicrobials affecting gut flora
sevelamer
BAS
hormonal contraception
Acute cellular rejection severity: banff IA, banff IB, banff IIA/IIB, banff III
banff IA least
banff IB
banff IIA/IIB
banff III most
Corticosteroids side effects
blood glucose
fluid retention
blood pressure
mental changes
acute cellular rejection meds to give during banff IA, banff IB, banff IIA/IIB, banff III
banff IA (no thymoglobin)
banff IB
banff IIA/IIB
banff III
treatment resistant
all methyprednislone 500 mg IV for 3 doses****
thymglobin
Plasmaphersis (PP)/ plasma exchange (PE) MOA and monitoring
filtering of plasma to target removal of a specific toxin or substance
hypocalcemia, hypotension, coagulopathy
IVIG MOA and side effects
autoantibody neutralization, block Fc, cytokine modulation, immune cell/complement regulation, passive immunity
infusion reaction, thromboemolism, hemolysis, fluid overload, aseptic meningitis, acute kidney injury, liver function, hypersensitivity, IgA related anaphylaxis
Bortezomib (velcase) MOA and side effects
proteasome inhibitor resulting in plasma cell apoptosis
bone marrow suppression, cardio, hepatoxicity, herpes reactivation, neuropathic pain, GI, glycemia, hypotension
Rituximab MOA and side effects
inhibit CD20 antigen on the surface of B cells
bone marrow suppression, Hep B reactivation, bowel perforation, infusion reaction
Eculizimab (soliris) MOA, side effects
humanized monoclonal IgG antibody that binds to complement protein C5, preventing cleavage into C5a and C5b
infusion reaction, bone marrow suppression, HTN, REMS
Acute antibody mediated rejection order of meds
IVIG + PP
IVIG + PP + bortezomib +/- rituximab
IVIF + PP
IVIG + PP + eculizimab
