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.
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