Week 8 Flashcards

Question

Thrombin time measures ________ sensitive to? normal = ? prolonged by?

Answer 1

measures procoagulant activity of fibrinogen Sensitive to anticoag effect of heparin or fibrin split products Normal = 12-18 secs Prolonged with heparin contamination or fibrinogen deficiency

Answer 2

measures platelet-vessel interaction, number / function of platelets Decrease in platelets (

Answer 3

In vitro bleeding time, determines platelet response to agonists

Answer 4

A --> Factor 8 B --> Factor 9 XR

Answer 5

normal PT, normal bleeding time low factor 8 or 9 Prolonged PTT

Answer 6

Severe → spontaneous hemorrhage in joints, muscles, soft tissues, CNS Moderate → usually need trauma for bleeding Mild → only bleed after trauma -Diagnosed after bad trauma or surgery Carrier females with bleeding = symptomatic carriers

Answer 7

recombinant factor treatment given by IV 2-3 times a week

Answer 8

AR Presents as postoperative hemorrhage Labs: Protime (PT) significantly prolonged, normal PTT

Answer 9

Massive trauma, hemorrhagic/septic shock, burns, acute leukemia, and drug reactions

Answer 10

→ intravascular deposition of fibrin → thrombosis of small/midsize vessels with organ failure Depletion of platelets and coagulation factors (fibrinogen, platelets, Factor VIII, V) → bleeding

Answer 11

1) Very low fibrinogen level 2) Low platelets 3) PT least affected, prolonged (in contrast to liver disease) 4) Greatly prolonged PTT (low factor 8) 5) Prolonged TT 6) Increased fibrin split products (D-Dimer)

Answer 12

Liver problem → deficiency in clotting factors (Factor V, vitamin K dependent Factors II, VII, IX, and X. Very severe liver disease, fibrinogen low

Answer 13

1) Prolonged PT (INR) 2) relatively less prolonged PTT (low IX and X) 3) if fibrinogen low → TT prolonged 4) Low platelets 5) Important to CHECK VITAMIN K DEFICIENCY

Answer 14

Common acquired abnormality → hypercoagulable state THROMBOTIC TENDENCY (Deep vein thrombosis, pulmonary embolism, etc.) Antiphospholipid Antibody Syndrome (APS): IgG ab anti phospholipid platelet membrane or endothelial cell

Answer 15

Prolongs PTT, BUT DO NOT have bleeding tendency Test specifically with Russell’s Viper Venom Test (dRVVT) Tests for lupus anticoagulant

Answer 16

Mix patient and control plasma 1:1 → assay PTT IF PTT corrects → factor deficiency (because factor in control blood) If acquired ab to factor 8 (lupus anticoagulant)→ PTT will NOT correct

Answer 17

- Test function of humoral immune system - Cheap, easily quantified - Not very sensitive to small abnormalities - Can be done on urine, CSF and blood

Answer 18

1) M spike in IgG 2) peaks are small 3) wider peak

Answer 19

Measures levels of individual immunoglobulin classes or subclasses -must be a multivalent antigen that can form precipitate with an appropriate ab

Answer 20

abs against autoantigens in the nucleus 1) Fix with agent that makes cell plasma membrane permeable so ab can penetrate 2) Wash and mix with labeled goat anti-human IgG

Answer 21

Immunofluorescence: -Used to identify antibody in patient’s tissues (direct) or in their blood (indirect) Immunohistochemistry: -Uses final ab labeled with an enzyme that produces a brown/black product that can be observed and archived for a long time

Answer 22

direct immunofluorescence test TEST FOR PRESENCE OF ANTIGEN

Answer 23

indirect immunofluorescence TEST FOR PRESENCE OF ANTIBODY

Answer 24

antigen-coated latex particles - test to detect ab 1) Couple antigens to RBCs or latex beads 2) → add dilutions of patient’s serum 3) Look for agglutination titer EX) Used for RF which can agglutinate latex particles coated with IgG Advantages: simple, cheap, anyone can do it

Answer 25

Test to detect antigen 1) Latex beads coated with abs 2) Add bead to patient fluid of choice 3) If they agglutinate → antigen present

