Cong Qiu Chu

Cell penetrating recombinant Foxp3 protein enhances Treg function and ameliorates arthritis.

Foxp3 is the master transcription factor for T regulatory (Treg) cell differentiation and function. This study aimed to test the therapeutic potential of cell penetrating recombinant Foxp3 protein in arthritis. Recombinant Foxp3 protein was fused to a cell penetrating polyarginine (Foxp3-11R) tag to facilitate intracellular transduction. In vitro Foxp3-11R treated CD4(+) T cells showed a 50% increase in suppressive function compared with control protein treated cells. Severity of arthritis in Foxp3-11R treated mice was significantly reduced compared with those treated with a control protein. CD4(+) T cells of lymph nodes and spleen from Foxp3-11R treated mice showed increased levels of Foxp3 expression compared with those of a control protein treated. These results demonstrated that Foxp3-11R can enhance T cell suppressive function and ameliorate experimental arthritis and suggest that cell penetrating recombinant Foxp3 is a potentially useful agent in therapy of arthritis.

Streptavidin Suppresses T Cell Activation and Inhibits IL-2 Production and CD25 Expression

Streptavidin is widely used as a detection tool in biology research because of its high affinity and specificity binding to biotin. Biotin-streptavidin system has also been explored for detection of infection and tumor in clinical medicine. Here, we show immunosuppressive property of streptavidin on T cell activation and proliferation. Upon CD3 and CD28 stimulation, CD4(+) T cells produce interleukin 2 (IL-2) and express IL-2 receptor α chain (CD25). Addition of streptavidin in T cell culture suppressed IL-2 synthesis and CD25 expression with no cytotoxicity. The immunosuppressive effect of streptavidin was reversed by excessive biotin. Conjugated to a single chain anti-CD7 variable fragment (scFvCD7), streptavidin was directly delivered to T cells and showed substantially more profound suppressive effect on T cell activation. These results suggest that streptavidin could potentially be used as a novel immunomodulator.

Do tumor necrosis factor inhibitors increase cancer risk in patients with chronic immune-mediated inflammatory disorders?

HighlightsTNFi are most commonly used in rheumatoid arthritis and inflammatory bowel diseases.TNFi is not associated with increased risks of overall cancer, lymphoma or melanoma.Inconsistent results among studies on risk in non‐melanoma skin cancer.Vigilance is advised in screening for risk factors for non‐melanoma skin cancer. ABSTRACT Inhibition of tumor necrosis factor (TNF) activity has profoundly changed the management of several immune‐mediated inflammatory diseases with great benefit for patients. The application of TNF inhibitors (TNFi), however, also brings a new concern, malignancy. We performed a systemic review to collect the studies reporting cancer incidences and risks in TNFi users regardless of indications. TNFi were most frequently used in treating patients with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). In RA patients without prior cancer history, the incidences of malignancies ranged from the lowest rate 0 per 1000 person‐years in etanercept users regarding lymphoma to the highest rate 35.62 per 1000 person‐years in adalimumab users on non‐melanoma skin cancer (NMSC), while in those patients with prior cancer history, the recurrent incidences of malignancies ranged from the lowest rate 5.05 per 1000 person‐years regarding melanoma to the highest rate 63.20 per 1000 person‐years on basal cell carcinoma (BCC) in TNFi users. In IBD patients, incidences ranged from 0 per 1000 person‐years in TNFi users on lymphoma to 34.0 per 1000 person‐years in infliximab users on overall cancer. However, these incidence rates of overall cancer, lymphoma and melanoma were not higher in comparison with those patients who were not treated with TNFi. Compared to general population, incidences of lymphoma were elevated in RA patients and rates of NMSC were higher in patients with psoriasis, RA and IBD. In conclusion, cancer incidences vary across different studies, indications, cancer types and studies with different individual TNFi. Treatment with TNFi is not associated with increased malignant risks of overall cancer, lymphoma or melanoma. Results of NMSC risk were inconsistent among studies. A latest prospective registry study demonstrated a small increased risk of squamous cell cancer in RA patients treated with TNFi (one additional case for every 1600 years of treatment experience). Further prospective studies are needed to verify whether TNFi users have higher NMSC risk than non‐TNFi users.

Superantigens induce IL-17 production from polarized Th1 clones

Differentiation of naïve CD4(+) T cells has been considered to be an irreversible event and, in particular, the plasticity is believed to be completely lost in Th1 subset in vitro after multiple stimulations. However, here we demonstrate that highly polarized myelin oligodendrocyte glycoprotein (MOG)- and herpes simples virus-specific Th1 clones were still capable of producing IL-17 upon superantigen stimulation. Anti-MHC class-II and anti-TCR αβ chains partially blocked superantigen-induced IL-17 production. These findings suggest that fully differentiated Th1 cells still have capability to produce cytokines of other Th subsets and production of IL-17 by MOG-specific Th1 cells may have implication in initiation and/or exacerbation of neurological autoimmune diseases.

Molecular probing of TNF: From identification of therapeutic target to guidance of therapy in inflammatory diseases.

Therapy by blocking tumor necrosis factor (TNF) activity is highly efficacious and profoundly changed the paradigm of several inflammatory diseases. However, a significant proportion of patients with inflammatory diseases do not respond to TNF inhibitors (TNFi). Prediction of therapeutic response is required for TNFi therapy. Isotope labeled anti-TNF antibodies or TNF receptor have been investigated to localize TNF production at inflammatory tissue in animal models and in patients with inflammatory diseases. The in vivo detection of TNF has been associated with treatment response. Recently, fluorophore labeled anti-TNF antibody in combination with confocal laser endomicroscopy in patients with Crohns disease yielded more accurate and quantitative in vivo detection of TNF in the diseased mucosa. More importantly, this method demonstrated high therapeutic predication value. Fluorophore labeled TNF binding aptamers in combination with modern imaging technology offers additional tools for in vivo TNF probing.

Regeneration of hyaline-like cartilage in situ with SOX9 stimulation of bone marrow-derived mesenchymal stem cells

Microfracture, a common procedure for treatment of cartilage injury, induces fibrocartilage repair by recruiting bone marrow derived mesenchymal stem cells (MSC) to the site of cartilage injury. However, fibrocartilage is inferior biomechanically to hyaline cartilage. SRY-type high-mobility group box-9 (SOX9) is a master regulator of chondrogenesis by promoting proliferation and differentiation of MSC into chondrocytes. In this study we aimed to test the therapeutic potential of cell penetrating recombinant SOX9 protein in regeneration of hyaline cartilage in situ at the site of cartilage injury. We generated a recombinant SOX9 protein which was fused with super positively charged green fluorescence protein (GFP) (scSOX9) to facilitate cell penetration. scSOX9 was able to induce chondrogenesis of bone marrow derived MSC in vitro. In a rabbit cartilage injury model, scSOX9 in combination with microfracture significantly improved quality of repaired cartilage as shown by macroscopic appearance. Histological analysis revealed that the reparative tissue induced by microfracture with scSOX9 had features of hyaline cartilage; and collagen type II to type I ratio was similar to that in normal cartilage. This short term in vivo study demonstrated that when administered at the site of microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage.