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PR3152 > IC5 > Flashcards

IC5 Flashcards

1
Q

cellular component for innate immunity

A

1) phagocyte (neutrophil, macrophage)
2) NK cell
3) dendritic cell
4) Mast cell

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2
Q

humoral component for innate immunity

A

cytokines, complement proteins

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3
Q

cellular component for adaptive immunity

A

T cell, B cell

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4
Q

humoral component for adaptive immunity

A

cytokines, antibodies

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5
Q

general features of antibodies

A
  • intra and inter disulfide bonds to maintain 3d configuration
  • glycosylation in Fc domain
  • 2 Fab 1 Fc
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6
Q

number of CDR on 1 antibody

A

3 CDR on light chain, 3 CDR on heavy chain = 6 CDR per Fab arm = 12 CDR per antibody

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7
Q

properties of antibody

A

1) antigen affinity

  • single antigenic site

2) antibody avidity

  • multiple antigenic site

3) antibody specificity

  • low specificity = cross reactivity
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8
Q

T cell receptor

A
  • alpha + beta chain
  • components of both chains:

1) extracellular domain (glycosylated): variable region bind to antigen), constant region (cysteine residue, form disulfide bond to link both chians)

2) transmembrane region

3) short cytoplasmic tail

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9
Q

why T cell receptor not enough to activate T cell?

A

cytoplasmic tail too short to mediate signal transduction for T cell activation

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10
Q

CD3 adaptor proteins

A
  • 6 monomers dimerise -> 3 invariant CD3 dimers -> octameric complex
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11
Q

ITAM

A
  • each TCR 10 ITAM
  • tyrosine phosphorylated -> downstream T cell signaling -> activation
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12
Q

antibody vs T cell receptor (no. of CDR)

A

antibody: 12 CDR
T cell receptor: 6 CDR

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13
Q

process of B cell activation

A

1) progenitor B cell in bone marrow rearrange Ig genes -> clones of immature B cell expressing B cell antigen receptor

2) B cell leave bone marrow -> circulate blood stream/lymphoid tissue

3) encounter pathogenic antigen -> activate -> mature -> produce 1st response antibody IgM

4) gene arrangement of constant region in Fc domain of IgM -> class switching to IgG

5) B cell undergo gene arrangement to VL and VH of IgG gene -> different hypervariable CDR w different antigen specificity -> produce IgG with different CDR

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14
Q

development of T cells

A

1) T lymphocyte progenitor travel from bone marrow to thymus for development into T lymphocytes

2) T cells localised in secondary peripheral lymphoid tissue -> interact & respond to antigens

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15
Q

how does T cells have memory

A

1) effector T cell die after interacting with pathogen

2) Remaining antigen-specific T cells differentiate into memory T cells

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16
Q

MHC class I

A
  • location: all nucleated cell & platelets, absent in RBC
  • bind to peptide fragment of endogenous antigen
  • present antigen through peptide-MHC I on cell surface
  • present antigen to CD8+ cytotoxic T cell
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17
Q

examples of endogenous antigens

A
  • normal self antigen
  • viral component from virus-infected cell
  • neoantigen (Cancer)
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18
Q

MHC class II

A
  • location: APC (macrophage, dendritic cell), B cell
  • bind to peptide fragment of exogenous (foreign) antigen
  • present antigen through peptide-MHC II on APC surface
  • present antigen to CD4+ helper T cell
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19
Q

regulation of MHC molecules

A
  • expression directly proportionate to T cell activation
  • regulated by cytokines
    1) IFN alpha
    2) IFN gamma
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20
Q

characteristics of MHC

A

1) polygenic (multiple genes)
- express different peptide binding specificities
- means different set of MHC = present different antigen = broad coverage

2) polymorphic
- each gene different alleles = broad coverage

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21
Q

general properties of cytokines

A
  • glycosylated for action/half life
  • short half life prevent uncontrolled action
  • act short range (paracrine/autocrine)
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22
Q

cytokine classes - interferons - source

A

produced by cells in response to viral infections, tumours, other biological inducers

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23
Q

cytokine classes - interferons - function

A

1) promote antiviral state in neighbouring cells
2) help regulate immune response, growth & differentiation

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24
Q

cytokine classes - interferons - type I

A

1) IFN alpha
- recombinant IFN alpha protein for upregulation of immune system for antiviral and/or anticancer therapy

2) IFN beta
- expressed by most somatic cells
- effective treatment for multiple sclerosis (inhibit IFN gamma)

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25
Q

cytokine classes - interferons - type II (IFN gamma)

