Real World Manipulation of the Immune Response Flashcards

1
Q

What is acquired immunity?

A

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

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2
Q

What can acquired immunity be a consequence of?

A

an active infection or an intentional vaccination

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3
Q

What is passive immunity?

A

transfer of immunity by Ab

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4
Q

How is passive immunity different from acquired immunity?

A

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

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5
Q

What are some examples of passive immunity?

A

protection from intestinal infection from mothers milk and colostrum

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

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6
Q

What does a protective level of immunity require?

A

multiple immunizations with vaccines

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7
Q

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

A

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

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8
Q

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

A

be safe

high proportion of population must be protected

immunity must be long lasting

inexpensive

offer herd immunity

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9
Q

What is herd immunity?

A

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

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10
Q

When is herd immunity effective?

A

if vaccine coverage is high

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11
Q

What are antigen sources?

A

killed/inactivated pathogen

toxoid

viral subunits

live attenuated virus

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12
Q

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

A

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

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13
Q

What must a vaccine do in all cases?

A

generate memory cells

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14
Q

What are the pros of dead pathogens?

A

may be safer, more stable than attenuated

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15
Q

What are the cons of dead pathogens?

A

weaker cell mediated response

boosters require contaminants

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16
Q

What are the pros of live attenuated pathogens?

A

provide a better cell mediated response than dead

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17
Q

What are the cons of live attenuated pathogens?

A

reversion - low risk of infection in immunocompromised patients

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18
Q

What are the pros of molecular components?

A

no living pathogen present

very stable

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19
Q

What are the cons of molecular components?

A

fewer epitopes

weaker cell mediated response

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20
Q

How can malignant cells be attacked by immune effectors?

A

via recognition of tumor associated antigens

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21
Q

What are tumor associated antigens?

A

mutant proteins, over expressed proteins, altered-self proteins

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22
Q

What are typical tumor antigens?

A

usually self proteins modified or selectively over expressed by a tumor

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23
Q

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

A

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

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24
Q

What are some examples of shared tumor associated antigens?

A

MAGE-3 (e.g. melanoma)

Carcinoembryonic antigen (CEA): colon and rectal cancer

HER2/neu: over expressed in breast cancer

25
Q

What are some examples of tumoral viral antigens?

A

HPV

26
Q

What does vaccination do as immunotherapy against tumors?

A

therapeutic: boosts ‘ineffective’ T cell responses

27
Q

What are some examples of specific antigen vaccines

A

synthetic peptide fragments: Gp100 209-217

recombinant proteins: Gp100 AA 209-217

DNA/RNA: nucleotides encoding Gp100 AA 209-217

28
Q

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

A

conventional adjuvants

viral (retroviral) delivery

dendritic cells - feed tumor Ag to a DC to stimulate response

29
Q

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

A

use adjuvants

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

30
Q

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

A

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

31
Q

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

A

direct lysing/killing of Ag expressing cells

32
Q

What are the anti-tumor effects of B cells?

A

produce Ab

33
Q

What are the anti-tumor effects of granulocytes?

A

Ab-Dependent Cytotoxicity (ADCC)

34
Q

What are the anti-tumor effects of macrophages?

A

cytokine-induced killing

ADCC

35
Q

What are the anti-tumor effects of NKs?

A

direct lysing of tumor cell targer

ADCC

36
Q

What are the anti-tumor effects of cytokines?

A

direct tumor killing (eg via TNF-alpha)

37
Q

what are the anti-tumor effects of Ab?

A

coating of tumor cell (ADCC)

38
Q

How do tumor cells escape the immune system?

A

antigenic loss variants and immune inhibition

39
Q

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

A

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

40
Q

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

A

TGF-beta, IL-10, induction of Tregs

41
Q

What is Rituximab, and what does it do?

A

anti-CD20

recognizes B-cell marker and activates B cells

induces growth arrest/apoptosis in vitro

42
Q

What is Herceptin?

A

anti-HER2

recognizes EGF like receptors regulating cellular proliferation (ERBB22)

induces growth arrest/apoptosis in vitro

43
Q

What are TILs and what do they do?

A

Tumor infiltrating lymphocytes

generates effector T cells

Take tumor fragments, cultivate with TILs and allow to expand, transfuse TILs into patient

44
Q

What is passive (adoptive) immunotherapy?

A

patients own T cells are activated in vitro and retransferred

provides an exogenous source of anti-tumor T cells

45
Q

How is tumor specificity generated for passive immunotherapy?

A

using defined tumor specific antigen

using TILs

46
Q

What is a CAR and how is it produced?

A

chimeric antigen receptor

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

47
Q

How can CAR be used to eliminate a tumor?

A

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

48
Q

How does CAR lead to killing of a tumor?

A

production of granzyme, perforin, and other apoptotic signals

release of pro-inflammatory cytokines IL-2, IFN-gamma, TNF-alpha

49
Q

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

A

CTLA-4 ligands, PD-1 ligands

act on T cells and NK cells

50
Q

What is the function of CTLA 4?

A

immune checkpoint that downregulates the immune response

51
Q

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

A

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

52
Q

When are CTLA4 receptors upregulated?

A

following T cell stimulation - prevents an overactive immune response

53
Q

What is the binding affinity of CTLA4 for B7

A

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

54
Q

What does Ipilimumab do?

A

Tumor cells can produce CTLA 4

Ipilimumab blocks CTLA4 which allows the costimulation by CD28 to continue

55
Q

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

A

Programmed cell death protein-1

found on T cells

56
Q

What does PD-1 bind?

A

PD-L-1 and PD-L-2

57
Q

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

A

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)

58
Q

How does ivolumab reinstate the T cell response?

A

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