RESUMEN
The effect of age on outcomes after simultaneous pancreas-kidney transplantation (SPK) among type II diabetes (T2DM) recipients remains inconclusive. This study aimed to analyze the relationship between the age at time of transplantation and mortality, graft loss and metabolic profiles of T2DM SPK recipients. A retrospective cohort consisting of T2MD SPK recipients in a single transplant center was established. The baseline clinical characteristics and outcomes were collected and analyzed based on the age groups divided by 55-year-old. Time-to-event data analysis was performed using Kaplan-Meier method, and competing risk method was adopted to calculate the cumulative incidence of graft loss. A mixed regression model was applied to compare metabolic outcomes including glycated hemoglobin (HbA1c), fasting blood glucose, triglyceride, cholesterol, low-density lipoprotein, and higher estimated glomerular filtration rate (eGFR). 103 T2DM SPK recipients were included, of which 35 were > = 55 years old and 68 were < 55 years old. Baseline characteristics were comparable between age groups. The results indicated that comparable 5-year survival outcomes between groups with functioning grafts perioperatively. Additionally, no relationship of age with graft loss, complications and metabolic outcomes was detected.
RESUMEN
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.
