Relationship between anxiety sensitivity and post-traumatic stress symptoms in trauma-exposed adults: A meta-analysis.

Given the high rate of trauma exposure among the general population, it is important to delineate the risk factors for post-traumatic stress disorder (PTSD). While historically implicated in panic disorder, anxiety sensitivity is increasingly found to play a role in PTSD. The present review investigated the size of the relationship between anxiety sensitivity and PTSD symptoms among trauma exposed adults. A systematic search on multiple electronic databases (PTSDpubs, CINAHL, MEDLINE and PsycINFO) generated a total of 1025 records, among which 52 (n = 15173) met study inclusion criteria and were included in our random effects meta-analysis. Our results indicated a medium effect size (r = .46, 95% CI =.41,.50) for the relationship between anxiety sensitivity and PTSD symptoms. There was significant between-study heterogeneity. Furthermore, sub-group analyses revealed that study design (cross-sectional vs. longitudinal) may significantly moderate the association between anxiety sensitivity and PTSD severity. No moderation effect was found for assessment of PTSD through interview versus questionnaire, interpersonal versus non-interpersonal trauma, or low versus high study quality. Such patterns of results are consistent with cognitive models of PTSD. Clinical implications, strengths and limitations of the review were discussed.

The prevalence, latent structure and psychosocial and cognitive correlates of complex post-traumatic stress disorder in an adolescent community sample.

Complex PTSD has received growing attention in recent years. However, the validity, prevalence and risk factors of this diagnosis remain unclear. This study examined PTSD presentations in adolescents using diagnostic criteria and latent class analysis (LCA). It then explored the role of demographics factors, trauma history factors, psychopathology factors and cognitive factors in predicting different PTSD presentations. A cross-sectional data comprising self-report measures of 342 community adolescents (12-15 years) were collected and analysed. 2.3 %, 5.6 % and 10 % of adolescents met the criteria for PTSD, CPTSD and disturbances in self-organisation (DSO) respectively. A three-class model (healthy class, CPTSD class and DSO class) were generated from LCA. Adolescents with CPTSD were most likely to be female and endorsed the most overall trauma types, interpersonal trauma types, depression, anxiety and maladaptive cognitive processes, followed by adolescents with DSO and subsequently healthy adolescents. CPTSD appeared to be a more common presentation than PTSD among community adolescents. The relatively high prevalence of DSO is noteworthy and suggests that DSO is not necessarily accompanied by PTSD. Given the strong associations between CPTSD and cognitive processes implicated in PTSD, CPTSD as a construct might be conceptually similar to PTSD.

Mindfulness Awareness Is Associated With a Lower Risk of Anxiety and Depressive Symptoms in Older Adults With Neurocognitive Disorders.

Background: Apart from depressive disorders, there are great interests in adopting mindfulness based interventions (MBIs) for other mental health conditions. Depression and anxiety are common in people with neurocognitive disorders (NCD). The potential of MBIs as an adjuvant treatment in this cognitively at-risk group should be further explored. Objectives: The current study explored the association between depression and anxiety symptoms with dispositional mindfulness in older adults, and if same association stays in the context of cognitive impairment. Methods: The Hong Kong Mental Morbidity Survey for Older People (MMSOP) is an ongoing epidemiology study of the prevalence of neurocognitive and mental disorders in adults aged 60 years or over in Hong Kong. MMSOP evaluated cognitive function, psychiatric symptoms (Clinical Interview Schedule-revised, CIS-R), chronic physical disease burden, psychosocial support, and resilience factors, including dispositional mindfulness as measured by the Mindful Attention Awareness Scale (MAAS). We analyzed the impact of MAAS on CIS-R and potential moderation effects of mindfulness. Results: In March 2021, 1,218 community dwelling participants completed assessments. The mean age of the sample is 69.0 (SD 6.9) years. Eight hundred and two participants (65.7%) were not demented (CDR 0) and 391 (32%) and 25 (2%) were categorized as having mild NCD (CDR 0.5) and major NCD (CDR 1 or more), respectively. One hundred forty-three (11.7%) satisfied ICD-10 criteria for anxiety or depressive disorder as measured by CIS-R. Linear regression analysis showed that female gender, CIRS, and MAAS scores were significant factors associated with CIS-R scores. MAAS scores moderated and attenuated the impact CIRS on CIS-R (adjusted R 2 = 0.447, p < 0.001). MAAS scores remained as significant moderator for CIRS in patients with NCD (CDR ≥ 0.5) (adjusted R 2 = 0.33, p < 0.001). Conclusion: Interim findings of the MMSOP suggested that dispositional mindfulness is associated with lower level of mood symptoms in community dwelling older adults in Hong Kong. The interaction effects further suggested that high mindful awareness may reduce the adverse effects of chronic physical morbidity on mental health. The observation stayed in the participants with cognitive impairment. We should further explore MBIs as a non-pharmacological treatment for in older adults at-risk of physical morbidity and cognitive decline.

