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Year 2 - T3 Theme 1 > L8 Regulating the immune responses: the role of cytokines and chemokines : the role of cytokines and chemokines > Flashcards

L8 Regulating the immune responses: the role of cytokines and chemokines : the role of cytokines and chemokines Flashcards

1
Q

How do cytokines act

A
  • All cytokines act by ligating their receptor (often two subunits) and triggering a signalling cascade leading to activated transcription of specific genes
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2
Q

Cytokines in hematopoiesis

A

IL-, interleukin, SCF, stem cell factor; G-(GM)-CSF, granulocyte (granulocyte/macrophage) colony stimulating factor: EPO, erythropoietin; TPO, thrombopoietin

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3
Q

What are interferons

A
  • Anti-viral mediators

- Products of virus-infected cells that interfere with viral replication

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4
Q

Examples of interferons

A
  • IFN-alpha (made by lymphocytes)
  • IFN-beta (made by fibroblasts)
  • IFN-gamma (made by lymphocytes and NK cells)
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5
Q

Immune activators that are involved in mediating host defense

A
  • Lymphocyte-activating cytokines (IL-1)
  • T cell growth factors (IL-2, -7, -9, -15; they share a co-receptor)
  • Macrophage-activating cytokines (IFN-gamma)
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6
Q

What are cytotoxins

A
  • Identified as products of activated lymphocytes or macrophages that can kill tumour cells
    eg. tumour necrosis factor; TNF, also known as TNF-alpha
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7
Q

Why wasn’t TNF used as an anticancer agent

A
  • TNF was cloned and produced with the hope it would be an anticancer agent
  • However, it turned out to te too toxic
  • Same story for IL-1, as a lymphocyte activator tested in AIDS
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8
Q

Three main types of armed effector T cells

A
  • Cytotoxic (killer) T cells (Peptide + MHC class I)

- Tn1 and Tn2 cells (peptide + MHC class II)

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9
Q

Effector molecules produced by cytotoxic (killer) T cells

A
  • Cytotoxic effector molecules
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10
Q

Effector molecules produced by Tn1 cells

A
  • Macrophage-activating effector molecules such as IFN-gamma and TNF-alpha
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11
Q

Effector molecules produced by Tn2 cells

A
  • B-cell activating effector molecules such as IL-4,5,15,10 and TGF-beta
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12
Q

How do Th1 (T-helper) and Th2 cells mainly act

A
  • Mainly act by activating other cells
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13
Q

Effects of IFN-gamma and CD40 ligands(produced by Th1 cells)

A
  • Activates macrophage to destroy engulfed bacteria
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14
Q

Effects of fox ligand or LT-alpha (produced by TH1)

A
  • Kills chronically infected cells, releasing bacteria to be destroyed by fresh macrophages
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15
Q

Effects of IL-2 (produced by Th1)

A
  • Induces T-cell proliferation, increasing numbers of effector cells
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16
Q

Effects of IL-3 + GM-CSF

A
  • Induces macrophage differentiation in the bone marrow
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17
Q

Effects of TNF-alpha + LT-beta

A
  • Activates endothelium to induce macrophage binding and exit from blood vessel at site of infection
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18
Q

What is X-linked SCID (severe combined immunodeficiency) caused by

A
  • Is caused by the genetic inactivation (by mutation) of one receptor that is a common signalling component of the IL-2, IL-4 and IL-7 receptors
19
Q

How was the inflammatory role of cytokines discovered

A
  • Was discovered by studying the immunopathogenesis of cachexia during infection
  • It was found that activated macrophages produce an inflammatory mediator (cytokine) that, among other things, induced cachexia
  • When they had its sequence, they found it was identical to TNF
20
Q

Cardinal signs of inflammation

A
  • Heat
  • Swelling
  • Redness
  • Pain
  • Tissue damage
21
Q

Examples of TNF-mediated diseases

A
  • Septic shock
  • Multiple organ failure
  • Respiratory distress syndrome
  • Rheumatoid arthritis
  • Inflammatory bowel disease
  • Graft-versus-host rejection
  • Diabetes
  • Pulmonary fibrosis
22
Q

