Integrin Inhibitor Research Articles

Laminin-bound integrin α6β4 promotes non-small cell lung cancer progression via the activation of YAP/TAZ signaling pathway.

Laminin is an extracellular matrix multidomain trimeric glycoprotein, that has a potential role in tumor progression. Here, we studied the effects of non-small cell lung cancer (NSCLC) cells interaction on laminin and explored the underlying mechanism of laminin associated NSCLC progression. Culture of A549 and NCI-1299 cells on 2D collagen gels (containing laminin) significantly promoted the proliferative and tumorigenic characteristics, as well as cell invasion of tumor cells in vitro. Consistently, comparing the clinical NSCLC tumor tissues, a poor overall survival was observed in patients with high laminin expression. Mechanistically, the expression of integrin α6β4 was required for the pro-tumor effects of laminin. Meanwhile, we showed that the downstream signaling of integrin α6β4, involved the focal adhesion kinase (FAK)/Yes-Associated Protein (YAP)/TAZ signaling pathway. The activation of FAK/YAP/TAZ signaling pathway induced by laminin was validated in tumor tissues from NSCLC patients. Suppression of integrin α6β4/FAK/YAP/TAZ signaling pathway efficiently suppressed the laminin-induced tumor growth, and strengthened the anticancer effects of chemotherapy, describing a novel target for NSCLC treatment.

Designing closure-stabilizing integrin inhibitors.

Designing closure-stabilizing integrin inhibitors.

Dysregulation of integrin αvβ3 and α5β1 impedes migration of placental endothelial cells in fetal growth restriction.

Placentas from pregnancies complicated by severe early-onset fetal growth restriction (FGR) exhibit diminished vascular development mediated by impaired angiogenesis, but underlying mechanisms remain unknown. In this study, we show that FGR endothelial cells demonstrate inherently reduced migratory capacity despite the presence of fibronectin, a matrix protein abundant in placental stroma that displays abnormal organization in FGR placentas. Thus, we hypothesized that aberrant endothelial-fibronectin interactions in FGR are a key mechanism underlying impaired FGR endothelial migration. Using human fetoplacental endothelial cells isolated from uncomplicated term control and FGR pregnancies, we assessed integrin α5β1 and αvβ3 regulation during cell migration. We show that endothelial integrin α5β1 and αvβ3 interactions with fibronectin are required for migration and that FGR endothelial cells responded differentially to integrin inhibition, indicating integrin dysregulation in FGR. Whole-cell expression was not different between groups. However, there were significantly more integrins in focal adhesions and reduced intracellular trafficking in FGR. These newly identified changes in FGR endothelial cellular processes represent previously unidentified mechanisms contributing to persistent angiogenic deficiencies in FGR.

P17.19.B Incidence of treatment-associated imaging changes in newly diagnosed MGMT promoter-methylated glioblastoma treated with cilengitide (EORTC 26071 - CENTRIC study): interim analysis

Abstract Background In patients with glioblastoma, radiological recurrence of enhancing tissue after chemoradiotherapy can originate from progressive disease (PD) or from pseudoprogression/treatment-associated changes. There are no widely approved consensus criteria for treatment-associated changes. In the randomised EORTC-CENTRIC study (NCT00689221), patients with MGMT promoter-methylated glioblastoma were treated with chemoradiotherapy or chemoradiotherapy with cilengitide, an integrin inhibitor. We assessed the rate of treatment-associated changes in these groups according to the modified response assessment in neuro-oncology (RANO) criteria of 2017. Methods CENTRIC patients from both study arms with ≥3 follow-up MRIs were included. Preliminary PD (PPD) was defined as a ≥25% increase of the sum of perpendicular diameter (SPD) of a new or increasing lesion compared to baseline or nadir on the T1-MRI with gadolinium. Subsequent PD was defined as a second ≥25% increase of the SPD, at least 4 weeks later, or as a new lesion outside the radiation field. Treatment-associated changes were defined as stabilisation on ≥2 follow-up MRIs after PPD, each one 4 weeks later, or partial/complete regression on ≥1 follow-up MRI 4 weeks later. Results In total, 4,051 MRIs from 584 patients were available. This interim analysis included data on 462 patients with similar proportions in the cilengitide and control arm (50.9% and 49.1%). Due to missing MRIs or values, 128 were excluded. Of the remaining 334 patients, 157 (47%) patients showed RANO measurable disease at baseline or nadir (median SPD, 0mm2; interquartile range (IQR) 552.1 (0-552.1). After chemoradiotherapy with or without cilengitide, PPD occurred in 214 patients (64.1%) after a median time of 6.08 months after finishing radiation (IQR 11.4 (2.4-13.8), and 3.65 months after baseline or nadir (IQR 6.4 (2.1-8.5). After follow-up of these 214 patients, treatment-associated changes were diagnosed in 62 (18.6%) and PD was diagnosed in 48 (14.4%). The remaining 104 (31.1%) patients had no further follow-up MRI after PPD, mostly because a clinical decision to call PD was made. In the cilengitide group of 178 patients, 37 (20.8%) patients developed treatment-associated changes, and 23 (12.9%) patients developed PD, whereas in the control group of 156 patients, 25 (16%) patients developed treatment-associated changes, and 25 (16%) patients PD. Conclusion With the modified RANO criteria, the rate of treatment-associated changes was low compared to previous studies in newly diagnosed MGMT promoter-methylated glioblastoma. This rate did not change with addition of cilengitide. RANO-recommended radiological follow-up was not always awaited, which reflects clinical practice. Full data will be presented.

