Real World Manipulation of the Immune Response

Question 1

What is acquired immunity?

Answer 1

active immunity that provides long lasting protection from the infectious agent (immunological memory)

Question 2

What can acquired immunity be a consequence of?

Answer 2

an active infection or an intentional vaccination

Question 3

What is passive immunity?

Answer 3

transfer of immunity by Ab

Question 4

How is passive immunity different from acquired immunity?

Answer 4

provides immediate protection but does not provide for long lasting immunity (no immunological memory)

Question 5

What are some examples of passive immunity?

Answer 5

protection from intestinal infection from mothers milk and colostrum

transfer of Ab for immediate protection from e.g. spider or snake venom

Question 6

What does a protective level of immunity require?

Answer 6

multiple immunizations with vaccines

Question 7

What does inactivation of the pathogen by heat or chemical means do?

Answer 7

the pathogen is not capable of reproduction in the host, but the epitopes still remain against which the host can mount an immune response

Question 8

In addition to provoking a protective immune response, what must effective vaccinations include?

Answer 8

be safe

high proportion of population must be protected

immunity must be long lasting

inexpensive

offer herd immunity

Question 9

What is herd immunity?

Answer 9

lowering the number of susceptible individuals lowers the number of possible infections, which reduces transmission.

Question 10

When is herd immunity effective?

Answer 10

if vaccine coverage is high

Question 11

What are antigen sources?

Answer 11

killed/inactivated pathogen

toxoid

viral subunits

live attenuated virus

Question 12

What must be known about a pathogen in order to devise an effective vaccine?

Answer 12

cell mediated immunity for intracellular infections

IL17 for fungal infections

B cell response for toxins and organisms that resist phagocytosis

T&B responses for viruses

Question 13

What must a vaccine do in all cases?

Answer 13

generate memory cells

Question 14

What are the pros of dead pathogens?

Answer 14

may be safer, more stable than attenuated

Question 15

What are the cons of dead pathogens?

Answer 15

weaker cell mediated response

boosters require contaminants

Question 16

What are the pros of live attenuated pathogens?

Answer 16

provide a better cell mediated response than dead

Question 17

What are the cons of live attenuated pathogens?

Answer 17

reversion - low risk of infection in immunocompromised patients

Question 18

What are the pros of molecular components?

Answer 18

no living pathogen present

very stable

Question 19

What are the cons of molecular components?

Answer 19

fewer epitopes

weaker cell mediated response

Question 20

How can malignant cells be attacked by immune effectors?

Answer 20

via recognition of tumor associated antigens

Question 21

What are tumor associated antigens?

Answer 21

mutant proteins, over expressed proteins, altered-self proteins

Question 22

What are typical tumor antigens?

Answer 22

usually self proteins modified or selectively over expressed by a tumor

Question 23

What are some examples of cell-type specific tumor antigens?

Answer 23

melanoma (essentially melanocyte specific): MART-1, tyrosinase, Gp-100

B cell lymphoma (essentially B cell specific): CD20

AML (essentially myeloid specific): CD33

Prostate Cancer: PSA (prostate specific antigen

Question 24

What are some examples of shared tumor associated antigens?

Answer 24

MAGE-3 (e.g. melanoma)

Carcinoembryonic antigen (CEA): colon and rectal cancer

HER2/neu: over expressed in breast cancer

Question 25

What are some examples of tumoral viral antigens?

Answer 25

HPV

Question 26

What does vaccination do as immunotherapy against tumors?

Answer 26

therapeutic: boosts 'ineffective' T cell responses

Question 27

What are some examples of specific antigen vaccines

Answer 27

synthetic peptide fragments: Gp100 209-217 recombinant proteins: Gp100 AA 209-217 DNA/RNA: nucleotides encoding Gp100 AA 209-217

Question 28

What are some examples of delivery vectors for specific antigen vaccines?

Answer 28

conventional adjuvants viral (retroviral) delivery dendritic cells - feed tumor Ag to a DC to stimulate response

Question 29

How is immunogenicity increased against a tumor by using whole tumor vaccine techniques?

Answer 29

use adjuvants use gene engineered tumor cells that will result in cytokines or upregulation of co-stimulatory molecules such as B7

Question 30

What are the anti-tumor effects of CD4+ T cells

Answer 30

produces cytokines and provides help for CD8+ T cells and C cells

Question 31

What are the anti-tumor effects of CD8+ T cells?