Targeted IgMs agonize ocular targets with extended vitreal exposure.

Treatment of ocular disease is hindered by the presence of the blood-retinal barrier, which restricts access of systemic drugs to the eye. Intravitreal injections bypass this barrier, delivering high concentrations of drug to the targeted tissue. However, the recommended dosing interval for approved biologics is typically 6-12 weeks, and frequent travel to the physician's office poses a substantial burden for elderly patients with poor vision. Real-world data suggest that many patients are under-treated. Here, we investigate IgMs as a novel platform for treating ocular disease. We show that IgMs are well-suited to ocular administration due to moderate viscosity, long ocular exposure, and rapid systemic clearance. The complement-dependent cytotoxicity of IgMs can be readily removed with a P436G mutation, reducing safety liabilities. Furthermore, dodecavalent binding of IgM hexamers can potently activate pathways implicated in the treatment of progressive blindness, including the Tie2 receptor tyrosine kinase signaling pathway for the treatment of diabetic macular edema, or the death receptor 4 tumor necrosis family receptor pathway for the treatment of wet age-related macular degeneration. Collectively, these data demonstrate the promise of IgMs as therapeutic agonists for treating progressive blindness.

PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer.

Inhibiting the programmed death-1 (PD-1) pathway is one of the most effective approaches to cancer immunotherapy, but its mechanistic basis remains incompletely understood. Binding of PD-1 to its ligand PD-L1 suppresses T-cell function in part by inhibiting CD28 signaling. Tumor cells and infiltrating myeloid cells can express PD-L1, with myeloid cells being of particular interest as they also express B7-1, a ligand for CD28 and PD-L1. Here we demonstrate that dendritic cells (DCs) represent a critical source of PD-L1, despite being vastly outnumbered by PD-L1+ macrophages. Deletion of PD-L1 in DCs, but not macrophages, greatly restricted tumor growth and led to enhanced antitumor CD8+ T-cell responses. Our data identify a unique role for DCs in the PD-L1-PD-1 regulatory axis and have implications for understanding the therapeutic mechanism of checkpoint blockade, which has long been assumed to reflect the reversal of T-cell exhaustion induced by PD-L1+ tumor cells.

Tetravalent biepitopic targeting enables intrinsic antibody agonism of tumor necrosis factor receptor superfamily members.

Agonism of members of the tumor necrosis factor receptor superfamily (TNFRSF) with monoclonal antibodies is of high therapeutic interest due to their role in immune regulation and cell proliferation. A major hurdle for pharmacologic activation of this receptor class is the requirement for high-order clustering, a mechanism that imposes a reliance in vivo on Fc receptor-mediated crosslinking. This extrinsic dependence represents a potential limitation of virtually the entire pipeline of agonist TNFRSF antibody drugs, of which none have thus far been approved or reached late-stage clinical trials. We show that tetravalent biepitopic targeting enables robust intrinsic antibody agonism for two members of this family, OX40 and DR5, that is superior to extrinsically crosslinked native parental antibodies. Tetravalent biepitopic anti-OX40 engagement co-stimulated OX40low cells, obviated the requirement for CD28 co-signal for T cell activation, and enabled superior pharmacodynamic activity relative to native IgG in a murine vaccination model. This work establishes a proof of concept for an engineering approach that addresses a major gap for the therapeutic activation of this important receptor class.

Cellular Mechanisms of Etrolizumab Treatment in Inflammatory Bowel Disease.

