Targeting Leukocyte Trafficking Research Articles

Integrin α3 promotes TH17 cell polarization and extravasation during autoimmune neuroinflammation.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by CNS-infiltrating leukocytes, including TH17 cells that are critical mediators of disease pathogenesis. Although targeting leukocyte trafficking is effective in treating autoimmunity, there are currently no therapeutic interventions that specifically block encephalitogenic TH17 cell migration. Here, we report integrin α3 as a TH17 cell-selective determinant of pathogenicity in experimental autoimmune encephalomyelitis. CNS-infiltrating TH17 cells express high integrin α3, and its deletion in CD4+ T cells or Il17a fate-mapped cells attenuated disease severity. Mechanistically, integrin α3 enhanced the immunological synapse formation to promote the polarization and proliferation of TH17 cells. Moreover, the transmigration of TH17 cells into the CNS was dependent on integrin α3, and integrin α3 deficiency enhanced the retention of CD4+ T cells in the perivascular space of the blood-brain barrier. Integrin α3-dependent interactions continuously maintain TH17 cell identity and effector function. The requirement of integrin α3 in TH17 cell pathogenicity suggests integrin α3 as a therapeutic target for MS treatment.

Recruitment and Residence of Intestinal T Cells - Lessons for Therapy in Inflammatory Bowel Disease.

Targeting leukocyte trafficking in the management of inflammatory bowel disease [IBD] has been a significant therapeutic advance over the past 15 years. However, as with other advanced therapies, phase III clinical trials report response to trafficking inhibitors in only a proportion of patients, with fewer achieving clinical remission or mucosal healing. Additionally, there have been significant side effects, most notably progressive multifocal leukoencephalopathy in association with the α4 inhibitor natalizumab. This article reviews the mechanisms underpinning T cell recruitment and residence, to provide a background from which the strength and limitations of agents that disrupt leukocyte trafficking can be further explored. The therapeutic impact of trafficking inhibitors is underpinned by the complexity and plasticity of the intestinal immune response. Pathways essential for gut homing in health may be bypassed in the inflamed gut, thus providing alternative routes of entry when conventional homing molecules are targeted. Furthermore, there is conservation of trafficking architecture between proinflammatory and regulatory T cells. The persistence of resident memory cells within the gut gives rise to local established pro-inflammatory populations, uninfluenced by inhibition of trafficking. Finally, trafficking inhibitors may give rise to effects beyond the intended response, such as the impact of vedolizumab on innate immunity, as well as on target side effects. With significant research efforts into predictive biomarkers already underway, it is ultimately hoped that a better understanding of trafficking and residence will help us predict which patients are most likely to respond to inhibition of leukocyte trafficking, and how best to combine therapies.

Targeting Leukocyte Trafficking in Inflammatory Bowel Disease.

In the last two decades, understanding of inflammatory bowel disease (IBD) immunopathogenesis has expanded considerably. Histopathological examination of the intestinal mucosa in IBD demonstrates the presence of a chronic inflammatory cell infiltrate. Research has focused on identifying mechanisms of immune cell trafficking to the gastrointestinal tract that may represent effective gut-selective targets for IBD therapy whilst avoiding systemic immunosuppression that may be associated with off-target adverse effects such as infection and malignancy. Integrins are cell surface receptors that can bind to cellular adhesion molecules to mediate both leukocyte homing and retention. In 2014, Vedolizumab (Entyvio®) was the first anti-integrin (anti-α4ß7 monoclonal antibody) treatment to be approved for use in IBD. Several other anti-integrin therapies are currently in advanced stages of development, including novel orally administered small-molecule drugs. Drugs targeting alternative trafficking mechanisms such as mucosal addressin cellular adhesion molecule-1 and sphingosine-1-phosphate receptors are also being evaluated. Here, we summarise key established and emerging therapies targeting leukocyte trafficking that may play an important role in realising the goal of stratified precision medicine in IBD care.

Past, Present and Future of Therapeutic Interventions Targeting Leukocyte Trafficking in Inflammatory Bowel Disease.

Studies in the 1990s using animal models of intestinal inflammation delineated the crucial molecules involved in leukocyte attraction and retention to the inflamed gut and associated lymphoid tissues. The first drug targeting leukocyte trafficking tested in inflammatory bowel diseases was the anti-ICAM-1 antisense oligonucleotide alicaforsen, showing only modest efficacy. Subsequently, the anti-α4 monoclonal antibody natalizumab proved efficacious for induction and maintenance of remission in Crohn's disease, but was associated with progressive multifocal leukoencephalopathy due to its ability to interfere with both α4β1 and α4β7 function. Later developments in this area took advantage of the fairly selective expression of MAdCAM-1 in the digestive organs, showing that vedolizumab, a more specific monoclonal antibody selectively blocking MAdCAM-1 binding to integrin α4β7, was efficacious for induction and maintenance of remission in ulcerative colitis and Crohn's disease, and it was not associated with neurological complications. Currently, other drugs targeting the β7 subunit, immunoglobulin superfamily molecules expressed on the endothelium, as well as blockade of lymphocyte recirculation in lymph nodes through modulation of sphingosine 1-phosphate receptors are under development. The potential use and risks of combined anti-trafficking therapy will be examined in this review.

