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Flashcards in Cytokines and chemokines Deck (32)
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1

What are cytokines?

 

Direct growth, development, maturation, activation and life span of immune cells

  • Small proteins, 5-10kDa
  • Bind to specific receptors on target cells
  • Alter gene expression
  • Alter function of proteins in the cell
  • Different cytokines have different effects
  • Can enhance or inhibit cellular responses

2

What are chemokines?

 

Direct the movement of white blood cells

 

3

How are cytokines and chemokines regulated?

 

 

Expression of key cytokines/chemokines and their receptors is highly regulated by timing of expression & location of expression

 

4

Mechanisms of action of cytokines

1. inducing stimulus to cytokine producing cell -> activate cytokine gene -> production of cytokines

2. cytokines are released -> bind to receptor -> intracellular gene activatoin for biological effects by the target cell

three modes of action: 

- autocrine action: cytokine for the cell itself

- paracrine action: cytokine for the nearby cell

- endocrine action: cytokine for the distant cell, circulated by blood

5

Structural cytokine families

 

  • Interferons
    • IFN alpha, beta, gamma. IFN alpha/beta: Play particularly important roles in viral infections 
  • Tumor Necrosis Factor
    • TNF alpha: major inflammatory cytokine in activating immue cells. TNF alpha is often targeted for inhibition for autoimmune disease mx
  • Interleukins: various roles in immune responses e.g. inflammation, growth of various immune cells 
  • Transforming Growth Factor 
  • Colony Stimulating Factors

6

Functional cytokine groups

 

  • Mediators and regulators of innate immunity
    • IL-1, IL-10, IL-12, TNFα, IL-6, IFNα/β, IFNγ
    • Act on endothelial cells and leukocytes to stimulate early innate responses
  • Mediators and regulators of adaptive immunity
    • IL-2, IL-4, IL-5, TGFβ
    • Act on lymphocytes to simulate and regulate adaptive responses to specific antigens
  • Stimulators of haematopoiesis
    • Stem cell factor, IL-3, IL-7, GM-CSF
    • Act on the bone marrow to stimulate growth and differentiation of leukocytes and lymphocytes

7

Structural chemokine families

 

  • C Chemokines
  • CC Chemokines
  • CXC Chemokines
  • CX3C Chemokines

8

Functional chemokine groups

 

  • Homeostatic Chemokines
    • CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL21, CXCL13
    • made at baseline. Control the migration of cells during the normal development and maintenance of tissues and lymphoid organs
  • Inflammatory Chemokines
    • CXCL8, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL10
    • Produced in response to infection or injury and direct the migration of leukocytes into the infected or damaged site
  • Angiogenic Chemokines
    • CXCL1-14
    • Promote or prevent the development of blood vessels

9

Describe interferons

- type I & II

- roles

 

  • More than 20 different IFNs identified
  • Produced by many cells in response to infections

Type I

  • IFNα/IFNβ
  • play particularly important roles in viral infections
  • Type I IFNs have been used as therapy in viral infections (HCV)

 

Type II

  • IFNγ
  • plays a major role in many immune responses and is particularly important for control of mycobacteria, viruses and other pathogens

10

Describe tissue necrosis factors

- roles

- clinical significance

 

  • Large super family of cytokines
  • Play major roles in immune cell
    • Activation
    • Differentiation 
    • Growth
    • Death
  • TNFα = major inflammatory cytokine involved in activating immune cells during infection and inflammation. 
  • TNFα blockade is a major therapeutic target in autoimmune disease

11

Roles of interleukins

 

  • More than 35 different Interleukins identified in humans
  • Play many key roles in immune responses:
    • IL-1 –inflammation
    • IL-2 –T cell growth
    • IL-4 –B cell growth
    • IL-5 –Eosinophil growth
    • IL-15 –NK cell growth
    • IL-10 –regulatory/suppressive

12

Cytokines involved in innate & acute phase responses (Th1)

IFN alpha/beta produced by virally infected cells -> promote antiviral state

IL-1beta, TNF alpha: can be produced by macrophages, dendritic cells, endothelium. promote inflammatory phase, acute phase response, fever. 