Background: Anti-integrin therapy is a new frontline strategy in the treatment of inflammatory bowel diseases (IBD). The anti-ß7 integrin antibody etrolizumab is currently being investigated for safety and efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in several phase III trials. Mechanistically, etrolizumab is known to block ß7 integrin ligand binding and reduces intestinal trafficking of ß7-expressing cells. Etrolizumab blocks ß7 integrin ligand binding and reduces ß7-positive lymphocyte migration and retention in the inflamed gut mucosa, but the exact mechanisms by which this inhibition occurs are not fully understood. Methods: Cellular effects of etrolizumab or etrolizumab surrogate antibody (etrolizumab-s) were investigated in cell culture models and analyzed by flow cytometry, fluorescence microscopy, ImageStream®, stimulated emission depletion (STED) microscopy and functional dynamic in vitro adhesion assays. Moreover, effects on α4ß7 integrin were compared with the pharmacodynamically similar antibody vedolizumab. Results: As demonstrated by several different approaches, etrolizumab and etrolizumab-s treatment led to internalization of ß7 integrin. This resulted in impaired dynamic adhesion to MAdCAM-1. Internalized ß7 integrin localized in endosomes and re-expression of ß7 was dependent on de novo protein synthesis. In vitro etrolizumab treatment did not lead to cellular activation or cytokine secretion and did not induce cytotoxicity. Internalization of α4ß7 integrin was increased with etrolizumab compared with vedolizumab. Discussion: Our data suggest that etrolizumab does not elicit secondary effector functions on the single cell level. Integrin internalization may be an important mechanism of action of etrolizumab, which might explain some but not all immunological effects observed with etrolizumab.

Corrigendum: A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action.

This corrects the article DOI: 10.1038/ncomms14234.

Tumour and host cell PD-L1 is required to mediate suppression of anti-tumour immunity in mice.

Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.

A broadly protective therapeutic antibody against influenza B virus with two mechanisms of action.

Influenza B virus (IBV) causes annual influenza epidemics around the world. Here we use an in vivo plasmablast enrichment technique to isolate a human monoclonal antibody, 46B8 that neutralizes all IBVs tested in vitro and protects mice against lethal challenge of all IBVs tested when administered 72 h post infection. 46B8 demonstrates a superior therapeutic benefit over Tamiflu and has an additive antiviral effect in combination with Tamiflu. 46B8 binds to a conserved epitope in the vestigial esterase domain of hemagglutinin (HA) and blocks HA-mediated membrane fusion. After passage of the B/Brisbane/60/2008 virus in the presence of 46B8, we isolated three resistant clones, all harbouring the same mutation (Ser301Phe) in HA that abolishes 46B8 binding to HA at low pH. Interestingly, 46B8 is still able to protect mice against lethal challenge of the mutant viruses, possibly owing to its ability to mediate antibody-dependent cellular cytotoxicity (ADCC).

Preclinical pharmacokinetics of MHAA4549A, a human monoclonal antibody to influenza A virus, and the prediction of its efficacious clinical dose for the treatment of patients hospitalized with influenza A.

MHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ∼2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively.

Preclinical pharmacokinetics, pharmacodynamics, tissue distribution, and tumor penetration of anti-PD-L1 monoclonal antibody, an immune checkpoint inhibitor.

MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development. The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg · kg(-1) and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg · kg(-1) were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined. The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above ∼ 0.5 µg · mL(-1). Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was ∼ 0.3; saturation of target-mediated uptake in non-tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent. The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.

The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.

Tumors constitute highly suppressive microenvironments in which infiltrating T cells are "exhausted" by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT's complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8(+) T cell-dependent responses.

An in vivo human-plasmablast enrichment technique allows rapid identification of therapeutic influenza A antibodies.

Recent advances enabling the cloning of human immunoglobulin G genes have proven effective for discovering monoclonal antibodies with therapeutic potential. However, these antibody-discovery methods are often arduous and identify only a few candidates from numerous antibody-secreting plasma cells or plasmablasts. We describe an in vivo enrichment technique that identifies broadly neutralizing human antibodies with high frequency. For this technique, human peripheral blood mononuclear cells from vaccinated donors are activated and enriched in an antigen-specific manner for the production of numerous antigen-specific plasmablasts. Using this technology, we identified four broadly neutralizing influenza A antibodies by screening only 840 human antibodies. Two of these antibodies neutralize every influenza A human isolate tested and perform better than the current anti-influenza A therapeutic, oseltamivir, in treating severe influenza infection in mice and ferrets. Furthermore, these antibodies elicit robust in vivo synergism when combined with oseltamivir, thus highlighting treatment strategies that could benefit influenza-infected patients.

Genetic deletion of JAM-C reveals a role in myeloid progenitor generation.