A
  • produced by T cells
  • immunomodulatory
    ** activate resting macrophage & monocyte -> increase phagocytic activity
    ** induce macrophage -> express cytokine (IL-2, TFN-alpha), MHC, immunoglobulin Fc receptor -> immunostimulation
26
Q

cytokine classes - interleukin - source

A

leukocytes

27
Q

cytokine classes - interleukin - function

A

1) Affect growth & differentiation of hematopoietic & immune cells
2) regulate immunity, inflammation, haematopoiesis

28
Q

cytokine classes - interleukin - types

A

1) IL-2
- T cell growth factor
- synthesised & secreted by T cells
- immunomodulatory properties

2) IL-11
- thrombopoietic growth factor
- produced by fibroblast & bone marrow stromal cell
- stimulate proliferation of haemotopoietic stem cell + induce megakaryocyte maturation -> increased platelet formation

29
Q

cytokine classes - chemokines

A

stimulate leukocyte chemotaxis & Activation

30
Q

cytokine classes - tumour necrosis factor (TNF)

A
  • pro inflammatory & pro apoptosis
  • contribute to insulin resistance
31
Q

cytokine classes - haemotopoeitic growth factor - general

A
  • single chain glycoprotein
  • used to restore deficiency from chemo/radio therapy
32
Q

cytokine classes - haemotopoeitic growth factor - types

A

1) colony stimulating factor (CSF)
- stimulate cellular division and differentiation of blood cells from bone marrow precursors

2) erythropoeitin, interleukin
- promote haematopoeisis

33
Q

polyclonal antibodies - antiserum - general

A
  • usage: passive immunisation
  • disadvantages: immunogenicity
34
Q

polyclonal antibodies - antiserum - production method

A

1) collect whole blood from animal
2) let blood clot/add coagulant
3) remove clotting factor
4) Centrifugation -> separate cellular component -> serum obtained as supernatant
5) purification
- eliminate serum protein
- enrich fraction of Ig that react w target Ag

35
Q

features of monoclonal antibodies (mab)

A

1) high specificity
- 1 B cell clone only recognise 1 epitope
- used in recombination protein purification work

2) high homogeneity
- effects highly reproducible
- uses: commercial development (test kit), research

36
Q

development process of mab: 1) murine mab

A
  • induce immunogenicity: human-anti-mouse antibody (HAMA) response
  • shorter half life, X trigger some effector functions
37
Q

development process of mab: 2) chimeric mab

A
  • CL, CH of Fc and Fab -> immunogenicity
  • replace AA in CH and CL that are not essential for antigen binding w human sequences to reduce immunogenicity & still retain antigen selectivity & affinity
38
Q

development process of mab: 3) humanised mab

A
  • replace all moues AA sequence except hypervariable CDR domains of Ig (inside VH and VL) in chimeric mab
39
Q

development process of mab: 4) recombinant human mab

A
  • genetically engineer mammalian host cell so everything human -> X immunogenicity
  • problem: $$$$, X remove impurities from mammalian host cell
40
Q

when do you not require Fc domain

A

1) enzyme inhibition
- antagonism of enzyme action by binding to enzyme active site

2) neutralise receptor ligands (hormones/cytokines)

3) counteract overproduction of cytokines

4) neutralise toxin

41
Q

types of antibody derivatives

A

1) Ig conjugate
- conjugated to cytokine/toxin/radioisotope -> antibody endocytosis into cell -> conjugate exert lethal effect

2) F(ab’)2
- only 2 same Fab arm, X Fc domain

3) ScFv
- synthetic
- single polypeptide chain of VL and VH

4) biospecific
- 2 different Fab arms
- bring 2 antigens close together
- used for cancer treatment

5) triomabs
- biospecific + Fc domain

6) defucosylated Abs
- remove fucose from N-glycan at Asn297 -> enhanced affinity towards FcgammaRIII -> increase ADCC induction by effector cell

42
Q

Tumour-infiltrating lymphocyte (TIL) therapy - general

A
  • autologous
  • more for solid tumours
43
Q

Tumour-infiltrating lymphocyte (TIL) therapy - process

A

1) take out patient tumour cell
2) remove lymphocyte from blood vessel in tumour
3) TIL expanded and reintroduced into patient

44
Q

Tumour-infiltrating lymphocyte (TIL) therapy - benefits

A

safe

45
Q

Tumour-infiltrating lymphocyte (TIL) therapy - limitations

A
  • sometimes excised tumour mass no/little TIL
  • varying antigen specificity -> X specific/lethal enough to kill cancer
  • X high affinity
46
Q