A general chemical principle for creating closure-stabilizing integrin inhibitors

Integrins are validated drug targets with six approved therapeutics. However, small-molecule inhibitors to three integrins failed in late-stage clinical trials for chronic indications. Such unfavorable outcomes may in part be caused by partial agonism, i.e., the stabilization of the high-affinity, extended-open integrin conformation. Here, we show that the failed, small-molecule inhibitors of integrins αIIbβ3 and α4β1 stabilize the high-affinity conformation. Furthermore, we discovered a simple chemical feature present in multiple αIIbβ3 antagonists that stabilizes integrins in their bent-closed conformation. Closing inhibitors contain a polar nitrogen atom that stabilizes, via hydrogen bonds, a water molecule that intervenes between a serine residue and the metal in the metal-ion-dependent adhesion site (MIDAS). Expulsion of this water is a requisite for transition to the open conformation. This change in metal coordination is general to integrins, suggesting broad applicability of the drug-design principle to the integrin family, as validated with a distantly related integrin, α4β1.

Arg-Gly-Asp-binding integrins activate hepatic stellate cells via the hippo signaling pathway

Background & aimsLiver fibrosis characterizes advanced chronic liver disease, and persistent activation of hepatic stellate cells (HSCs) is the primary cause of excessive hepatic fibrogenesis. CWHM12, an analog of the arginine-glycine-aspartic acid (RGD) amino acid sequence found in specific integrins, improves liver fibrosis; however, the detailed mechanisms remain unclear. This study aimed to clarify the cell signaling mechanisms of CWHM12 in activated HSCs. MethodsImmortalized human HSC lines, LX-2 and TWNT-1, were used to evaluate the effects of CWHM12 on intracellular signaling via the disruption of RGD-binding integrins. ResultsCWHM12 strongly promoted phosphorylation and inhibited the nuclear accumulation of Yes-associated protein (YAP), which is a critical effector of the Hippo signaling pathway, leading to the inhibition of proliferation, suppression of viability, promotion of apoptosis, and induction of cell cycle arrest at the G1 phase in activated HSCs. Further investigations revealed that inhibition of TGF-β was involved in the consequences of CWHM12. Moreover, CWHM12 suppressed focal adhesion kinase (FAK) phosphorylation; consequently, Src, phosphatidylinositol 3-kinase, pyruvate dehydrogenase kinase 1, and serine-threonine kinase phosphorylation led to the translocation of YAP. These favorable effects of CWHM12 on activated HSCs were reversed by inhibiting FAK. ConclusionsThese results indicate that pharmacological inhibition of RGD-binding integrins suppresses activated HSCs by blocking the Hippo signaling pathway, a cellular response which may be valuable in the treatment of hepatic fibrosis.

Delivery of Bioactive Albumin from Multi-Functional Polyampholyte Hydrogels.