Answer 31

direct lysing/killing of Ag expressing cells

Question 32

What are the anti-tumor effects of B cells?

Answer 32

produce Ab

Question 33

What are the anti-tumor effects of granulocytes?

Answer 33

Ab-Dependent Cytotoxicity (ADCC)

Question 34

What are the anti-tumor effects of macrophages?

Answer 34

cytokine-induced killing ADCC

Question 35

What are the anti-tumor effects of NKs?

Answer 35

direct lysing of tumor cell targer ADCC

Question 36

What are the anti-tumor effects of cytokines?

Answer 36

direct tumor killing (eg via TNF-alpha)

Question 37

what are the anti-tumor effects of Ab?

Answer 37

coating of tumor cell (ADCC)

Question 38

How do tumor cells escape the immune system?

Answer 38

antigenic loss variants and immune inhibition

Question 39

What are the antigenic loss variants that allow a tumor to evade the immune system?

Answer 39

loss of antigen targets: loss of CD4 and CD8 epitopes, loss of binding to CD20 loss of MHC class I/Ag processing: mutation of TAP - prevents Ag from entering the ER

Question 40

What do tumor cells produce that can inhibit the immune system?

Answer 40

TGF-beta, IL-10, induction of Tregs

Question 41

What is Rituximab, and what does it do?

Answer 41

anti-CD20 recognizes B-cell marker and activates B cells induces growth arrest/apoptosis in vitro

Question 42

What is Herceptin?

Answer 42

anti-HER2 recognizes EGF like receptors regulating cellular proliferation (ERBB22) induces growth arrest/apoptosis in vitro

Question 43

What are TILs and what do they do?

Answer 43

Tumor infiltrating lymphocytes generates effector T cells Take tumor fragments, cultivate with TILs and allow to expand, transfuse TILs into patient

Question 44

What is passive (adoptive) immunotherapy?

Answer 44

patients own T cells are activated in vitro and retransferred provides an exogenous source of anti-tumor T cells

Question 45

How is tumor specificity generated for passive immunotherapy?

Answer 45

using defined tumor specific antigen using TILs

Question 46

What is a CAR and how is it produced?

Answer 46

chimeric antigen receptor take Vh and Vl and combine it with the TCR zeta signaling complex via a CD8 transmembrane unit

Question 47

How can CAR be used to eliminate a tumor?

Answer 47

create a CAR against a specific tumor antigen, expand and infuse into patient so that the transduced T cells can mount a T cells response against the tumor

Question 48

How does CAR lead to killing of a tumor?

Answer 48

production of granzyme, perforin, and other apoptotic signals release of pro-inflammatory cytokines IL-2, IFN-gamma, TNF-alpha

Question 49

What are some inhibitory signaling molecules that tumors can use to inactivate the immune system?

Answer 49

CTLA-4 ligands, PD-1 ligands act on T cells and NK cells

Question 50

What is the function of CTLA 4?

Answer 50

immune checkpoint that downregulates the immune response

Question 51

On what cells is CTLA 4, and what does it bind?

Answer 51

on the surface of T cells, binds B7 on APC cells and acts as an off switch

Question 52

When are CTLA4 receptors upregulated?

Answer 52

following T cell stimulation - prevents an overactive immune response

Question 53

What is the binding affinity of CTLA4 for B7

Answer 53

high - higher than CD28, which allows CTLA4 to stop the immune response

Question 54

What does Ipilimumab do?

Answer 54

Tumor cells can produce CTLA 4 Ipilimumab blocks CTLA4 which allows the costimulation by CD28 to continue

Question 55

What is PD-1 and on what cells is it found?

Answer 55

Programmed cell death protein-1 found on T cells

Question 56

What does PD-1 bind?

Answer 56

PD-L-1 and PD-L-2

Question 57

How can tumor cells co-opt PD-1 to evade the immune system?

Answer 57

tumor cells can upregulate PDL-1/2 on their surface, neutralizing the cytotoxic T cell response (cause death of T cells that express PD-1)

Question 58

How does ivolumab reinstate the T cell response?

Answer 58

mAb against PD-1 receptor on T cells which prevents binding by PD-L1 on tumor cells