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Table 4 Effector cytokines as targets

From: Treatment of allergic asthma: Modulation of Th2 cells and their responses

Cytokine

Relation to Th2 cells in asthma

References

Was the target used in clinical trials in asthma?

Clinical study, Reference*

IL-2

Important for survival of mature Tregs

Required for generation of effector and survival of memory T cells

[175]

[222]

Yes, daclizumab targeting its soluble IL-2 receptor CD25, improves FEV1 and reduced daily asthma symptoms

NCT00028288

IL-3

Secreted by Th2 cells, regulates eosinophil and basophil differentiation, migration and survival

Inhibition of IL-3/IL-5/GM-CSF common β receptor inhibits Th2 differentiation

[223, 224]

[225]

No

-

IL-4

Crucial for Th2 cell differentiation

Induction of IgE production of B cells

[226]

Yes, numerous mAbs and other compounds, development of most mAbs was discontinued, pitrakinra (IL-4 mutant protein binding to IL-4 and IL-13 receptors) improves lung function, stabilises asthma symptom scores and reduces beta-agonist use

[9, 11, 227–229], NCT00801853, NCT00941577

IL-5

Th2 cell cytokine involved in eosinophil differentiation, maturation, recruitment and survival

[230, 231]

Yes, does not inhibit eosinophilia or AHR, but new indications suggest use in difficult-to-treat and severe asthma

[232–234], NCT01000506, NCT00292877

IL-6

Polarises CD4+ T cells to Th2 or Th17 subtype

Soluble IL-6 receptor induces apoptosis of Th2 cells in the lungs & induces Tregs

[235, 236]

[237]

No

-

IL-9

Secreted by Th2 cells

Over expression in mice enhances inflammation and AHR

[238]

[239, 240]

Yes, appears to have acceptable safety profile and to decrease FEV1

[241, 242]

IL-10

Secreted by Th2 cells and some Tregs, plays multiple roles in the immune processes

[243]

No

-

IL-12

Essential for differentiation, proliferation and activation of Th1 cells

Suppresses Th2 immune responses in murine models

[244]

[245]

Yes, reduction in the number of circulating blood eosinophils, but not sputum eosinophilia, the late-phase response or airway hyper-responsiveness

[246]

IL-13

Involved in lung inflammation, mucus hypersectretion, subepithelial fibrosis and eotaxin production

[247]

Yes, clinical trials for numerous mAbs are in progress; pitrakinra (IL-4 mutant protein binding to IL-4 and IL-13 receptors) improves lung function, stabilises asthma symptom scores and reduces beta-agonist use

[229, 248, 249],

(NCT00873860, NCT00801853, NCT00941577)

IL-15

Th1 cytokine that appears to counterbalance Th2 immune response

[250]

No

-

IL-17A

Implicated in infiltration of neutrophils after allergen exposure

Might regulate established Th2 response

[251]

[252]

No

-

IL-17F

Implicated in infiltration of neutrophils after allergen exposure

[251]

No

-

IL-18

Cytokine involved in Th1 and Th2 immunity

Delivery of IL-18 gene reduced allergic inflammation in a mouse asthma model

[253]

[254]

No

-

IL-19

Produced by epithelial cells and mediates IL-4, IL-5, IL-10 and IL-13 production

[255, 256]

No

-

IL-21

Secreted by CD4+ T cells

Involved in proliferation, differentiation and regulation of T cells, B cells, DCs and natural killer cells

Stimulates IgG responses instead of IgE

[23, 257]

No

-

IL-22

Required for the onset of allergic asthma in mice, but negatively regulates acute inflammation in lungs

[258]

No

-

IL-23

Lung-specific expression enhances allergen-induced inflammation, mucus hyperproduction and AHR

Its inhibition protects against allergic asthma in mice

[259]

[260]

No

-

IL-25

Induces Th2 immunity, enhances Th2 cell survival and stimulates Th2 cytokine secretion

Its inhibition prevents inflammation in mouse models of asthma

[261, 262]

No

-

IL-27

Th1 cytokine decreases Th2 response in murine models of asthma

[263]

No

-

IL-31

Secreted by Th2 cells, expressed at higher levels in asthmatic patients

[264, 265]

No

-

IL-33

IL-33 receptor, ST2, is a marker for Th2 cells

IL-33 activates Th2 cells

[266, 267]

[268]

No

-

IFN-γ

Th1 cytokine that inhibits Th2 cell polarisation in vitro

Appears to be involved in pathogenesis of severe allergic asthma

[40]

[269, 270]

Yes, but treatment did not improve monitored clinical parameters

[271]

TGF-ß

TGF-ß inhibits expression of transcription factor GATA-3

Its neutralisation exacerbates or has no effect on inflammatory responses in mouse models of asthma

[272]

[273, 274]

No

-

TNF-α

Pleiotropic cytokine, chemoattractant for eosinophils and contributes to the activation of T cells

[275]

Yes, divergent results, severe side-effects

[276, 277]

  1. * Numbers starting with NTC represent clinical study code from http://clinicaltrials.gov/