Answer 26

**measures antibody** 1) Antigen couple to a plate 2) Add test serum 3) If there is ab to antigen it will bind 4) Identified using enzyme-coupled antibody to expected serum antibody

Answer 27

**measures antigen** 1) Use 2 different monoclonal abs to specific antigen of interest 2) Capture antibody: one ab on a plate so it’s stuck there 3) Add patient serum, Wash 4) Add second ab with enzyme coupled to it 5) Add colorless substrate that produces a colored product 6) Measure intensity of product color in a plate spectrophotometer

Answer 28

1) mAbs to CD3, CD4, or CD8 → count fluorescent cells under a microscope 2) Flow cytometry

Answer 29

1) Skin test for Th1 activity - Best overall test to measure Th1 activity 2) Challenge DTH test 3) Mitogens (PHA or Con A) → stimulate T cells, observe proliferation or IL-2, IL-4, or IFNy production 4) Chest x-ray - look at thymus in infants 5) Lymphoid biopsy - check for suspected primary immunodeficiency 6) Killer cell assays

Answer 30

serum protein electrophoresis

Answer 31

Rapid screen EX) strep test, dipstick pregnancy test

Answer 32

measures number of B and T cells - Pump cells in suspension through orifice in single file - Cells bound to fluorescent-tagged antibody → quantify light emitted

Answer 33

1) Decreased blood flow (venous stasis) 2) Inflammation of or near the blood vessels (altered vessels) 3) Intrinsic alterations in the nature of the blood itself (altered coagulability)

Answer 34

complete obstruction of venous outflow from an extremity 1) Extremely swollen 2) Blue 3) Painful

Answer 35

Arterial = white thrombi - aggregated platelets - small amounts of fibrin - few red cells Venous = red thrombi - large amounts of fibrin - numerous red cells

Answer 36

high shear stress (vWF critical for platelet adhesion) slow blood flow

Answer 37

ATHEROSCLEROSIS HTN turbulent blood flow at arterial branch points

Answer 38

TIME is critical! Acute: 1) Heparin → prevent further clot formation 2) tPA (fibrinolytic agent) → lyse existing clot Long-Term: 1) Aspirin (inhibit COX) - ANTIPLATELET THERAPY

Answer 39

stasis, immobility, obesity, direct trauma, surgery, extrinsic compression, right-sided heart failure, presence of foreign body (IV, catheter) Risk Factors: obesity, trauma, post-surgery, age, pregnancy NOT HTN, hyperlipidemia → arterial problems

Answer 40

part of thrombus breaks off and travels through major veins, past right heart, and into pulmonary artery circulation until it becomes lodged → prevents gas exchange → infarct Signs/Symptoms: chest pain, dyspnea, anxiety, cough, syncope, cyanosis, chronic pulmonary HTN

Answer 41

Anticoagulant therapy 1) Heparin - stops clot from getting bigger 2) Warfarin - prevent additional clots (slow to start working)

Answer 42

1) First thrombosis age less than 50 2) Recurrent episodes of thrombosis 3) Family history of thrombosis 4) Thrombosis at unusual sites 5) Neonatal thrombosis 6) Thrombosis without apparent antecedent thrombogenic event (idiopathic)

Answer 43

Formed when cross-linked fibrin degraded by plasmin through fibrinolysis Very sensitive but not specific Positive D-dimer means further studies should be performed high negative predictive value for DVT, but negative D-dimer rules out thrombosis

Answer 44

DVT in legs - 95% specificity and sensitivity

Answer 45

1) Antithrombin inactivates thrombin, 10a, 9a, and 2a, so Antithrombin deficiency → hypercoagulable 2) AD - homozygotes fatal in utero 3) VENOUS thrombosis before age 50 4) Can cause heparin resistance - heparin is a cofactor of AT-III

Answer 46

1) Protein C inactivates factors 5a and 8a to inhibit coagulation, VitK dependent 2) AD 3) Can be made worse by Warfarin therapy

Answer 47

1) VitK dependent, facilitates anticoagulant activity of activated protein C 2) Thrombosis in atypical areas 3) AD

