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BC4022 AM > Lecture 4 > Flashcards

Lecture 4 Flashcards

1
Q

3 kinds of signals APCs deliver to naive T cells

A
  1. Activation
  2. Survival
  3. Differentiation
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2
Q

What is Belatacept?

A

A human fusion protein that combines a modified extracellular portion of CTLA-4 with the IgG1 Fc domain

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3
Q

What is Belatacept used for?

A

Co-stimulatory blockade to induce tolerance in graft. May promote both Treg infiltration in renal allografts and facilitate recovery from rejection.

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4
Q

IL-12 and IFN-𝛾 drive…

A

Th1 cell differentiation

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5
Q

IL-6 and IL-23 drive…

A

Th17 cell differentiation

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6
Q

What is Abatacept?

A

1st generation human CTLA4-Ig fusion protein

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7
Q

Effect of Abatacept in the treatment of rheumatoid arthritis?

A
  • reduced T cell & B cell activation
  • reduced T cell activation of osteoclasts (halts bone erosion)
  • decreased cytokine activity (and therefore, decreased inflammatory markers)
  • reduced disease activity
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8
Q

What is Rituximab, and how does it treat RA?

A

Anti-CD20 mAb
- induces ADCC and apoptosis of B cells
- reduced autoAbs
- enhanced Tregs
- reduced disease activity & inflammatory markers
- effective as a monotherapy

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9
Q

Rituximab is only used in patients who have failed on __

A

anti-TNF

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10
Q

Key inflammatory cytokines in RA

A

TNFα, IL-1, IL-6

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11
Q

Drugs that target TNFα in RA treatment

A
  • Infliximab (Remicade) - first, anti-TNFα mAb, first in class in IBD, reduced disease progression with MTX
  • Etanercept (Enbrel) - sTNFR construct
  • Adalimumab (Humira) - first fully human mAb binding TNF
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12
Q

Use of anti-TNFs has significant decreased surgery rates from…

A

90% to 10%

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13
Q

Issues with anti-TNFs

A
  • non-responder rate (TNF not involved in patient’s pathology)
  • induction of remission rates
  • loss of response over time (e.g. accelerated clearance of mAb)
  • adverse effects (infusion reaction, immunosuppression)
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14
Q

IL-1 receptor antagonist used for juvenile RA

A

Anakinra (Kineret)

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15
Q

IL-6 receptor antagonist licensed for use in RA

A

Tocilizumab
- first line mAb in patients not responding to TNF inhibitors
- blocks IL-6 to switch balance from Th17 back to Treg

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16
Q

How is IL-6 involved in humoral immunity?

A
  • Regulation of Blimp-1 by STAT3 is linked to Ab secretion
  • IL-6 controls IL-21 expression in T cells to enhance Bcl-6 expression & Tfh generation
  • IL-6 (in combination with IL-1β) provides the necessary signals for generation of IL-10-secreting regulatory B cells
17
Q

How does T cell activation alter responsiveness to IL-6?

A
  • Promotes IL-6R shedding; loss of STAT1 signal
  • IL-2 inhibits IL-6R presentation on cell surface
  • Switch from classic to trans-signalling
18
Q

IL-6R two signalling methods

A
  1. Classic signalling: IL-6R & gp130 on membrane; homeostatic functions; glucose metabolism
  2. Trans-signalling: sIL-6R binds secreted IL-6; increases half-life, promotes its bioavailability to gp130. Recruitment & apoptosis of leukocytes, maintain Teff cells & inflammation of stromal tissues.
19
Q

What cytokine is thought to be a central mediator of toxicity in CRS?

A

IL-6 (trans-signalling particularly important)

20
Q

Excluding RA, Tocilizumab is licensed for use in…

A

CRS, related to CAR-T cell therapy

21
Q

Treg cell therapy was first applied in __

A

GVHD

22
Q

What is Ustekinumab, and how does it work?

A
  • anti-p40 mAb
  • blocks the effects of IL-12 and IL-23
  • very effective in psoriasis
23
Q

Examples of anti-integrins (block trafficking)

A
  • Natalizumab (Tysabil): anti-alpha-4 integrin that prevents interaction of VLA-4 with VCAM-1, which prevents T cells crossing BBB
  • Vedolizumab: binds specifically to α4β7 integrin
  • Etrolizumab: anti-β7 integrin
24
Q

Concern over Natalizumab use

A

Progressive multifocal leukoencephalopathy (PML) caused by JC polyoma virus

25
Q

Example of an oral JAK inhibitor

A

Tofacitinib

26
Q

What is Mongersen, and how does it work?

A

Oral SMAD7 antisense oligonucleotide
- downregulates SMAD7; removes inhibition of TGF-β1 receptor signalling

27
Q

What is Fingolimod (Gilenya)?

A

A sphingosine-1 phosphate receptor modulator used in the treatment of RRMS

28
Q

How does Fingolimod work?

A

Downmodulation of lymphocytic S1P1 receptors leads to retention of self-reactive T cells in lymph nodes and prevents their invasion into CNS and their local clonal expansion & differentiation

29
Q

Characteristics of an ideal immunosuppressant

A
  • Strongly immunosuppressive
  • Specific (no overall immunosuppression)
  • Anti-infection ability
  • Low toxicity for vital organs
  • Low cost
  • Long in vivo bioactivity
  • Easy to use

BC4022 AM (8 decks)

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