Hematopoietic stem cells (HSCs) have the capacity to self-renew and continuously differentiate into all blood cell lineages throughout life. At each branching point during differentiation, interactions with the environment are key in the generation of daughter cells with distinct fates. Here, we examined the role of the cell adhesion molecule JAM-C, a protein known to mediate cellular polarity during spermatogenesis, in hematopoiesis. We show that murine JAM-C is highly expressed on HSCs in the bone marrow (BM). Expression correlates with self-renewal, the highest being on long-term repopulating HSCs, and decreases with differentiation, which is maintained longest among myeloid committed progenitors. Inclusion of JAM-C as a sole marker on lineage-negative BM cells yields HSC enrichments and long-term multilineage reconstitution when transferred to lethally irradiated mice. Analysis of Jam-C-deficient mice showed that two-thirds die within 48 hours after birth. In the surviving animals, loss of Jam-C leads to an increase in myeloid progenitors and granulocytes in the BM. Stem cells and myeloid cells from fetal liver are normal in number and homing to the BM. These results provide evidence that JAM-C defines HSCs in the BM and that JAM-C plays a role in controlling myeloid progenitor generation in the BM.

Solid-phase synthesis of dual alpha4beta1/alpha4beta7 integrin antagonists: two scaffolds with overlapping pharmacophores.

Two structural classes of dual alpha4beta1/alpha4beta7 integrin antagonists were investigated via solid-phase parallel synthesis. Using an acylated amino acid backbone, lead compounds containing biphenylalanine or tyrosine carbamate scaffolds were optimized for inhibition of alpha4beta1/VCAM and alpha4beta7/MAdCAM. A comparison of the structure-activity relationships in the inhibition of the alpha4beta7/MAdCAM interaction for substituted amines employed in both scaffolds suggests a similar binding mode for the compounds.

Selective alpha4beta7 integrin antagonists and their potential as antiinflammatory agents.

The accumulation of leukocytes in various tissues contributes to the pathogenesis of numerous human autoimmune diseases. The integrin alpha4beta7, expressed on the surface of B and T lymphocytes, plays an essential role in lymphocyte trafficking throughout the gastrointestinal (GI) tract via interaction with its primary ligand, mucosal addressin cell adhesion molecule (MAdCAM). Elevated MAdCAM expression in the intestines and liver has been linked to GI-associated autoimmune disorders, including Crohn's disease, ulcerative colitis, and hepatitis C. Monoclonal antibodies that block the interaction of alpha4beta7 with MAdCAM inhibit lymphocyte homing to murine intestines without effecting migration to peripheral organs; this suggests that alpha4beta7-selective antagonists might be useful as GI specific antiinflammatory agents. Here, we report the discovery of highly potent and selective alpha4beta7 antagonists affinity selected from a random peptide-phage library. Subsequent optimization of initial peptide leads afforded alpha4beta7-selective heptapeptide inhibitors that competitively inhibit binding to MAdCAM in vitro and inhibit lymphocyte homing to murine intestines in vivo. Substitution of a single carboxylate moiety alters selectivity for alpha4beta7 by more than 500-fold to afford a potent and selective alpha4beta1 antagonist. The antagonists described here are the first peptides to demonstrate potency and selectivity for alpha4beta7 compared to other integrins.

Vascular endothelial-junctional adhesion molecule (VE-JAM)/JAM 2 interacts with T, NK, and dendritic cells through JAM 3.

Screening expressed sequence tag databases for endothelial-specific homologs to human junctional adhesion molecule (JAM) and A33-Ag, we identified a protein of 298 aa that represents the recently described vascular endothelial-JAM (VE-JAM)/JAM 2. We confirmed VE-JAM/JAM 2 expression to be restricted to the high endothelial venule of tonsil and lymph nodes, and we further expanded the localization to the endothelium of arterioles in and around inflammatory and tumor foci. In our functional characterizations of VE-JAM/JAM 2, we discovered that it can function as an adhesive ligand for the T cell line J45 and can interact with GM-CSF/IL-4-derived peripheral blood dendritic cells, circulating CD56(+) NK cells, circulating CD56(+)CD3(+) NK/T cells, and circulating CD56(+)CD3(+)CD8(+) cytolytic T cells. In the course of our studies, we also isolated and characterized the functional VE-JAM/JAM 2 receptor, which, upon cloning, turned out to be a submitted sequence representing JAM 3 (accession number NP 113658). With these understandings, we have characterized a protein-interacting pair that can be important in the role of T, NK, and dendritic cell trafficking and inflammation.