Anti-hCD20 Antibody Ameliorates Murine PBC

There is considerable interest in expanding B cell-targeted therapies in human autoimmune diseases. However, clinical trials in human primary biliary cholangitis (PBC) using a chimeric antibody against human CD20 (hCD20) have showed limited efficacy. Two potential explanations for these disappointing results are the appearance of anti-drug antibodies (ADAs) and the high frequency of patients with moderate PBC or patients who had failed ursodeoxycholic acid treatment. Here, we studied a novel humanized IgG1 antibody against hCD20 and explored its efficacy in early stage PBC using a well-defined murine model. We developed a unique murine model consisting of dnTGF-bRII mice expressing hCD20 and human Fcg receptors (hFcγRs). Beginning at 4–6 weeks of age, equivalent to stage I/II human PBC, female mice were given weekly injections of an anti-hCD20 antibody (TKM-011) or vehicle control, and monitored for liver histology as well as a broad panel of immunological readouts. After 16 weeks’ treatment, we observed a significant reduction in portal inflammation, a decrease in liver-infiltrating mononuclear cells as well as a reduction in liver CD8+ T cells. Importantly, direct correlations between numbers of liver non-B cells and B cells (r = 0.7426, p = 0.0006) and between numbers of liver memory CD8+ T cells and B cells (r = 0.6423, p = 0.0054) were apparent. Accompanying these changes was a dramatic reduction in anti-mitochondrial antibodies (AMAs), interleukin (IL)-12p40 and IL-5, and elevated levels of the anti-inflammatory chemokine CXCL1/KC. In mice that developed ADAs, clinical improvements were less pronounced. Sustained treatment with B cell-targeted therapies may broadly inhibit effector pathways in PBC, but may need to be administered early in the natural history of PBC

Anti-drug Antibodies Against a Novel Humanized Anti-CD20 Antibody Impair Its Therapeutic Effect on Primary Biliary Cholangitis in Human CD20- and FcγR-Expressing Mice

There is considerable interest in expanding B cell-targeted therapies in human autoimmune diseases. However, clinical trials in human primary biliary cholangitis (PBC) using a chimeric antibody against human CD20 (hCD20) have showed limited efficacy. Two potential explanations for these disappointing results are the appearance of anti-drug antibodies (ADAs) and the high frequency of patients with moderate PBC or patients who had failed ursodeoxycholic acid treatment. Here, we studied a novel humanized IgG1 antibody against hCD20 and explored its efficacy in early stage PBC using a well-defined murine model. We developed a unique murine model consisting of dnTGF-βRII mice expressing hCD20 and human Fcγ receptors (hFcγRs). Beginning at 4–6 weeks of age, equivalent to stage I/II human PBC, female mice were given weekly injections of an anti-hCD20 antibody (TKM-011) or vehicle control, and monitored for liver histology as well as a broad panel of immunological readouts. After 16 weeks' treatment, we observed a significant reduction in portal inflammation, a decrease in liver-infiltrating mononuclear cells as well as a reduction in liver CD8+ T cells. Importantly, direct correlations between numbers of liver non-B cells and B cells (r = 0.7426, p = 0.0006) and between numbers of liver memory CD8+ T cells and B cells (r = 0.6423, p = 0.0054) were apparent. Accompanying these changes was a dramatic reduction in anti-mitochondrial antibodies (AMAs), interleukin (IL)-12p40 and IL-5, and elevated levels of the anti-inflammatory chemokine CXCL1/KC. In mice that developed ADAs, clinical improvements were less pronounced. Sustained treatment with B cell-targeted therapies may broadly inhibit effector pathways in PBC, but may need to be administered early in the natural history of PBC

Influencing Indicators and Quantitative Assessment of Water Resources Security in Karst Region Based on PSER Model—The Case of Guizhou

An important basis to achieve a sustainable balance between water availability and demand is effectively identifying the factors affecting water resource security and evaluating the effectiveness of existing water resource management measures. To reasonably evaluate water resource security in Guizhou Province, this study combined the water resource security features, selected the indicator system based on the Press–Status–Effect–Response (PSER) framework, and used Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) and grey correlation analysis for the province from 2001 to 2015. This allowed us to identify the main driving factors affecting water resource security. The results showed that: (1) Water resource security in Guizhou Province showed an overall trend of improvement from 2001 to 2015 and reached a maximum index of 0.57 in 2015. This amelioration in water security was mainly due to the continuous improvement of the response and effect subgroup as a result of improvements in its existing subgroup factors (policies), such as water consumption per unit of gross domestic product (GDP), the proportion of water conservancy investment, and the proportion of the tertiary industry. Increased water stress due to rapid economic development, such as water supply for the reservoir, and the instability of the status subgroup, were the main factors negatively affecting water resource security. (2) Reduction of water consumption per USD of industrial value added, the control force of water and soil erosion being strengthened, and investment in water resources being increased, are the key factors for achieving water resource security in Guizhou during this period of rapid social and economic development. This indicates that the existing water resource management measures have been improving water resource security. The management measures need to be further improved in the future to protect water resource

Evaluating Water Resource Security in Karst Areas Using DPSIRM Modeling, Gray Correlation, and Matter–Element Analysis