Answer 48

1) AD mutation of factor V gene → partial resistance to inactivation by proteolytic cleavage by protein C (NOT a deficiency) 2) Factor V Leiden inactivated 10x more slowly 3) Most common inherited predisposition to hypercoagulability in Caucasian populations 4) Increased coagulation AND decreased anticoagulation

Answer 49

1) AD mutation in factor 2 2) Associated with VENOUS thrombosis 3) Very minor hypercoagulability 4) Causes elevated concentrations of plasma prothrombin

Answer 50

1) Increased risk for thrombosis, obstetric complications, and fetal death 2) Clots in veins and arteries, any vascular bed, any age or gender 3) Prolongs APTT - due to in vitro lab artifact (see Stabler’s lecture)

Answer 51

1) Vascular thrombosis 2) Complications of pregnancy Labs: 1) Anticardiolipin antibodies (ACA) 2) Lupus anticoagulant 3) Beta2-glycoprotein-I antibodies 4) High titers for APab

Answer 52

- 1 unprovoked event or provoked DVT --> 3 months of anticoagulation - 2nd unprovoked event, Cancer, APLS, high-risk thrombophilia --> indefinite anticoagulation

Answer 53

1. Heparin binds antithrombin III (serine protease inhibitor)→ increased rate of thrombin inactivation by 1000x 2. Accelerates decay of 9a, 10a, and 12a by antithrombin III 3. Heparin released by antithrombin and reused once thrombin binds complex (reversible binding to antithrombin)

Answer 54

*Venous thrombosis, *PE, MI, during/after coronary angioplasty, during surgery requiring cardiopulmonary bypass, kidney dialysis

Answer 55

1. unfractionated | 2. Low molecular weight

Answer 56

unfractionated

Answer 57

1. Binds antithrombin/thrombin complex 2. Not absorbed from GI tract - must be given IV or IM 3. Poor bioavailability, short half life → unpredictable dose response 4. Requires hospital admission for careful monitoring - ONLY INPATIENT 5. Does NOT cross placenta (can use during pregnancy)

Answer 58

DO NOT inhibit thrombin by antithrombin b. Selectively binds to and inactivates factor 10a by antithrombin i. Only has 15 saccharide units, so cannot bind thrombin, only can inactivate factor 10a

Answer 59

1. Given IM 2. Longer half life, better bioavailability → more predictable dose response 3. Requires less monitoring (OUTPATIENT treatment)

Answer 60

1. excessive bleeding 2. heparin induce thrombocytopenia 3. allergic reactions

Answer 61

Stop use → anticoagulation effect disappears within hours Can reverse life-threatening bleeding with protamine sulfate

Answer 62

(Thrombosis) 1. Platelet count decreases 2. Abs to platelet factor 4/heparin complexes → platelets activated into prothrombotic state → venous thromboembolism, stroke, MI, arterial thrombosis 3. Less likely with LMWH

Answer 63

chondroitin sulfate | contaminant in heparin supply

Answer 64

Argatroban (Novastan) - small molecule inhibitor of thrombin Lepirudin (Refludan) - recombinant form of hirudin anticoagulant from leeches → inhibits thrombin

Answer 65

rapid onset of action, absence of food interactions, do not require monitoring

Answer 66

contraindicated with kidney disease, greater GI bleeding, shorter half life (problem with compliance), cost, NO ANTIDOTE

Answer 67

for afib, approved in 2015 - thrombin inhibitor

Answer 68

for afib approved in 2012 - factor Xa inhibitor

Answer 69

Vitamin K analogue - inhibits enzymes that use vitamin K as a cofactor 1.Factor 2, 7, 9, 10 undergo vitamin K dependent gamma carboxylation of N-terminal glutamates → cannot bind calcium → non functional

Answer 70

Venous thromboembolism, systemic embolism (pts with prosthetic heart valves or afib), stroke, recurrent infarction

Answer 71

i. Hemorrhage - Takes 24-48 hrs for reversal - coagulation factors must be resynthesized - Can transfuse plasma to replace coagulation factors or Vit. K ii. Cannot be used during pregnancy - crosses placenta iii. Drug and food interactions iv. Requires Monitoring - genetic variability in ability to metabolize Warfarin v. Delayed onset of action