Tissue engineered scaffolds are currently being explored to aid in healing and regeneration of non-union fractures in bone. Additionally, albumin has been demonstrated to provide benefits to healing when applied to injury sites. This paper focuses on delivery of calcium modified, bioactive bovine serum albumin (BSA) from a multi-functional polyampholyte polymer scaffold. First, the inherent nonfouling and conjugation properties of the polyampholyte hydrogel were verified to determine the impact of calcium exposure. The polyampholyte hydrogel delivery platform was then assessed with calcium titrations and osteoblast-like cell (MC3T3-E1) adhesion, proliferation, and viability evaluations. Finally, integrin inhibitors were used to identify the binding mechanisms that mediate cell adhesion to the calcium-modified BSA-conjugated hydrogels. An increase in cell adhesion was observed following calcium exposure up to 0.075 M, although this and higher calcium concentrations affected hydrogel stability and cell growth. BSA exposed to 0.05 M calcium and delivered from polyampholyte hydrogels promoted the most promising viable cell adhesion over 7 days. Cell adhesion to the calcium-modified BSA-conjugated hydrogels appeared to be regulated by arginine-glycine-aspartic acid (RGD) and collagen specific integrins. These results demonstrate that the delivery of calcium modified BSA from an implantable polymer scaffold is promising for bone tissue engineering applications.

FRI152 - Dual inhibition of integrins alpha-v/beta-6 and alpha-v/beta-1 decreases portal pressure and liver fibrosis in rats with biliary cirrhosis

FRI152 - Dual inhibition of integrins alpha-v/beta-6 and alpha-v/beta-1 decreases portal pressure and liver fibrosis in rats with biliary cirrhosis

Development of New Potential Inhibitors of β1 Integrins through In Silico Methods-Screening and Computational Validation.

Integrins are transmembrane receptors that play a critical role in many biological processes which can be therapeutically modulated using integrin blockers, such as peptidomimetic ligands. This work aimed to develop new potential β1 integrin antagonists using modeled receptors based on the aligned crystallographic structures and docked with three lead compounds (BIO1211, BIO5192, and TCS2314), widely known as α4β1 antagonists. Lead-compound complex optimization was performed by keeping intact the carboxylate moiety of the ligand, adding substituents in two other regions of the molecule to increase the affinity with the target. Additionally, pharmacokinetic predictions were performed for the ten best ligands generated, with the lowest docking interaction energy obtained for α4β1 and BIO5192. Results revealed an essential salt bridge between the BIO5192 carboxylate group and the Mg2+ MIDAS ion of the integrin. We then generated more than 200 new BIO5192 derivatives, some with a greater predicted affinity to α4β1. Furthermore, the significance of retaining the pyrrolidine core of the ligand and increasing the therapeutic potential of the new compounds is emphasized. Finally, one novel molecule (1592) was identified as a potential drug candidate, with appropriate pharmacokinetic profiles, similar dynamic behavior at the integrin interaction site compared with BIO5192, and a higher predicted affinity to VLA-4.

Integrins Bidirectionally Regulate the Efficacy of Inhibitory Synaptic Transmission and Control GABAergic Plasticity.

For many decades, synaptic plasticity was believed to be restricted to excitatory transmission. However, in recent years, this view started to change, and now it is recognized that GABAergic synapses show distinct forms of activity-dependent long-term plasticity, but the underlying mechanisms remain obscure. Herein, we asked whether signaling mediated by β1 or β3 subunit-containing integrins might be involved in regulating the efficacy of GABAergic synapses, including the NMDA receptor-dependent inhibitory long-term potentiation (iLTP) in the hippocampus. We found that activation of β3 integrin with fibrinogen induced a stable depression, whereas inhibition of β1 integrin potentiated GABAergic synapses at CA1 pyramidal neurons in male mice. Additionally, compounds that interfere with the interaction of β1 or β3 integrins with extracellular matrix blocked the induction of NMDA-iLTP. In conclusion, we provide the first evidence that integrins are key players in regulating the endogenous modulatory mechanisms of GABAergic inhibition and plasticity in the hippocampus.SIGNIFICANCE STATEMENT Epilepsy, schizophrenia, and anxiety are just a few medical conditions associated with dysfunctional inhibitory synaptic transmission. GABAergic synapses are known for their extraordinary susceptibility to modulation by endogenous factors and exogenous pharmacological agents. We describe here that integrins, adhesion proteins, play a key role in the modulation of inhibitory synaptic transmission. Specifically, we show that interference with integrin-dependent adhesion results in a variety of effects on the amplitude and frequency of GABAergic mIPSCs. Activation of β3 subunit-containing integrins induces inhibitory long-term depression, whereas the inhibition of β1 subunit-containing integrins induces iLTP. Our results unveil an important mechanism controlling synaptic inhibition, which opens new avenues into the usage of integrin-aimed pharmaceuticals as modulators of GABAergic synapses.