IL-6 produced by dendritic cells, macrophages, and can increase acute phase reactant, cause fever, T+B cell growth.

13

Cytokines promoting innate to adaptive responses (Th1/Th17)

IFNgamma produced by Th1, NK cells -> activae macrophages, promote Ig class switch. 

IL-17 produced by Th17 cells, recruit neutrophils, promote inflammation

TNF beta produced by Th1 cells, kill tumour cells, activate neutrophils & endothelium to allow trafficking

IL-2 produced by Th1/0, proliferate lymphocytes

IL-12/23 produced by DCs and macrophages, activate T cell IFNgamma or IL-17 production. 

14

Th2 mediated cytokines

generally less inflammatory than Th1/17 mediated cytokines

IL-4/5 produced by Th2 allow T+B cell growth, differentiation, IgG/A/E production, allergic responses

IL-10 produced by Th2, Tregs; promote B cell growth, inhibi Th1/17 responses

15

Cytokines mediated by T regulatory cells

anti-inflammatory cytokines

IL-10 produced by Tregs & Th2 cels promote B cell growth, inhibit Th1/17 responses

TGF beta produced by Tregs, suppress all immune responses, promote tolerance, wound healing. 

16

Examples of Growth factors/haematopoietic cytokines

GM-CSF/M-CSF, IL-3/7/2

 

GM-CSF/M-CSF: produced by stromal cells, T cells -> promote haematopoiesis, directed growht & differentiation of monocytes & granulocytes

IL-3 produced by CD4 T cells, keratinocytes -> promote haematopoiesis, directed growht & differentiation of monocytes & granulocytes

IL-7 by bone marrow stroma -> growth of pre-B cells and T cells, NK cells

IL-2 produced by CD4 T cells -> proliferate lymphocytes

17

Role of cytokines in autoimmunity

 

  • Important role in host defense
  • Orchestrate innate immunity
  • Important in adaptive immunity
  • Tissue damage if excessive responses occur
  • Direct and mediate autoimmunity

18

Major acute innate cytokines & their roles

 

  • IL-1, TNFα, IL-6, IL-12, CXCL8, G-CSF, GM-CSF
  • Activate endothelial cells and local tissue leukocytes
  • Trigger cytokine mediated amplification loops
  • Generate endothelial cell adhesion molecule expression
  • Slow blood flow
  • Increase vascular permeability
  • Recruit and activate a range of leukocytes 

19

Cytokines in autoimmunity

IL-1, IL-6, TNF alpha

20

Cytokines in adaptive host defence

21

What target cytokines as therapeutic targets?

 

  • Glucocorticoids
    • Target transcription factors inducing transcription of inflammatory cytokines
    • Affect intracellular signaling and effector cytokine mRNA stability
    • Attenuate TNFα and IL1β enhanced endothelial cell adhesion molecule expression
    • Reduce number of circulating T cells and inhibit IL2 production
    • Th cell differentiation shows a shift to Th2 with attenuation of monocyte IL12 → reduced Th1 responses favouring Th17
  • Pentoxifylline
  • Thalidomide

22

Describe cytokines as therapeutic targets 

 

  • Monoclonal antibody mediated immunoneutralization
  • Modified cytokine receptor: competitive inhibitors
  • Upstream drugs with efficacy through cytokine attenuation
  • Immunomodulating cytokines as therapeutic agents
  • Cytokine gene therapy
  • Examples
    • TNFα blockade: Rheumatoid Arthritis, Ankylosing Spondylitis, Psoriasis
    • IL-6 blockade: RA, Castleman's disease
    • IL-2 blockade: transplant rejection (e.g. basiliximab)
    • IL-1 blockade: RA (e.g. anakinra)
    • IL12/23 blockade: psoriasis (e.g. ustekinumab)
    • IL-17A blockade: psoriasis, AS
    • IL-10 blockade: psoriasis

23

Therapeutics targeting TNF alpha

- examples

- indications

 