Efficacy of Leukadherin-1 in the Prevention of Hyperoxia-Induced Lung Injury in Neonatal Rats.

Lung inflammation plays a key role in the pathogenesis of bronchopulmonary dysplasia (BPD), a chronic lung disease of premature infants. The challenge in BPD management is the lack of effective and safe antiinflammatory agents. Leukadherin-1 (LA1) is a novel agonist of the leukocyte surface integrin CD11b/CD18 that enhances leukocyte adhesion to ligands and vascular endothelium and thus reduces leukocyte transendothelial migration and influx to the injury sites. Its functional significance in preventing hyperoxia-induced neonatal lung injury is unknown. We tested the hypothesis that administration of LA1 is beneficial in preventing hyperoxia-induced neonatal lung injury, an experimental model of BPD. Newborn rats were exposed to normoxia (21% O2) or hyperoxia (85% O2) and received twice-daily intraperitoneal injection of LA1 or placebo for 14 days. Hyperoxia exposure in the presence of the placebo resulted in a drastic increase in the influx of neutrophils and macrophages into the alveolar airspaces. This increased leukocyte influx was accompanied by decreased alveolarization and angiogenesis and increased pulmonary vascular remodeling and pulmonary hypertension (PH), the pathological hallmarks of BPD. However, administration of LA1 decreased macrophage infiltration in the lungs during hyperoxia. Furthermore, treatment with LA1 improved alveolarization and angiogenesis and decreased pulmonary vascular remodeling and PH. These data indicate that leukocyte recruitment plays an important role in the experimental model of BPD induced by hyperoxia. Targeting leukocyte trafficking using LA1, an integrin agonist, is beneficial in preventing lung inflammation and protecting alveolar and vascular structures during hyperoxia. Thus, targeting integrin-mediated leukocyte recruitment and inflammation may provide a novel strategy in preventing and treating BPD in preterm infants.

Targeting leukocyte trafficking for the treatment of inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammatory disease of the intestine that includes both Crohn's disease and ulcerative colitis, and afflicts nearly 1 million people throughout North America. As our understanding of IBD pathogenesis grows, several new therapies have been developed that use monoclonal antibodies to specifically target key mediators and biological pathways implicated in IBD immune dysfunction. One important pathway involves leukocyte trafficking and infiltration into the affected intestinal tissues. This review provides a summary of the different therapies that have been developed to inhibit leukocyte trafficking to the inflamed gut, and evaluates the relative safety and efficacy of these novel drugs within the context of existing medical therapies for IBD.

Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation

Adhesive interactions of leukocytes and endothelial cells initiate leukocyte migration to inflamed tissue and are important for immune surveillance. Acute and chronic inflammatory diseases show a dysregulated immune response and result in a massive efflux of leukocytes that contributes to further tissue damage. Therefore, targeting leukocyte trafficking may provide a potent form of anti-inflammatory therapy. Leukocyte migration is initiated by interactions of the cell adhesion molecules E-, L-, and P-selectin and their corresponding carbohydrate ligands. Compounds that efficiently address these interactions are therefore of high therapeutic interest. Based on this rationale we investigated synthetic dendritic polyglycerol sulfates (dPGS) as macromolecular inhibitors that operate via a multivalent binding mechanism mimicking naturally occurring ligands. dPGS inhibited both leukocytic L-selectin and endothelial P-selectin with high efficacy. Size and degree of sulfation of the polymer core determined selectin binding affinity. Administration of dPGS in a contact dermatitis mouse model dampened leukocyte extravasation as effectively as glucocorticoids did and edema formation was significantly reduced. In addition, dPGS interacted with the complement factors C3 and C5 as was shown in vitro and reduced C5a levels in a mouse model of complement activation. Thus, dPGS represent an innovative class of a fully synthetic polymer therapeutics that may be used for the treatment of inflammatory diseases.

Targeting leukocyte trafficking to inflamed skin – still an attractive therapeutic approach?

Research into leukocyte trafficking and its therapeutic exploitation appears to be a multistep process, just like the trafficking cascade itself. The initial euphoria evoked by an early understanding of the trafficking steps was followed by considerable disappointment following the clinical failure of the first selectin antagonist Cylexin (CY-1503), a sialyl Lewis(X) mimetic. The research area recovered and identified additional attractive pharmacological targets such as chemokine receptors and integrins. However, after lack of efficacy in anti-chemokine trials and the fatalities associated with anti VLA-4 therapy (Tysabri), the question arose again whether targeting leukocyte trafficking is really promising or whether such a complex, multistep process with many redundant and/or functionally overlapping molecules is simply too challenging to deal with. In this article, we delineate some pros and cons of this approach followed by a brief update on where we stand in the field and where we might move in the future.