InVivoMAb anti-mouse/human/rat/ monkey/hamster/canine/bovine TGF-β

Peritoneal fibrosis is a common complication in peritoneal dialysis (PD) patients, which results in ultrafiltration failure (UFF) and PD withdrawal. PD patients demonstrate altered structural and functional profiles of the gut microbiota. Herein, we investigated the role of the gut microbiota and trimethylamine N-oxide (TMAO), a bacterial metabolite, in the pathogenesis of PD-associated peritoneal fibrosis. PD mice displayed mesenchymal transition features and fibrosis in the peritoneum, which were accompanied by an altered gut microbiota profile and elevated serum TMAO levels, and these peritoneal histologic abnormalities were ameliorated by gut microbiota depletion. Fecal microbiota transplantation (FMT) from PD patients induced mesenchymal and fibrotic alterations within the peritoneum of wild-type mice, and the effect was more pronounced in mice receiving FMT from PD patients with UFF. Intraperitoneal supplementation with TMAO enhanced PD-induced peritoneal fibrosis in wild-type mice. On the contrary, PD- or FMT-induced mesenchymal features and fibrosis within the peritoneal membrane were lessened in flavin-containing monooxygenase 3 gene knockout mice, which were incapable of synthesizing TMAO. TMAO treatment enhanced high glucose-mediated phenotypic transition and fibrogenesis in cultured peritoneal mesothelial cells and fibroblasts, partly by increasing TGF-β1 synthesis and secretion and subsequent phosphorylation of Smad2/3 and activation of the Wnt/β-catenin pathway. Collectively, we found that altered gut microbiota plays an important role in the development of PD-associated peritoneal fibrosis through dysregulated production of the bacterial metabolite TMAO.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by aberrant germinal center (GC) reactions and autoantibody production. Expansion of T follicular helper (TFH) cells is a hallmark of SLE that contributes to disease progression. Accordingly, TFH cells represent a promising therapeutic target for SLE. Here, we repurposed obeticholic acid (OCA), an FDA-approved drug for primary biliary cholangitis, as a potential treatment for SLE. OCA selectively inhibited the differentiation of TFH cells both in vitro and in vivo by suppressing the transcription factor ETV5, thereby downregulating SPP1, a key ETV5 target that promotes the development of TFH cells. In lupus-prone mice, OCA treatment reduced TFH- and GC B-cell populations and alleviated lupus-like manifestations, including autoantibody production and tissue pathology. These findings highlight OCA as a promising immunomodulatory candidate for SLE, providing avenues for devising a therapeutic strategy targeting the TFH cell-GC axis in systemic autoimmunity.

Glioblastoma (GBM) is immunologically cold and responds poorly to immune-based therapies owing to its highly heterogeneous and immunosuppressive tumor microenvironment (TME). However, strategies to achieve a cold-to-hot transition remain elusive, and suitable research models are still lacking. Here, TME profiling classifies our refractory G422TN-GBM model as the TMEMed (heterogeneous immune populations, "cold") subtype of human GBM, which can be shifted toward the TMEHigh (immune-high, "hot") subtype by inhibiting TGF-β signaling. In the multi-drug regimen, only αTGF-β combining temozolomide chemoradiotherapy and αPD-1 achieves immune-cure (ICu, passing tumor rechallenge, 12.5%). ICu screening reveals a newly identified Csmd3+ microglial subset with innate immune memory potential, which likely initiates durable anti-GBM immune memory and closely associates with effective GBM therapy and favorable prognosis. MGOE•Csmd3, BV2 (Csmd3-overexpressed microglial BV2) elicit robust anti-GBM effects and achieve a notably 100% tumor rechallenge success in G422TN-GBM mice via promoting TMEMed-to-TMEHigh remodeling. Taken together, our findings identify an immunologically cold TMEMed GBM mouse model and provide a proof-of-concept for microglia-based TME reprogramming and cell therapy in GBM.

The efficacy of immune checkpoint blockade (ICB) is heterogeneous across patients. Tumour immune phenotype classification (immune-inflamed, -excluded, and -desert) represents a foundational but inadequate framework for predicting ICB efficacy. Here we aimed to develop an integrated immunogenomic classification to improve ICB response prediction and identify subtype-specific therapeutic vulnerabilities.