Answer 72

Rapid onset - Heparin acts quickly, but transitioned into an oral anticoagulant

Answer 73

SLOW onset of action - must have turnover of factors before effective

Answer 74

I. t-PA (Tissue Plasminogen Activator): serine protease that binds fibrin, cleaves plasminogen → plasmin (degrades fibrin, degrades clot) - Used to dissolve clots in emergency setting ii. u-PA (Urokinase): converts plasminogen to plasmin (does NOT bind fibrin) iii. Streptokinase: non-enzymatic protein from B-hemolytic strep - Forms complex with plasminogen → activates it → converts to plasmin

Answer 75

i. Acute MI (in combo with ASA) ii. Ischemic stroke (within 3 hrs after stroke) iii. DVT (in combo with heparin/warfarin) iv. PE **high risk agents (hemorrhage, systemic lytic state)**

Answer 76

1. Aspirin 2. ADP receptor antagonists 3. Gp IIb/IIIa inhibitors

Answer 77

inhibit formation of platelet products 1. Irreversibly inactivates COX1 → inhibit formation of thromboxane A2 2. Effects last life of platelet (7-10 days) 3. Used for prevention of AMI and stroke pts with atherosclerosis

Answer 78

prevent platelet aggregation (Plavix) 1.Block platelet activation by ADP → inhibits secretion of alpha granules, blocks expression of adhesion proteins GPIIb/IIIa 2. Slow onset (5-7 days) 3. Effects last for life span of platelet (7-10 days)

Answer 79

block adhesion proteins 1. Block adhesion protein (integrin) on surface of platelets that is a receptor for fibrinogen → block platelet aggregation 2. Given IV 3. Before, during and after angioplasty

Answer 80

HIV-Seropositive: people with antibody to HIV-1 virus AIDS: once symptoms of opportunistic infections, Kaposi’s sarcoma, or Th (CD4+) cells fall below 200/uL

Answer 81

HIV-1 i. Lentivirus: Non-transforming retrovirus 1. RNA virus with no oncogene - copies its RNA into DNA (reverse transcriptase) ii. DNA not being transcribed in host cell → latent until T cell is activated

Answer 82

i. Evolved from SIV in the 1940s in Zaire (Congo) | ii. First in US in 1978, in Africa in 1959

Answer 83

Congo → rest of Africa → Caribbean → Europe → USA

Answer 84

i. USA: 1.1 million people living with AIDS in US (16% don’t know it) 1. 50,000 new cases a year ii. World: 35 million people living with HIV in 2013 1. 36 million people have died from AIDS so far 2. 5th leading cause of death

Answer 85

1. People with two CCR DELTA32 alleles do NOT express any surface CCR5 → can become chronically infected with HIV but DO NOT become ill - “Long Term Survivors” 2. HLA-B57: - “Elite Controllers” → become infected with HIV but did not progress to AIDS - Make effective CTL cells

Answer 86

i. HIV-1 is VERY antigenically variable - Reverse transcriptase highly error prone → many variants of HIV ii. Single exposure infection → Blood virus level peak at 6 weeks, Antibody to HIV peaks at 9 weeks → virus levels fall (but not to zero) = “Set Point” - Set point determined by patient’s immune system - Systemic infection between 6-9 weeks with loss of CD4 cells in gut mucosa, increased gut permeability

Answer 87

1. Dendritic cells | 2. Th CD4+ cells

Answer 88

a. Upon initial infection adheres to lectin on DC = DC-SIGN | b. Trojan horse → lymph nodes for Th cells

Answer 89

Mode of entry of virus into cell: i. HIV binds by its envelope glycoprotein gp120 to CD4 molecule on surface of Th cells ii. → conformational change in gp120 and CD4 on cell surface iii. → conformational change allows CD4 to bind co-receptor CCR5 iv. → gp41 binds cell membrane and allows fusion of virus with cell membrane v. Binding to gp120/gp41 and conformational change creates hydrophobic region on T cell that allows virus to fuse with T cell membrane Injects core into cell, activates reverse transcriptase i.RNA → DNA → insert into nucleus of T cell with viral integrase

