Lecture 4 Flashcards
3 kinds of signals APCs deliver to naive T cells
- Activation
- Survival
- Differentiation
What is Belatacept?
A human fusion protein that combines a modified extracellular portion of CTLA-4 with the IgG1 Fc domain
What is Belatacept used for?
Co-stimulatory blockade to induce tolerance in graft. May promote both Treg infiltration in renal allografts and facilitate recovery from rejection.
IL-12 and IFN-𝛾 drive…
Th1 cell differentiation
IL-6 and IL-23 drive…
Th17 cell differentiation
What is Abatacept?
1st generation human CTLA4-Ig fusion protein
Effect of Abatacept in the treatment of rheumatoid arthritis?
- 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
What is Rituximab, and how does it treat RA?
Anti-CD20 mAb
- induces ADCC and apoptosis of B cells
- reduced autoAbs
- enhanced Tregs
- reduced disease activity & inflammatory markers
- effective as a monotherapy
Rituximab is only used in patients who have failed on __
anti-TNF
Key inflammatory cytokines in RA
TNFα, IL-1, IL-6
Drugs that target TNFα in RA treatment
- 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
Use of anti-TNFs has significant decreased surgery rates from…
90% to 10%
Issues with anti-TNFs
- 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)
IL-1 receptor antagonist used for juvenile RA
Anakinra (Kineret)
IL-6 receptor antagonist licensed for use in RA
Tocilizumab
- first line mAb in patients not responding to TNF inhibitors
- blocks IL-6 to switch balance from Th17 back to Treg
How is IL-6 involved in humoral immunity?
- 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
How does T cell activation alter responsiveness to IL-6?
- Promotes IL-6R shedding; loss of STAT1 signal
- IL-2 inhibits IL-6R presentation on cell surface
- Switch from classic to trans-signalling
IL-6R two signalling methods
- Classic signalling: IL-6R & gp130 on membrane; homeostatic functions; glucose metabolism
- 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.
What cytokine is thought to be a central mediator of toxicity in CRS?
IL-6 (trans-signalling particularly important)
Excluding RA, Tocilizumab is licensed for use in…
CRS, related to CAR-T cell therapy
Treg cell therapy was first applied in __
GVHD
What is Ustekinumab, and how does it work?
- anti-p40 mAb
- blocks the effects of IL-12 and IL-23
- very effective in psoriasis
Examples of anti-integrins (block trafficking)
- 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
Concern over Natalizumab use
Progressive multifocal leukoencephalopathy (PML) caused by JC polyoma virus