T cell receptor engineered T cell (TCR-T) therapy - process

A

insert Valpha & Vbeta tumor antigen specific gene clones into vector -> transduce T cells isolated from patient’s peripheral blood

47
Q

T cell receptor engineered T cell (TCR-T) therapy - table of summary

A

1) what changes
- express specific TCR that recognise cancer specific antigens

2) TCR
- full TCR complex but modified to recognise cancer specific antigen

3) antigen recognition
- antigen presentation by MHC complex
- dependent on specific HLA type

4) types of tumours
- solid & haematological tumour

48
Q

T cell receptor engineered T cell (TCR-T) therapy - advantages

A

more effective than CAR-T

49
Q

T cell receptor engineered T cell (TCR-T) therapy - disadvantages

A
  • limited for use in patient with specific MHC/HLA allele recognised by TCR
  • not as safe as TIL
    ** on target toxicity: T cell target normal tissue
    ** off target toxicity: T cell not specific
    ** cytokine storm
50
Q

Chimeric antigen receptor T cell (CAR-T) therapy - process

A

withdraw T cell from patient -> transduce T cell by vector carrying CAR gene -> T cell express CAR on surface -> expansion -> release back into patient to target cancer cell

51
Q

Chimeric antigen receptor T cell (CAR-T) therapy - developmental process

A

1) gen 1
- extracellular: single chain variable fragment connecting VH & VL
- intracellular: CD3 complex (not full TCR)

2) gen 2
- same extracellular
- intracellular: CD3 + CD28 (costimulatory)
- more potent anti tumour effect but in vitro

3) gen 3
- same extracellular
- intracellular: CD3 + CD28 + 4-1BB (costimulatory)

4) gen 4
- similar to gen 3 but additional transgene that express cytokines
** cytokines autocrine +/- paracrine effect
** CAR-T activation -> activate transgene -> release cytokines (IL-2) -> activate more T cells at target site
** only gen that target anti-negative cancer cells (X release antigens) cuz IL-2 act on endogenous T cells -> target other cells

52
Q

Chimeric antigen receptor T cell (CAR-T) therapy - summary table

A

1) change what
- express CAR on TCR surface to recognise specific antigen on cancer cell surface

2) TCR
- replaced w synthetic CAR -> X full TCR complex

3) antigen recognition
- X HLA restricted
- only bind directly to surface antigen

4) type of tumours
- more effective for haematological tumours *cuz X get through intra tumoural space)

53
Q

Chimeric antigen receptor T cell (CAR-T) therapy - advantages

A

X TCR complex = recognise antigen wo MHC protein

54
Q

Chimeric antigen receptor T cell (CAR-T) therapy - disadvantages

A
  • scFv guide CAR-T cell into antigen-independent mechanism = failed therapy
  • less effective than TCR-T
  • adverse effect
    ** on target off tumour toxicity: B cell aplasia
    ** off target toxicity
    ** cytokine storm
55
Q

immune check point inhibitor - CTLA-4

A
  • APC present MHC antigen -> bind to TCR
  • CD80/CD68 on APC bind to CD28 -> stimulate CD28 to release cytokines -> T cell activation
  • CTLA4 compete w CD28 -> no activation when bind to CD80/CD86
56
Q

immune check point inhibitor - PD-1

A

PD-L1 or PD-L2 bind to PD-1 on T cell -> suppress T cell activity

57
Q

limitations of immune checkpoint inhibitors

A
  • transient efficacy
  • X all cancer patients show response
  • possible immune-related AR
58
Q

types of cancer vaccine - cell vaccine

A

1) tumour cell vaccine
- antigens expressed by tumour cell induce patient T cells

2) dendritic cell vaccine
- tumour antigenic proteins/peptides or tumour cell loaded on DC -> adminsitered to induce T cell

59
Q

types of cancer vaccine - protein/peptide

A
  • antigenic peptide fragments derived from tumour-associated antigens -> recognised by T cell -> Activation
  • limitations: not strong immune response
    ** X include neoantigens
    ** X bind to MHC class II = X CD4+ help
    ** antigenic peptide of short chain bind to any cell wo triggering further process = induce anergy (X immune response) = immune tolerance BUT can be rectified if manufacture longer peptide chains
60
Q

types of cancer vaccines - nucleic acid

A
  • RNA/DNA w viral vector/non vector based system
  • considerations:
    1) DNA: risk of carcinogenicity if insertion of DNA gene cause mutation
    2) RNA: X risk of carcinogenicity but problem of formulation stability/stability upon adminsitration
61
Q

types of CDR

A

1) CDR 1 & 3: bind to peptides
2) CDR 2: bind to MHC

PR3152 (6 decks)

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