Racial and ethnic differences in COVID-19 outcomes: a call to action.

Racial and ethnic differences in COVID-19 outcomes: a call to action.

Real clinical practice of complicated Crohn’s disease treatment with ustekinumab: clinical case presentation

Crohn’s disease (CD) is a severe immune-mediated disease with segmental transmural inflammation and ulcers in gastrointestinal tract most often in terminal ileum and colon. The disease is often associated with severe complications such as fistulas and strictures that require aggressive treatment or surgery. CD treatment remains the unresolved and one of the most serious problems in gastroenterology. Glucocorticosteroids (GCS) are the essential treatment options for many years but unfortunately the frequency of steroid resistance and steroid dependence are constantly increasing. In the cases of steroid refractory CD treatment options include biologics of different classes: tumour necrosis factor alfa - inhibitors (iTNF-α), α4β7 integrin inhibitor (vedolizumab), IL-12/23 inhibitor (ustekinumab). Any of these drugs can be used in bio-naïve CD patients, however secondary loss of response was noted for all biologics over time.In the cases of the first line treatment failure the problem of correct choice of the second and subsequent lines of biologics appears, since some biologics may show lower efficacy in the second line of treatment. Real clinical practice will allow us to make a more correct choice of next biologic. Ustekinumab, a human interleukin -12/23 monoclonal antibody is one of biologics that is highly effective in the first-line CD therapy and remains effective in the subsequent lines of treatment. We present a clinical case of complicated CD in young female with negative disease prognosis and loss of response to three iTNF-α. In this case the high efficacy of ustekinumab after multiple iTNF-α failure was demonstrated.

Integrins in cardiac fibrosis

For the last 20 years, integrins have been a therapeutic target of interest in the treatment of fibrotic diseases, particularly regarding the integrins of the αV family. Initially developed as anti-cancer drugs but with modest benefits, inhibitors of integrins (such as the anti-αV cilengitide) have shown interesting anti-fibrotic effects in different organs including the heart. Cardiac fibrosis is defined as an accumulation of stiff extracellular matrix in the myocardium, and ultimately leads to heart failure, one of the leading causes of mortality worldwide. Understanding the determinants of cardiac fibrosis and the involvement of integrins is a major matter of public health. This review presents the current knowledge on the different types of cardiac fibrosis and their etiologies, and report on first data supporting specific integrin inhibition therapy as a novel anti-fibrotic strategy, in particular to treat cardiac fibrosis.

D-dimer and CoV-2 spike-immune complexes contribute to the production of PGE2 and proinflammatory cytokines in monocytes.

An overreactive inflammatory response and coagulopathy are observed in patients with severe form of COVID-19. Since increased levels of D-dimer (DD) are associated with coagulopathy in COVID-19, we explored whether DD contributes to the aberrant cytokine responses. Here we show that treatment of healthy human monocytes with DD induced a dose dependent increase in production of pyrogenic mediator, Prostaglandin E2 (PGE2) and inflammatory cytokines, IL-6 and IL-8. The DD-induced PGE2 and inflammatory cytokines were enhanced significantly by co-treatment with immune complexes (IC) of SARS CoV-2 recombinant S protein or of pseudovirus containing SARS CoV-2 S protein (PVCoV-2) coated with spike-specific chimeric monoclonal antibody (MAb) containing mouse variable and human Fc regions. The production of PGE2 and cytokines in monocytes activated with DD and ICs was sensitive to the inhibitors of β2 integrin and FcγRIIa, and to the inhibitors of calcium signaling, Mitogen-Activated Protein Kinase (MAPK) pathway, and tyrosine-protein kinase. Importantly, strong increase in PGE2 and in IL-6/IL-8/IL-1β cytokines was observed in monocytes activated with DD in the presence of IC of PVCoV-2 coated with plasma from hospitalized COVID-19 patients but not from healthy donors. The IC of PVCoV-2 with convalescent plasma induced much lower levels of PGE2 and cytokines compared with plasma from hospitalized COVID-19 patients. PGE2 and IL-6/IL-8 cytokines produced in monocytes activated with plasma-containing IC, correlated well with the levels of spike binding antibodies and not with neutralizing antibody titers. Our study suggests that a combination of high levels of DD and high titers of spike-binding antibodies that can form IC with SARS CoV-2 viral particles might accelerate the inflammatory status of lung infiltrating monocytes leading to increased lung pathology in patients with severe form of COVID-19.

