RT Journal Article
SR Electronic
T1 Blockade of thymic stromal lymphopoietin receptor (TSLPR) reduces atopic inflammation in a cynomolgus monkey model of asthma
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P2329
VO 40
IS Suppl 56
A1 Donavan T. Cheng
A1 Jens Niewoehner
A1 Martin Dahl
A1 Angela Tsai
A1 Waldemar Gonsiorek
A1 Cynthia Ma
A1 Subbu Apparsundaram
A1 Achal Pashine
A1 Palanikumar Ravindran
A1 Jimmy Jung
A1 John Allard
A1 Hans Bitter
A1 Catherine Tribouley
A1 Stephen Wilson
A1 Maria E. Fuentes
YR 2012
UL http://erj.ersjournals.com/content/40/Suppl_56/P2329.abstract
AB TSLP pathway blockade is a potential strategy for asthma treatment, as TSLP modulates cytokine production by mast cells and regulates the activation of dendritic cells (DCs), which prime the differentiation of naïve T cells into inflammatory Th2 cells. We thus tested the effects of TSLPR blockade on the development of allergic inflammation and bronchoconstriction in cynomolgus monkeys after Ascaris suum allergen challenge. Antibodies against human TSLPR were generated and confirmed to be cross-reactive to cynomolgus. Animals were dosed weekly with either vehicle (n=8) or TSLPR HuMAb (n=8) for 6 weeks and their responses to A.Suum challenge at baseline, week 2 and week 6 were assessed. TSLPR HuMab treated subjects showed reduced bronchoalveolar lavage (BAL) eosinophil counts (p=0.04), reduced lung resistance (RL) area under the curve (p=0.04), and reduced IL-13 cytokine levels in BAL fluid (p=0.03) in response to challenge at 6 weeks compared to control subjects. To understand the molecular changes underlying these differences, pre- and 8h post-challenge BAL samples from Mab-treated and control subjects were profiled using expression microarrays. Genes up-regulated by allergen challenge overlapped strongly with 11 genes up-regulated in DCs when stimulated by TSLP (TSLP-DC signature). At 6 weeks, treatment with TSLPR HuMAb reduced the overall number of differentially expressed genes and significantly reduced the induction of the TSLP-DC signature relative to control subjects (p = 0.05). These results demonstrate promising efficacy for TSLPR blockade in an allergen challenge model where TSLP activation of DCs may play a key role.