Answer 90

Viruses bud en masse from infected cell, tearing holes in membrane → cell dies

Answer 91

1. Seropositive without symptoms | 2. Therapy can prevent next stages of disease progression

Answer 92

1. Th1: site of HIV infection - Orchestrates CTL killing - has molecules that bind GP120 → generates IL-2 → stimulates HIV transcription 2. Tfh: site of HIV persistence in lymph node - harbors virus reservoir, has molecules that bind GP120, resides in lymph node follicles i. Suppress viral replication but can’t eliminate virus DNA from nuclei ii. When Tfh activated by its correct antigen → clone of virus producing cells 3. Th2: has molecules that bind GP120, required for production of antibodies for antibody class switching required to stimulate antibody production

Answer 93

1. Candida Albicans (yeast) - mouth, esophagus, rectum a. Fevers, night sweats, weight loss, fatigue 2. TB: leading cause of death in people infected with HIV 3. Malignancy (Kaposi sarcoma, Burkitt lymphoma)

Answer 94

due to brain cells infected with HIV (macrophages, microglia)

Answer 95

Infections that require T cell mediated immunity 1. Cytomegalovirus, hepatitis, HSV, VZV 2. TB, Fungi (Candida albicans, pneumocystis jirovecii)

Answer 96

i. Virus able to replicate faster and longer than you can re-make CD4 cells - Estimated that entire population of virus replaced daily, and CD4 cells every 3 days - Eventually CD4 cells lost, unable to make them as fast ii. Eventually can’t keep up, and CD4/CD8 ratio falls in blood iii. → Immune system can no longer cope, opportunistic infection takes hold

Answer 97

1. When virus is replicating gp120/gp41 made early and inserted into cell plasma membrane → allows fusion of infected cell to nearby uninfected CD4 cells → syncytia 2. Antibodies patient make are not protective but they do bind the virus and block attachment to and infection of Th cells - BUT neutralizing epitope on virus shielded by carbohydrate

Answer 98

1. Antibody measured by an ELISA, confirmed by Western Blot analysis 2. Virus then sequenced to see what drugs it is susceptible to ($$) 3. PCR identification of virus RNA

Answer 99

i. Reverse Transcriptase Inhibitors: Nucleosides (NRTI): competitive inhibitors, chain terminators Non-Nucleoside (NRTI): binds enzyme, changes conformation at catalytic site (common resistance mutation) ii. Protease Inhibitors iii. Fusion inhibitors iv. CCR5 antagonist: blocks viral entry into CD4+ cells by changing conformation of CCR5 preventing engagement of gp120 v. Integrase inhibitor: blocks viral DNA insertion into cell DNA vi. Antiretroviral Therapy (ART): two NRTIs and a third drug from a different class

Answer 100

Need a vaccine that can preferentially stimulate Th1 cells and CTL Currently vaccines best at inducing ab response - ab not protective

Answer 101

Broadly neutralizing antibodies (bnAb) can block infection by almost all HIV strains and mutant forms Directed against gp120 that binds CD4

Answer 102

1. V(D)J of bnAb mutates very quickly and thus becomes ineffective at binding site on HIV 2. Tremendous global genetic diversity of HIV 3. Immense mutational capacity (evasion of T and B cell immunity) 4. Latency in host genome - can’t be eliminated by antiretroviral drugs 5. No known example of spontaneous immune clearance 6. bnAbs have been found but are rare and take years to develop

Answer 103

i. Volunteer donation ii. Answer questions about current/past illnesses, surgery, travel, vaccination, high-risk behavior iii. Call back with symptoms iv. Abbreviated physical exam v. Test hematocrit and platelet count vi. Skin prep for phlebotomy (reduce bacterial contamination)

Answer 104

1. whole blood 2. packed red blood cells (PRBCs) 3. Fres frozen plasma (FFP) 4. Cryopreciptate 5. Platelet concentrates 6. Granulocyte (WBC) concentrates

Answer 105

1. Keep at 4-6 C for 35 days 2. Hct is 36-40% 3. Platelet / neutrophil function degenerate by 24-48 hrs of storage 4. Red cells well maintained 5. Loss of clotting factors more slowly

