Background: Clinical application of islet transplantation to treat type-1 diabetes has been limited by islet allograft destruction by both allogeneic and autoimmune diabetogenic T-cell responses. The current study aims at determining whether an anti- T-cell receptor (TCR) monoclonal antibody (mAb) has potential as a novel and potent induction immunotherapy for islet transplantation. Methods: We have investigated the therapeutic efficacy and mechanisms of action of anti-TCR therapy in four different murine models, which comprise either allo- or auto- immune responses alone or in combination. Results: The T-cell response to islet allografts was potently abrogated by a brief treatment with an anti-TCRβ mAb (clone H57-597), resulting in long-term survival (MST: 93.1±30.0 days compared to the untreated group: 15.6±1.7 days, p < 0.001) of BALB/c islet allografts in Streptozotocin-induced diabetic B6 mice. Moreover, transient anti-TCR treatment permanently prevented BALB/c skin allograft rejection on Rag1-/- B6 recipients that were reconstituted with Foxp3+ regulatory T-cell depleted B6 splenocytes, but did not impair the ability of the reconstituted cells to reject the later transplanted C3H skin allografts (transplanted at 120 days after BALB/c skin grafting). Transient anti-TCR treatment was also able to completely prevent diabetes onset in NOD.SCID.γc-/- mice that were transferred with lymphocytes from diabetic NOD mice. Next, transient anti-TCR treatment significantly prolonged the survival of transplanted BALB/c islets in overtly diabetic NOD mice (MST: 28.0±7.7 days vs. untreated group: 8.7±0.6 days; p < 0.05), a model in which there are both allogeneic and autoimmune diabetogenic T-cell responses to the transplanted islets. Conclusions: Overall, anti-TCR mAb induced peripheral tolerance to specific alloantigens even in the absence of Foxp3-expressing natural regulatory T-cells. These findings reveal the potential for using TCR-targeting mAbs as induction immunotherapy for islet transplantation.
Purpose:The aim of this study is to identify factors influencing BK viral clearance and graft outcomes for Polyomavirus BK-associated nephropathy (BKVAN). Methods:Between 2006 and 2013, we diagnosed BKVAN in 39 (7.9%) of 491 patients with transplant biopsies by simian virus 40 (SV40) staining and quantitative polymerase chain reaction(PCR) assay for BKV DNA load in urine and plasma and quantitative assay of urine cytology. At diagnosis, we either reduced cyclosporine A by 30%(n=1), or reduced tacrolimus(Tac) by 30%-50%(n=22), or switched from Tac to cyclosporine A (n=13), or switched from Tac to Rapamycin(n=3). Data from these 39 patients were analyzed for graft functional decline, graft loss, graft survival rate, the time for viral PCR reduction in plasma by 1 log(90%) (≤7weeks or >7weeks), and influence factors. Results:During 28.5 ± 25.3 months follow-up, the frequencies of any short-term(3 months after diagnosis) functional decline, any long-term functional decline, and graft loss were 25.6%, 33.3%, and 25.6% respectively.The 1-, 3-, 5- graft survival rate were 100%, 77.4%, and 61.2%. More extensive interstitial inflammation(OR 9.020, p=0.027), but not viral load in blood and urine, nor the creatinine at diagnosis correlated with worse creatinine at 3 months. Viral reduction by 1 log was rapid in 51.4% (≤7 weeks) and slow in 48.6% (>7 weeks). On long-term follow-up, rapid viral reduction was associated with stable graft function(94.7%), compared with slow viral reduction (44.4%, p=0.001). Tac treatment had a negative influence on viral reduction time(OR 8.20, p=0.023). Defining 1-log viral load reduction as an event, Tac compared with non- Tac was associated with slow viral reduction (P=0.044).Multivariate analysis showed that extensive interstitial inflammation (HR 19.0, p=0.020) at diagnosis and slow viral reduction(HR 30.3, p=0.009) were associated with long-term functional decline. Clearance of viremia(78.4%) was associated with better graft survival at 3 years (89.2% versus 15.0%, p<0.001).Conclusions:Tac treatment prolongs BK viral reduction time. The extent of interstitial inflammation and viral reduction time influence short and long-term graft outcomes in patients with BKVAN.
Slippery liquid-infused porous surfaces, emerging bio-inspired surfaces which have attracted widespread research interest over the past few years, have great potential in both corrosion protection and biofouling prevention.
Osteosarcoma is a malignant tumor originating from mesenchymal bone tissue, characterized by high malignancy and poor prognosis. Despite progress in comprehensive treatment approaches, the five-year survival rate remains largely unchanged, highlighting the need to clarify its underlying mechanisms and discover new therapeutic targets.
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