Cytokines in allergy

A
  • While Th1 cytokines are important in inflammatory diseases, Th2 cytokines are important in allergic diseases
23
Q

What is Th1/Th2 differentiation viewed as a balance between

A
  • Inflammation/Asthma

- Inflammatory/anti-inflammatory

24
Q

T cell subsets - Naive CD4

A

Th1 - IFN-gamma - inflammation

Th2 - IL-4,5,9 and 13 - allergy, anti-inflammation

Th17 - IL-17 - inflammation

Treg - IL-10, inhibit activity of other T cells - anti-inflammation

25
Q

What is MCP-1/CCL2

A

The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) - is a chemokine

CCL2 recruits monocytes, memory T cells, and dendritic cells to the sites of inflammation produced by either tissue injury or infection

26
Q

Therapeutic use of IFN-gamma

A
  • Macrophage activation
27
Q

Therapeutic use of IFN-beta

A
  • ‘Immunomodulation’
28
Q

Therapeutic use of IL-2

A

Host defense - Melanoma, renal cell carcinoma

29
Q

Therapeutic use of IFN-alpha

A

Host defense - Hairy cell leukemia, kaposi, viral hepatitis

30
Q

Therapeutic use of GM-CSF

A

Hemopoiesis

- Myeloreconstitution following bone marrow transplant, chemotherapy-induced neutropenia

31
Q

Therapeutic use of G-CSF

A

Hemopoiesis

- Chemotherapy-induced neutropenia

32
Q

Therapeutic use of IL-11

A

Hemopoiesis

- Thrombocytopenia in oncology

33
Q

Therapeutic use of EPO

A

Hemopoiesis

- Anaemia

34
Q

Therapeutic use of anti-tNF and sTNFR

A
  • Rheumatoid arthritis, crohn’s, ulcerative colitis, psoriasis
35
Q

Therapeutic use of IL-1Ra

A
  • Rheumatoid arthritis, cryopyrin-associated periodic syndromes, CAPS
36
Q

Therapeutic use of anti-IL-6, IL-6R

A
  • Rheumatoid arthritis
37
Q

Therapeutic use of anti-IL-17,-12,-23

A
  • Psoriasis, psoriatic arthritis, ankylosing spondylitis, crohn
38
Q

Therapeutic use of anti-IL-5

A
  • Reslizumab, mepolizumab; approved FDA 2016-2017 for asthma and eosinophilic granulomatosis
39
Q

Therapeutic use of anti-IL-4R

A
  • Dupilumab; approved FDA 2017 for atopic dermatitis (eczema)
40
Q

Examples of cytokine inhibitors

A
  • Antibodies anti-cytokine or their soluble receptors (to mop them up); antibodies to their receptor (to block their binding site)
41
Q

What is ustekinumab

A
  • Is an antibody directed against the p40 subunit of IL-12 and IL-23, so it inhibits both
  • Approved for psoriasis and crohn’s disease
42
Q

What does pleiotropic mean

A
  • Acts on many different targets (has many actions)
43
Q

Consequences of pleiotrophic effects

A
  • The success and effectiveness of anti-TNF therapy (and other anti-cytokine drugs) in chronic inflammatory diseases should not let us forget their role in innate immunity
  • Side effects of anti-TNF, anti-IL-17, anti-IL-6 include increased susceptibility to TB and serious opportunistic infections, including listeria, pneumocytosis and others
44
Q

Example of pleiotrophic medication and its side effects

A
  • Enbrel
  • Serious infections including sepsis and TB have been reported
  • TB (including disseminated or extrapulmonary presentation) has been observed in patients receiving TNF-blocking agents such as enbrel
  • TB may be due to reactivation of latent TB infection or to new infection
  • Reactivation of hep B and worsening of hep C

Year 2 - T3 Theme 1 (15 decks)

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