VLA-2 blockade in vivo by vatelizumab induces CD4+FoxP3+ regulatory T cells

Abstract

Integrin α2β1, also known as very late antigen (VLA)-2, is a collagen-binding molecule expressed constitutively on platelets. Vatelizumab, a monoclonal antibody targeting the α2 subunit (CD49b) of VLA-2, was recently investigated for its safety and efficacy during a Phase 2 clinical study in multiple sclerosis patients, as integrin-mediated collagen binding at the site of inflammation is central to a number of downstream pro-inflammatory events. In the course of this study, we could show that VLA-2 is expressed ex vivo on platelets, platelet–T-cell aggregates, as well as a small population of highly activated memory T cells. Even though the clinical trial did not meet its primary clinical end-point (reduction in the cumulative number of new contrast-enhancing lesions on magnetic resonance imaging (MRI)), we observed enhanced frequencies of regulatory T cells (TREG) following vatelizumab treatment. Elevated TREG frequencies might be explained by the inhibition of p38 mitogen-activated protein kinase (MAPK) signaling, which is critically involved in the polarization of T helper 17 (TH17) cells and is activated by the α2 integrin cytoplasmic domain. Our findings suggest that blockade of VLA-2 might be a way to safely shift the TH17/TREG balance by inducing TREGin vivo.

Integrin α2β1 regulates collagen I tethering to modulate hyperresponsiveness in reactive airway disease models

“…Our demonstration that inhibition of integrin-mediated airway smooth muscle tethering can inhibit pathological force generation in smooth muscle through a mechanism independent of conventional bronchodilator therapy identifies an exciting opportunity for the development of new treatments for diseases characterized by exaggerated airway narrowing. Inhibitors of integrin α 2 β 1 have been administered to humans in numerous clinical trials targeting multiple sclerosis (45), inflammatory bowel disease (46), and cancer (47) and are generally well tolerated; the only side effect is minimal inhibition of platelet adhesion (less than that caused by low-dose aspirin) (48,49). These results suggest that toxicity is not likely to be an impediment to the development of potent α 2 β 1 inhibitors that can be accelerated into clinical trials for asthma.…”

Current and emerging disease‐modulatory therapies and treatment targets for multiple sclerosis

“…Additional integrin modulators include vatelizumab, a monoclonal blocker of α2‐integrin, as well as firategrast and zaurategrast, two oral α4β‐integrin modulators. Whilst vatelizumab did not meet its primary imaging outcome in a RRMS trial (NCT02222948), it was shown to increase the frequency of regulatory T cells [90]. A placebo‐controlled phase II trial of firategrast at different doses demonstrated a reduction of new contrast‐enhancing MRI lesions with higher doses [91].…”

Phototherapy in the treatment of microbial eczema

“…Эффекты на ЦНС исследовались на мышиной модели с аутоиммунной патологией ЦНС (экспериментальный аутоиммунный энцефаломиелит). А также на пациентах с перемежающимся множественным склерозом, получавших фотолечение узкополосным ультрафиолеовым излучением спектра B. Иммуномодулирующие эффекты были оценены с помощью патоморфологических исследований, изучения сывороточных образцов и подсчета иммунных клеток периферической крови [44].…”

“…Экспериментальное удаление клеток Лангерганса отменяет системные реакции в ответ на облучение. Локальное же облучение кожи индуцирует работу дендритных клеток, образование Т-регуляторов и тем самым меняет системные иммунные реакции, снижая аутоиммунизацию путем повышенной миграции Т-регуляторов в ЦНС [44].…”