Monoclonal antibody (AMG 157) against a new target in asthma, thymic stromal lymphopoietin (TSLP)

What is TSLP?

Thymic stromal lymphopoietin (TSLP) is an epithelial-cell–derived cytokine that may be important in allergic inflammation. TSLP, which was discovered as a growth factor for lymphocyte progenitors, is a protein released from epithelial cells in response to irritating stimuli. It initiates signaling pathways leading to inflammation driven by type 2 helper T (Th2) cells.

What is the immunology basis for TSLP effects?

Cytokine receptors include the following types:

- Type I (hematopoietin receptors - IL-3 and Epo)
- Type II
- IL-1 family receptors - they share Toll-like/IL-1 receptor (TIR) domain
- TNF receptors
- Seven-transmembrane α-helical receptors


(click to enlarge the image)

Interleukin-7 receptor (IL7R)

Interleukin 7 receptor (IL7R) is also known as CD127 (Cluster of Differentiation 127) is a type I cytokine receptor. Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands.

Type I cytokine receptors are mediated through JAK/STAT and bind: IL-2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, GM-CSF.


Key steps of the JAK-STAT pathway. Image source: Wikpedia, public domain.

IL7R plays a critical role in the V(D)J recombination during lymphocyte development. A defect in IL-7RA leads to SCID (T-/B+/NK+).

Thymic stromal lymphopoietin (TSLP)

Thymic stromal lymphopoietin (TSLP) signals through a heterodimeric receptor complex composed of the TSLP receptor and the IL-7R alpha chain. Some researchers have classified TSLP as a "master regulator" of the Th2 response due to overexpression of the cytokine in pulmonary tissue and skin cells result in Th2-induced asthma and dermatitis.

TSLP is produced mainly by non-hematopoietic cells as fibroblasts, epithelial cells and different types of stromal cells.

Anti-TSLP is a potential new therapeutic target in asthma.

TSLP could be a master switch in the signaling between airway epithelium and other inflammatory cascades or it could be a part of a concerted action by several parallel pathways (e.g., those involving interleukin-33, interleukin-25, and interleukin-17).

Anti-TSLP (AMG 157) as asthma treatment

AMG 157 is a humanized anti-TSLP monoclonal immunoglobulin G2delta that binds human TSLP and prevents receptor interaction.

A small double-blind, placebo-controlled study included 31 patients with mild allergic asthma who received three monthly doses of AMG 157 (700 mg) or placebo IV. AMG 157 decreased measures of allergen-induced early and late asthmatic responses (FEV1, blood and sputum eosinophils before and after the allergen challenge, FeNO).

TSLP could play a key role in allergen-induced airway responses and persistent airway inflammation in allergic asthma. Whether anti-TSLP therapeutics will have clinical value cannot be determined yet from these data. The study was funded by the AMG manufacturer, Amgen, and published in the NEJM.

References:

Effects of an Anti-TSLP Antibody on Allergen-Induced Asthmatic Responses — NEJM http://buff.ly/1kntbHZ

TSLP in Asthma — A New Kid on the Block? — NEJM http://buff.ly/1knte6T

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