Answer 106

1. Keep at 4-6 C for 35 days or longer (42 days with special solutions) 2. Hct is 70% without plasma 3. RBCs only cell you want in there a. Can get some WBCs in there that you don’t want → use leukodepleted units 4. Frozen/glycerolized RBC can last 10 years in freezer

Answer 107

1. Acellular product 2. Keep at -18 C for one year 3. > 80% all clotting and anti-coagulant proteins a. Contains all plasma proteins (procoagulant, anti-coagulant, complement proteins)

Answer 108

1. Made from fresh plasma frozen quickly at -80 C → sit for 18hrs at 4 C 2. Cryoprecipitable proteins isolated and frozen at -18 C for one year

Answer 109

a. Cryopreciptiable proteins b. 80-100 U factor 8 per bag c. vW Ag d. Fibrinogen e. Factor 13 f. Fibronectin

Answer 110

tx for pts with low count or poor function 1. Random donor unit (RDUs) or Apheresis platelet concentrates a. Leukoreduced b. Stored at 22-24 C for 5-7 days in gas permeable bags

Answer 111

1. Collected by apheresis 2. No storage allowed 3. Keep at room temp - transfuse within 8-12 hours 4. Use for severe infections in neutropenic patients

Answer 112

serologic determination of ABO and Rh(D) antigens of patients/donors i. A: H antigen + fucose + N-acetylgalactosamine ii. B: H antigen + fucose + D-galactose iii. AB: H antigen + fucose + D-galactose + N-acetylgalactosamine iv. O: H antigen + fucose v. Rh alleles

Answer 113

Massive transfusions to replace oxygen carrying capacity AND blood volume ii. ABO, Rh(D) type specific iii. Must be crossmatched

Answer 114

Transfused for oxygen carrying capacity: chronic anemia, acute blood loss ii. ABO, Rh(D) type specific iii. Must be crossmatched

Answer 115

Coagulopathy related procoagulant deficiency (DIC, liver failure, VitK deficiency) ii. Use specific anticoags for inherited deficiencies iii. ABO type specific iv. No crossmatch

Answer 116

Bleeding associated with thrombocytopenia and/or platelet dysfunction ii.ABO type specific or compatible

Answer 117

1) Typed for ABO and Rh(D) - Weak expression of D can be mistake for Rh- 2) Screened for antibodies other than ABO 3) Major Crossmatch

Answer 118

Mix donor cells and recipients serum in vitro → evaluate for agglutination 1. Add Coombs reagent to look for IgG or complement 2. Remarkably reduces possibility of immediate hemolytic transfusion reactions

Answer 119

1. Give O Rh(D) negative - For males and non-childbearing females can use O Rh(D)+ 2. Abbreviated testing of ABO and Rh(D) types and ab screen without crossmatch

Answer 120

Syphilis, Hep A, Hep B, Hep C, HIV, WNV, CMV

Answer 121

HIV, West Nile Virus, Hep C

Answer 122

1. Febrile nonhemolytic transfusion reactions and mild allergic reactions 2. Acute hemolytic transfusion reactions 3. Delayed hemolytic reactions 4. Anaphylactic reactions 5. Dilutional coagulopathy 6. GvH disease 7. Iron overload

Answer 123

1. Caused by leukoagglutinins in recipient cytokines | 2. TX: antipyretics, antihistamine

Answer 124

preformed alloantibodies and autoantibodies after infusing incompatible blood products (ABO) → intravascular hemolysis of transfused cells with activation of clotting (DIC) 1.Life threatening, severe → renal failure

Answer 125

alloantibody production and slow destruction of transfused RBCs by extravascular hemolysis

Answer 126

bronchospasm, airway response 1.TX: epinephrine, benadryl, steroids

Answer 127

massive blood loss and transfusion with replacement of fluids or blood components - deficient clotting factors → Bleeding TX: replace clotting factors or platelets

Answer 128

lymphocytes from donor transfused in an immunoincompetent host

Answer 129

no physiologic mechanism to excrete excess iron

Answer 130

Theory that adaptive immune response evolved less for dealing with foreign substances than as a way of detecting changes in the body’s own cell surfaces

