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
cytokine classes - interferons - type II (IFN gamma)
- 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
cytokine classes - interleukin - source
leukocytes
27
cytokine classes - interleukin - function
1) Affect growth & differentiation of hematopoietic & immune cells 2) regulate immunity, inflammation, haematopoiesis
28
cytokine classes - interleukin - types
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
cytokine classes - chemokines
stimulate leukocyte chemotaxis & Activation
30
cytokine classes - tumour necrosis factor (TNF)
- pro inflammatory & pro apoptosis - contribute to insulin resistance
31
cytokine classes - haemotopoeitic growth factor - general
- single chain glycoprotein - used to restore deficiency from chemo/radio therapy
32
cytokine classes - haemotopoeitic growth factor - types
1) colony stimulating factor (CSF) - stimulate cellular division and differentiation of blood cells from bone marrow precursors 2) erythropoeitin, interleukin - promote haematopoeisis
33
polyclonal antibodies - antiserum - general
- usage: passive immunisation - disadvantages: immunogenicity
34
polyclonal antibodies - antiserum - production method
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
features of monoclonal antibodies (mab)
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
development process of mab: 1) murine mab
- induce immunogenicity: human-anti-mouse antibody (HAMA) response - shorter half life, X trigger some effector functions
37
development process of mab: 2) chimeric mab
- 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
development process of mab: 3) humanised mab
- replace all moues AA sequence except hypervariable CDR domains of Ig (inside VH and VL) in chimeric mab
39
development process of mab: 4) recombinant human mab
- genetically engineer mammalian host cell so everything human -> X immunogenicity - problem: $$$$, X remove impurities from mammalian host cell
40
when do you not require Fc domain
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
types of antibody derivatives
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
Tumour-infiltrating lymphocyte (TIL) therapy - general
- autologous - more for solid tumours
43
Tumour-infiltrating lymphocyte (TIL) therapy - process
1) take out patient tumour cell 2) remove lymphocyte from blood vessel in tumour 3) TIL expanded and reintroduced into patient
44
Tumour-infiltrating lymphocyte (TIL) therapy - benefits
safe
45
Tumour-infiltrating lymphocyte (TIL) therapy - limitations
- sometimes excised tumour mass no/little TIL - varying antigen specificity -> X specific/lethal enough to kill cancer - X high affinity
46
T cell receptor engineered T cell (TCR-T) therapy - process
insert Valpha & Vbeta tumor antigen specific gene clones into vector -> transduce T cells isolated from patient's peripheral blood
47
T cell receptor engineered T cell (TCR-T) therapy - table of summary
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
T cell receptor engineered T cell (TCR-T) therapy - advantages
more effective than CAR-T
49
T cell receptor engineered T cell (TCR-T) therapy - disadvantages
- 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
Chimeric antigen receptor T cell (CAR-T) therapy - process
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
Chimeric antigen receptor T cell (CAR-T) therapy - developmental process
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
Chimeric antigen receptor T cell (CAR-T) therapy - summary table
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
Chimeric antigen receptor T cell (CAR-T) therapy - advantages
X TCR complex = recognise antigen wo MHC protein
54
Chimeric antigen receptor T cell (CAR-T) therapy - disadvantages
- 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
immune check point inhibitor - CTLA-4
- 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
immune check point inhibitor - PD-1
PD-L1 or PD-L2 bind to PD-1 on T cell -> suppress T cell activity
57
limitations of immune checkpoint inhibitors
- transient efficacy - X all cancer patients show response - possible immune-related AR
58
types of cancer vaccine - cell vaccine
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
types of cancer vaccine - protein/peptide
- 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
types of cancer vaccines - nucleic acid
- 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
types of CDR
1) CDR 1 & 3: bind to peptides 2) CDR 2: bind to MHC