To evaluate the long-term security of water resources in Guizhou, this paper presents an evaluation index that incorporates the driving force–pressure–state–impact–response–management (DPSIRM) framework, the gray correlation method, and matter–element analysis. For the period of 2005–2012, our results show that water resources were within the “generally safe” limits for all years except 2006 and 2011, which were characterized by drought conditions. In karst regions, drought has a relatively large impact on water security and is compounded in Guizhou by rapid economic development, nonpoint-source agricultural pollution, and inadequate sewage treatment. Nonetheless, recent efforts to return farmland to forest and grassland and to control desertification have led to increased forest cover and higher levels of soil and water conservation, while systems have been implemented to foster the effective management of water resources in karst areas. In this study, we used both gray matter–element analysis and a DPSIRM framework to assess the state of water resources in Guizhou, the results of which were compared and verified by the gray set pair method, and to provide a reference for evaluating other karst areas

Access to enantioenriched compounds bearing challenging tetrasubstituted stereocenters via kinetic resolution of auxiliary adjacent alcohols

A large number of enantiopure substances, such as those with tetrasubstituted carbon centres bearing several similar substituents, are inaccessible due to the incapability of chiral catalysts/ligands to recognize those substrates. Here, the authors develop kinetic resolution of auxiliary adjacent alcohols (KRA*) strategy to access various optically enriched compounds with two, three or four spatially and electronically similar groups

Ninjurin 2, a Cell Adhesion Molecule and a Target of p53, Modulates Wild-Type p53 in Growth Suppression and Mutant p53 in Growth Promotion

The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. However, the biology of NINJ2 has not been well-explored. By using multiple in vitro cell lines and genetically engineered mouse embryo fibroblasts (MEFs), we showed that NINJ2 is induced by DNA damage in a p53-dependent manner. Moreover, we found that the loss of NINJ2 promotes p53 expression via mRNA translation and leads to growth suppression in wild-type p53-expressing MCF7 and Molt4 cells and premature senescence in MEFs in a wild-type p53-dependent manner. Interestingly, NINJ2 also regulates mutant p53 expression, and the loss of NINJ2 promotes cell growth and migration in mutant p53-expressing MIA-PaCa2 cells. Together, these data indicate that the mutual regulation between NINJ2 and p53 represents a negative feedback loop, and the NINJ2-p53 loop has opposing functions in wild-type p53-dependent growth suppression and mutant p53-dependent growth promotion

Mutated Pkhd1 alone is sufficient to cause autoimmune biliary disease on the nonobese diabetic (NOD) genetic background

We previously reported that nonobese diabetic (NOD) congenic mice (NOD.c3c4 mice) developed an autoimmune biliary disease (ABD) with similarities to human primary biliary cholangitis (PBC), including anti-mitochondrial antibodies and organ-specific biliary lymphocytic infiltrates. We narrowed the possible contributory regions in a novel NOD.Abd3 congenic mouse to a B10 congenic region on chromosome 1 ("Abd3") and a mutated Pkhd1 gene (Pkhd1del36-67) upstream from Abd3, and we showed via backcrossing studies that the NOD genetic background was necessary for disease. Here, we show that NOD.Abd3 mice develop anti-PDC-E2 autoantibodies at high levels, and that placing the chromosome 1 interval onto a scid background eliminates disease, demonstrating the critical role of the adaptive immune system in pathogenesis. While the NOD genetic background is essential for disease, it was still unclear which of the two regions in the Abd3 locus were necessary and sufficient for disease. Here, using a classic recombinant breeding approach, we prove that the mutated Pkhd1del36-67 alone, on the NOD background, causes ABD. Further characterization of the mutant sequence demonstrated that the Pkhd1 gene is disrupted by an ETnII-beta retrotransposon inserted in intron 35 in an anti-sense orientation. Homozygous Pkhd1 mutations significantly affect viability, with the offspring skewed away from a Mendelian distribution towards NOD Pkhd1 homozygous or heterozygous genotypes. Cell-specific abnormalities, on a susceptible genetic background, can therefore induce an organ-specific autoimmunity directed to the affected cells. Future work will aim to characterize how mutant Pkhd1 can cause such an autoimmune response

Antibody glycosylation in autoimmune diseases

The glycosylation of the fragment crystallizable (Fc) region of immunoglobulins (Ig) is critical for the modulation of antibody effects on inflammation. Moreover, antibody glycosylation may induce pathologic modifications and ultimately contribute to the development of autoimmune diseases. Thanks to progress in the analysis of glycosylation, more data are available on IgG and its subclass structures in the context of autoimmune diseases. In this review, we focused on the impact of Ig glycosylation in autoimmunity, describing how it modulates the immune response and how glycome profiles can be used as biomarkers of disease activity. The analysis of antibody glycosylation demonstrated specific features in human autoimmune and chronic inflammatory conditions, including rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease and autoimmune liver diseases, among others. Within the same disease, different patterns are associated with disease severity and treatment options. Future research may increase the information available on the distinct glycome profiles and expand their potential role as biomarkers and as targets for treatment, ultimately favoring an individualized approach