IL-21 Receptor Blockade Shifts the Follicular T Cell Balance and Reduces De Novo Donor-Specific Antibody Generation.

Donor-specific antibodies (DSAs) play a key role in chronic kidney allograft injury. Follicular T helper (Tfh) cells trigger the humoral alloimmune response and promote DSA generation, while T-follicular regulatory (Tfr) cells inhibit antibody production by suppressing Tfh and B cells. Interleukin (IL)-21 exerts a distinct effect on Tfh and Tfr. Here, we studied whether blocking IL-21R with anti-IL-21R monoclonal antibody (αIL-21R) changes the Tfh/Tfr balance and inhibits DSA generation. First, we investigated the impact of αIL-21R on CD4+ T cell proliferation and apoptosis. The results showed that αIL-21R did not have cytotoxic effects on CD4+ T cells. Next, we examined Tfh and regulatory T cells (Tregs) in an in vitro conditioned culture model. Naïve CD4+ T cells were isolated from 3-month-old C57BL/6 mice and cultured in Tfh differentiation inducing conditions in presence of αIL-21R or isotype IgG and differentiation was evaluated by CXCR5 expression, a key Tfh marker. αIL-21R significantly inhibited Tfh differentiation. In contrast, under Treg differentiation conditions, FOXP3 expression was inhibited by IL-21. Notably, αIL-21R rescued IL-21-inhibited Treg differentiation. For in vivo investigation, a fully mismatched skin transplantation model was utilized to trigger the humoral alloimmune response. Consistently, flow cytometry revealed a reduced Tfh/Tfr ratio in recipients treated with αIL-21R. Germinal center response was evaluated by flow cytometry and lectin histochemistry. We observed that αIL-21R significantly inhibited germinal center reaction. Most importantly, DSA levels after transplantation were significantly inhibited by αIL-21R at different time points. In summary, our results demonstrate that αIL-21R shifts the Tfh/Tfr balance toward DSA inhibition. Therefore, αIL-21R may be a useful therapeutic agent to prevent chronic antibody mediated rejection after organ transplantation.

Development and validation of CT imaging-based preoperative nomogram in the prediction of unfavorable high-grade small renal masses.

PURPOSE: In recent years, there has been an increase in the incidence of small renal masses (SRMs) and nephrectomy was the standard management of this disease in the past. Currently, the use of active surveillance has been recommended as an alternative option in the case of some patients with SRMs due to its heterogenicity. However, limited studies focused on the regarding risk stratification. Therefore, in the current study, we developed a nomogram for the purpose of predicting the presence of high-grade SRMs on the basis of the patient information provided (clinical information, hematological indicators, and CT imaging data). PATIENTS AND METHODS: A total of 329 patients (consisting of development and validation cohort) who had undergone nephrectomy for SRMs between January 2013 and May 2016 retrospectively were recruited for the present study. All preoperative information, including clinical predictors, hematological indicators, and CT predictors, were obtained. Lasso regression model was used for data dimension reduction and feature selection. Multivariable logistic regression analysis was applied for the establishment of the predicting model. The performance of the nomogram was assessed with respect to its calibration and discrimination properties and externally validated. RESULTS: The predictors used in the assessment of the nomogram included tumor size, CT tumor contour, CT necrosis, CT tumor exophytic properties, and CT collecting system oppression. Based on these parameters, the nomogram was evaluated to have an effective discrimination and calibration ability, and the C-index was found to be 0.883 after internal validation and 0.887 following external validation. CONCLUSION: Based on the aforementioned findings, it can be concluded that CT imaging-based preoperative nomogram is an effective predictor of SRMs and hence can be used in the preoperative evaluation of SRMs, due to its calibration and discrimination abilities.