Inhibiting the β1integrin subunit increases the strain threshold for neuronal dysfunction under tensile loading in collagen gels mimicking innervated ligaments.

Stretch injury of the facet capsular ligament is a cause of neck pain, inducing axonal injury, neuronal hyperexcitability, and upregulation of pain neuromodulators. Although thresholds for pain and collagen reorganization have been defined and integrins can modulate pain signaling with joint trauma, little is known about the role of integrin signaling in neuronal dysfunction from tensile loading of the innervated capsular ligament. Using a well-characterized biomimetic collagen gel model of the capsular ligament's microstructure and innervation, this study evaluated extrasynpatic expression of N-Methyl-D-Aspartate receptor subtype 2B (NR2B) as a measure of neuronal dysfunction following tensile loading and determined mechanical thresholds for its upregulation in primary sensory neurons, with and without integrin inhibition. Collagen gels with dissociated dorsal root ganglion neurons (n = 16) were fabricated; a subset of gels (n = 8) was treated with the β1 integrin subunit inhibitor, TC-I15. Gels were stretched to failure in tension and then immunolabeled for axonal NR2B. Inhibiting the integrin subunit does not change the failure force (p = 0.12) or displacement (p = 0.44) but does reduce expression of the β1 subunit by 41% (p < 0.001) and decrease axonal NR2B expression after stretch (p = 0.018). Logistic regressions estimating the maximum principal strain threshold for neuronal dysfunction as evaluated by Analysis of Covariance determine that integrin inhibition increases (p = 0.029) the 50th percentile strain threshold (7.1%) above the threshold for upregulation in untreated gels (6.2%). These results suggest that integrin contributes to stretch-induced neuronal dysfunction via neuron-integrin-collagen interactions.

Substrate Stiffness Determines the Establishment of Apical-Basal Polarization in Renal Epithelial Cells but Not in Tubuloid-Derived Cells.

Mechanical guidance of tissue morphogenesis is an emerging method of regenerative medicine that can be employed to steer functional kidney architecture for the purpose of bioartificial kidney design or renal tissue engineering strategies. In kidney morphogenesis, apical-basal polarization of renal epithelial cells is paramount for tubule formation and subsequent tissue functions like excretion and resorption. In kidney epithelium, polarization is initiated by integrin-mediated cell-matrix adhesion at the cell membrane. Cellular mechanobiology research has indicated that this integrin-mediated adhesion is responsive to matrix stiffness, raising the possibility to use matrix stiffness as a handle to steer cell polarization. Herein, we evaluate apical-basal polarization in response to 2D substates of different stiffness (1, 10, 50 kPa and glass) in Madin Darby Canine Kidney cells (MDCKs), a classic canine-derived cell model of epithelial polarization, and in tubuloid-derived cells, established from human primary cells derived from adult kidney tissue. Our results show that sub-physiological (1 kPa) substrate stiffness with low integrin-based adhesion induces polarization in MDCKs, while MDCKs on supraphysiological (>10 kPa) stiffness remain unpolarized. Inhibition of integrin, indeed, allows for polarization on the supraphysiological substrates, suggesting that increased cellular adhesion on stiff substrates opposes polarization. In contrast, tubuloid-derived cells do not establish apical-basal polarization on 2D substrates, irrespective of substrate stiffness, despite their ability to polarize in 3D environments. Further analysis implies that the 2D cultured tubuloid-derived cells have a diminished mechanosensitive capacity when presented with different substrate stiffnesses due to immature focal adhesions and the absence of a connection between focal adhesions and the cytoskeleton. Overall, this study demonstrates that apical-basal polarization is a complex process, where cell type, the extracellular environment, and both the mechanical and chemical aspects in cell-matrix interactions performed by integrins play a role.