Answer 131

1) Immunodeficient/ Immunosuppressed people (particularly of T cells) have higher incidence of tumors (organ transplant, AIDS, chemo drugs) 2) Activated T cells in a tumor is a good prognostic sign 3) Spontaneous regression of some tumors 4) Paraneoplastic syndromes - symptoms at distant organ that doesn’t contain tumor cells

Answer 132

1) Elimination 2) Equilibrium 3) Escape

Answer 133

- elimination of most cells that get initiated by a mutagenic event via immune surveillance - Malignant clone recognized as abnormal by both innate and adaptive immune systems, and thus eliminated

Answer 134

- lymphocytes infiltrate tumor but do not fully destroy it - Remain in equilibrium until drop in host immune response - can occur for any number of reasons → further mutations accumulate and lead to reactivation

Answer 135

-tumor cells fight back Examples: 1) Checkpoint inhibitory surface receptor ligands upregulated (CTLA-4 and PD1 receptors) 2) Immunosuppressive factors expressed by tumor cells (TGF-B) 3) Downregulate expression of MHC class I on tumor → less CTL recognition

Answer 136

Antigens overexpressed or abnormally expressed by the tumor -Driver or passenger mutations

Answer 137

TAA recognized by T cells → destruction of tumor small subset of TAAs

Answer 138

Example of a TAA - Oncofetal antigen - Found in blood of patients with colon carcinoma and other cancers - Can test for CEA with high suspicion of colon cancer, to confirm complete excision, or to warn of recurrence

Answer 139

1) recognize TRA presented by MHC class I 2) CTL activated in nodes (not at tumor site) via interactions with APCs 3) Activated TRA-specific T cells leave lymph node and migrate to tumor → induce apoptosis via perforin (secretion-based) or Fas-mediated (transmembrane signaling) pathways PROBLEM: tumors down regulate MHC class I receptors on their cells

Answer 140

CD4+ cells recognize tumor antigens, make lymphokines and attract M1 macrophages -Problem is tumor make themselves resistant to M1 and only susceptible to M2 macrophages which protect tumors

Answer 141

1) Stress markers --> NK killing 2) MHC class I --> suppress NK cells 3) Receptors for Fc for IgG --> ADCC killing

Answer 142

Tumor cells downregulate MHC to avoid CTL → makes them NK targets

Answer 143

- inhibitory receptor on T cell surface, engaged by PD-L1 on APC - Upregulated late in T cell activation - Keeps immune response in check

Answer 144

-Inhibitory receptor that appears on T cell surface that effectively turns off CTL

Answer 145

PDL1 and CTLA-4 ligands T cells there, just have their off buttons pushed

Answer 146

- innocent bystander killing - Inject directly into tumor - Causes delayed-type hypersensitivity reaction to BCG - Tumor cells killed as innocent bystanders by M1 macrophages - Treatment of choice for superficial bladder carcinoma

Answer 147

monoclonal antibodies against PD-1

Answer 148

- bind PD-1 and prevent it from receiving inhibitory signal from PD-L1 - Cover up off switch so tumor can’t push it - Not very toxic, and highly effective

Answer 149

Monoclonal Abs against CTLA-4 - effective, but toxic (big immune responses, including autoimmunity) - Prevent immune system from being turned off → autoimmunity

Answer 150

extent of PD-L1 expression on tumor associated cells (more PD-L1 = better response) AND directly correlated to number of tumor mutations

Answer 151

cells directly from tumor Can be used in Autologous cell therapy T cells expanded in culture → irradiate patient’s immune system → reintroduce T cells into the immune-depleted patient to kill remaining tumor cells

Answer 152

- activate oncogenes, inactivate tumor-suppressor genes - The reason the tumor grows - “Undruggable”

Answer 153

Greatly outnumber drivers - Not causative, but incidental to disorder that exists in transformed cells - “Neoantigens” - The more passenger mutations a tumor has the more likely it is to be well-controlled by therapies that relieve the CTL from “Checkpoint Blockade”

Answer 154

Re-arms CTLs making them have higher affinity for MHC-peptide-TCR system - Light chain/heavy chain variable domain + transmembrane domain + T cell stimulatory domain - NO MHC RESTRICTION - Triggered via normal TCR-associated pathway to become fully-cytotoxic

Week 8 Flashcards

(179 cards)