Vaccination inhibits the human adenoviral transduction in a mouse keratoconjunctivitis model

Adenovirus infections are a major cause of epidemic keratoconjunctivitis (EKC), which can lead to corneal subepithelial infiltrates and multifocal corneal opacity. In the current study, we investigated the use of an E1/E3-deleted adenovirus serotype 5 (Ad5) vector as a vaccine administered intramuscularly (IM) or intranasally (IN) against subsequent challenges with a luciferase-expressing Ad5 (Ad5-Luci) vector via eyedrop. We evaluated the adaptive immune response to Ad5 vector vaccination and confirmed a robust polyfunctional CD8 T cell response in splenic cells. Neutralizing Ad5 antibodies were also measured in the sera of vaccinated mice as well as Ad5 antibody in the eye wash solutions. Upon challenge with Ad5-Luci vector 8 weeks post the primary immunization, transduction was significantly reduced by > 70% in the vaccinated mice, which was slightly better in IM- vs. that in IN-vaccinated animals. Resistance to subsequent challenge was observed 10 months post primary IM vaccination, with sustained reduction up to 60% in the Ad5-Luci vector transduction. Passive immunization of naive mice with antisera from IM to vaccinated mice subsequently challenged with the Ad5-Luci vector resulted in approximately 40% loss in transduction efficiency. Furthermore, the mice that received IM immunization with or without CD8 T cell depletion showed > 40% and 70% reductions, respectively, in Ad8 genomic copies after Ad8 topical challenge. We conclude that Ad-vector vaccination successfully induced an adaptive immune response that prevented subsequent Ad transduction in the cornea and conjunctiva-associated tissues in a mouse model of adenovirus keratoconjunctivitis, and that both cellular and humoral immunity play an important role in preventing Ad transduction.     

Measuring disease activity and response to treatment in rheumatoid arthritis

Introduction: Effective treatment of rheumatoid arthritis (RA) requires suppression of the underlying inflammation. Measurement of such inflammation, the disease activity, is mandatory to target treatment and maximize outcomes. However, this is not as straightforward as it may seem.

Areas covered: The many tools developed to measure disease activity in RA, from composite scores and patient-reported outcomes, to laboratory markers and imaging are discussed, with a focus on their utility in guiding therapy and assessing response. The complex issues in measuring disease activity in RA, whether in clinical trials or normal clinical practice, and in the context of national guidelines and recommendations, available time, and resources are considered.

Expert commentary: The key to effective management of RA is the rapid suppression of inflammation, ideally to remission, with maintenance of such remission. The aim is to prevent disability and maximize quality of life. Central to this is the ability to determine disease activity (potentially open to suppression) as opposed to damage (irreversible). A variety of measures are currently available, allowing better assessment of response to treatment. In the future, the development of predictive biomarkers allowing targeting of drugs may revolutionize this field and render the tools of today redundant.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

Germline gain-of-function MMP11 variant results in an aggressive form of colorectal cancer

Matrix metalloproteinase-11 (MMP11) is an enzyme with proteolytic activity against matrix and nonmatrix proteins. Although most MMPs are secreted as inactive proenzymes and are later activated extracellularly, MMP11 is activated intracellularly by furin within the constitutive secretory pathway. It is a key factor in physiological tissue remodeling and its alteration may play an important role in the progression of epithelial malignancies and other diseases. TCGA colon and colorectal adenocarcinoma data showed that upregulation of MMP11 expression correlates with tumorigenesis and malignancy. Here, we provide evidence that a germline variant in the MMP11 gene (NM_005940: c.232C>T; p.(Pro78Ser)), identified by whole exome sequencing, can increase the tumorigenic properties of colorectal cancer (CRC) cells. P78S is located in the prodomain region, which is responsible for blocking MMP11's protease activity. This variant was detected in the proband and all the cancer-affected family members analyzed, while it was not detected in healthy relatives. In silico analyses predict that P78S could have an impact on the activation of the enzyme. Furthermore, our in vitro analyses show that the expression of P78S in HCT116 cells increases tumor cell invasion and proliferation. In summary, our results show that this variant could modify the structure of the MMP11 prodomain, producing a premature or uncontrolled activation of the enzyme that may contribute to an early CRC onset in these patients. The study of this gene in other CRC cases will provide further information about its role in CRC development, which might improve patient treatment in the future.     

Vaccines and autoimmunity during the COVID-19 pandemic

To control the pandemic, efficient vaccines must be applied to the population, including patients with autoimmune diseases. Therefore, one can expect that coronavirus disease 2019 (COVID-19) vaccines may influence the underlying autoimmune processes in these patients. Additionally, it is essential to understand whether COVID-19 vaccines would be effective, safe, and provide long-lasting immunological protection and memory. However, the currently available and approved COVID-19 vaccines turned out to be safe, effective, and reliable in patients with autoimmune inflammatory and rheumatic diseases. Furthermore, most patients said they felt safer after getting vaccinations for COVID-19 and reported enhanced overall quality of life and psychological wellbeing. In general, the COVID-19 vaccines have been highly tolerated by autoimmune patients. Such findings might comfort patients who are reluctant to use COVID-19 vaccines and assist doctors in guiding their patients into receiving vaccinations more easily and quickly.     

B细胞介导的体液免疫应答在肝移植急性排斥反应中的作用

目前，国内外肝移植学界对肝移植术后急性排斥反应(AR)的机制阐释为T细胞介导的细胞免疫应答，但为获得长期生存仍需长期乃至终身服用免疫抑制剂。即使如此，临床上AR仍时有发生，并导致相当一部分受者移植肝功能丧失，更重要的是受者术后还受到感染、肿瘤和其他一系列不良反应及沉重经济负担的影响。因此，为肝移植AR机制提出新的理论解释，更全面深入阐明肝移植免疫排斥反应的内在机制，进而依据新的机制研制出新型免疫抑制剂已势在必行。本文就B细胞介导的体液免疫应答在肝移植AR中的作用作一综述。     

Detection of recombinant and endogenous mouse melatonin receptors by monoclonal antibodies targeting the C‐terminal domain

Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression, and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non‐24‐hour sleep‐wake disorders, and major depressive disorders. In mammals, two melatonin receptors (MTRs) exist, MT₁ and MT₂, belonging to the G protein‐coupled receptor (GPCR) superfamily. Similar to most other GPCRs, reliable antibodies recognizing melatonin receptors proved to be difficult to obtain. Here, we describe the development of the first monoclonal antibodies (mABs) for mouse MT₁ and MT₂. Purified antibodies were extensively characterized for specific reactivity with mouse, rat, and human MT₁ and MT₂ by Western blot, immunoprecipitation, immunofluorescence, and proximity ligation assay. Several mABs were specific for either mouse MT₁ or MT₂. None of the mABs cross‐reacted with rat MTRs, and some were able to react with human MTRs. The specificity of the selected mABs was validated by immunofluorescence microscopy in three established locations (retina, suprachiasmatic nuclei, pituitary gland) for MTR expression in mice using MTR‐KO mice as control. MT₂ expression was not detected in mouse insulinoma MIN6 cells or pancreatic beta‐cells. Collectively, we report the first monoclonal antibodies recognizing recombinant and native mouse melatonin receptors that will be valuable tools for future studies.