  • 4 mAbs (infliximab, centolizumab, adalimumab and golimumab)
  • TNF receptor fused to Fc portion of IgG -competitive inhibitor (Etanercept)
  • PBS Indications:
    • Rheumatoid Arthritis
    • Active Ankylosing Spondylitis 
    • Severe Plaque Psoriasis
    • Severe Psoriatic Arthritis
    • Severe Active Juvenile Idiopathic Arthritis
    • Mod-Severe Ulcerative Colitis (but not effective at reducing colectomy rates)
    • Mod-Severe Crohn’s Disease

24

Therapeutics targeting IL-6

- characteristics of IL-6

- example

- indications

 

  • Pleiotrophic cytokine produced by T cells, macrophages and endothelial cells
  • Potent inducer of local and systemic inflammation
  • Plays a key role in the acute phase response
  • Tocilizumab is a monoclonal Ab targeting the IL-6Ra
  • Indications:
  • Severe active juvenile idiopathic arthritis
  • Severe active rheumatoid arthritis
  • Giant Cell Arteritis

25

Therapeutics targeting IL-1

- characteristics of IL-1

- example

- indications

 

  • Innate cytokine, activates macrophages and epithelial cells
  • Has a natural antagonist, IL-1RA 
  • Anakinra –human recombinant IL-1RA
  • Indications
    • Severe Cryoporin Associated Periodic Syndromes (CAPS)
    • Neonatal onset multisystem inflammatory disease
    • Muckle Wells Syndrome
    • Acute and chronic gout
    • RA & Juvenile RA
    • Behcet’s Disease
    • Ankylosing Spondylitis
    • Uveitis

26

Therapeutics targeting IL-2

- characteristics of IL-2

- examples

- indications

 

  • Growth factor for activated T cells
  • CD28 dependent co-stimulation of activated T cells induces expression of the high affinity IL-2 receptor
  • Basiliximab binds and blocks the IL-2Rc on activated T cells
  • Indications
    • Prevention of kidney transplant rejection
    • Prevention of cardiac and liver transplant rejection
    • Treatment of refractory acute GVHD
    • Uveitis

27

Therapeutics targeting IL-12/23

- characteristics of IL-12/23

- examples

- indications

 

  • Dimeric molecules sharing one chain in common (p40)
  • Targeting p40 offers the opportunity to attenuate both Th1 (driven by IL-12) and Th17 (enhanced by IL-23) pathways of Th differentiation
  • Ustekinumab and Briakinumab are p40 monoclonal antibodies
  • Indications
    • Severe refractory Crohn’s disease
    • Severe Psoriatic Arthropathy
    • Severe chronic plaque psoriasis
    • Active RA despite treatment with MTX –Phase II May 2017
    • Refractory GCA –GC sparing efficacy
    • Takayasu Arteritis –case series
    • Ankylosing Spondylitis –proof of concept clinical trial
    • Behcet’s–case reports

28

Therapeutics targeting IL-17

- characteristics of IL-17

- examples

- indications

 

  • Important in host defense to mobilise and activate neutrophils
  • Pathologic IL-17A responses lead to the development of autoimmunity
  • Secukinumab–inhibitory IL-17A mAb
  • Indications
    • Psoriasis
    • Psoriatic Arthropathy
    • Ankylosing Spondylitis
    • No benefit Crohn’s disease - actually may worsen.
    • Future therapeutics: Multiple Sclerosis

29

Therapeutics targeting IL-10

- characteristics of IL-10

- examples

- indications

 

  • Can attenuate the production of inflammatory cytokines
  • No readily available therapeutics targeting IL-10 on the market. Not effective for psoriatic arthropathy, RA, UC.
    • Human rIL-10 in Psoriatic Arthropathy: Improved skin but not articular disease (McInnes(2001) J Immunol)
    • Human rIL-10 in Rheumatoid Arthritis: Phase 1 + cytokine study –did not attenuate RA activity
    • Human rIL-10 in Ulcerative Colitis: Ineffective when administered at doses not associated with SEs

30

Describe cytokine gene therapy

 

  • Gene therapy demonstrated to be an effective way of treating pathologic inflammation
  • e.g. removal of rheumatoid synovia -> transfected & reimplanted with the gene for IL-1Ra -> attenuated disease