Effects of human TFPI and CD47 expression and selectin and integrin inhibition during GalTKO.hCD46 pig lung perfusion with human blood.

Loss of barrier function when GalTKO.hCD46 porcine lungs are perfused with human blood is associated with coagulation pathway dysregulation, innate immune system activation, and rapid sequestration of human formed blood elements. Here, we evaluate whether genetic expression of human tissue factor pathway inhibitor (hTFPI) and human CD47 (hCD47), alone or with combined selectin and integrin adhesion pathway inhibitors, delays GalTKO.hCD46 porcine lung injury or modulates neutrophil and platelet sequestration. In a well-established paired ex vivo lung perfusion model, GalTKO.hCD46.hTFPI.hCD47 transgenic porcine lungs (hTFPI.hCD47, n=7) were compared to GalTKO.hCD46 lungs (reference, n=5). All lung donor pigs were treated with a thromboxane synthase inhibitor, anti-histamine, and anti-GPIb integrin-blocking Fab, and were pre-treated with Desmopressin. In both genotypes, one lung of each pair was additionally treated with PSGL-1 and GMI-1271 (P- and E-selectin) and IB4 (CD11b/18 integrin) adhesion inhibitors (n=6 hTFPI.hCD47, n=3 reference). All except for two reference lungs did not fail within 480 min when experiments were electively terminated. Selectin and integrin adhesion inhibitors moderately attenuated initial pulmonary vascular resistance (PVR) elevation in hTFPI.hCD47 lungs. Neutrophil sequestration was significantly delayed during the early time points following reperfusion and terminal platelet activation was attenuated in association with lungs expressing hTFPI.hCD47, but additional adhesion pathway inhibitors did not show further effects with either lung genotype. Expression of hTFPI.hCD47 on porcine lung may be useful as part of an integrated strategy to prevent neutrophil adhesion and platelet activation that are associated with xenograft injury. Additionally, targeting canonical selectin and integrin adhesion pathways reduced PVR elevation associated with hTFPI.hCD47 expression, but did not significantly attenuate neutrophil or platelet sequestration. We conclude that other adhesive mechanisms mediate the residual sequestration of human formed blood elements to pig endothelium that occurs even in the context of the multiple genetic modifications and drug treatments tested here.

The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNFα, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo, as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.

Update on immunosuppressive strategies in intestinal transplantation.

The intestine is the most immunologically complex solid organ allograft with the greatest risk of both rejection and graft-versus-host disease (GVHD). High levels of immunosuppression are required, further increasing morbidity. Due to low volume of transplants and few centers with experience, there is paucity of evidence-based, standardized, and effective therapeutic regimens. We herein review the most recent data about immunosuppression, focusing on novel and emerging therapies. Recent data are moving the field toward increasing use of basilixumab and consideration of alemtuzumab for induction and inclusion of mammalian target of rapamycin inhibitors and antimetabolites for maintenance. For rejection, we highlight novel roles for tumor necrosis factor-α inhibition, α4β7 integrin inhibition, microbiome modulation, desensitization protocols, and tolerance induction strategies. We also highlight emerging novel therapies for GVHD, especially the promising role of Janus kinase inhibition. New insights into immune pathways associated with rejection and GVHD in intestinal allografts have led to an evolution of therapies from broad-based immunosuppression to more targeted strategies that hold promise for reducing morbidity from infection, rejection, and GVHD. These should be the focus of further study to facilitate their widespread use.

Integrins as a drug target in liver fibrosis.

As the worldwide prevalence of chronic liver diseases is high and continuing to increase, there is an urgent need for treatment to prevent cirrhosis-related morbidity and mortality. Integrins are heterodimeric cell-surface proteins that are promising targets for therapeutic intervention. αv integrins are central in the development of fibrosis as they activate latent TGFβ, a known profibrogenic cytokine. The αv subunit can form heterodimers with β1, β3, β5, β6 or β8 subunits and one or more of these integrins are central to the development of liver fibrosis, however, their relative importance is not understood. This review summarises the current knowledge of αv integrins and their respective β subunits in different organs, with a focus on liver fibrosis and the emerging preclinical and clinical data with regards to αv integrin inhibitors.