Elevated serum IL-21 levels are associated with stable immune status in kidney transplant recipients and a mouse model of kidney transplantation

Abstract

Allograft rejection after renal transplantation remains a challenge to overcome. Interleukin (IL)-21, a cytokine with pleiotropic effects, maintains immune homeostasis post-transplantation. Here, we report higher levels of IL-21 in kidney transplant recipients with non-rejection (NR) than in recipients with T cell-mediated rejection (TCMR, P < 0.001) and antibody-mediated rejection (ABMR, P = 0.005). We observed a negative correlation between IL-21 and creatinine (Cr) levels ( P = 0.016). The receiving operating characteristic (ROC) curve showed a promising diagnostic value of IL-21 to identify acute rejection with an area under the curve (AUC) of 0.822 ( P < 0.001). In contrast, exogenous administration of IL-21 accelerated acute rejection in a comparative translational kidney transplant (KT) mouse model. Reduced IL-21 levels in the peripheral blood were observed in KT mice after IL-21 injection. Further analysis revealed that increased IL-21 levels in the spleen induced proliferation of CD4+ T cells and CD19+ B cells after IL-21 treatment. Our findings suggest a critical function of IL-21 in kidney transplantation and the potential involvement of the IL-21/IL-21R pathway in acute rejection management.

Helper T Cell (CD4+) Targeted Tacrolimus Delivery Mediates Precise Suppression of Allogeneic Humoral Immunity

“…After presensitization with alloskin transplantation, transplanted allokidney from the same donor resulted in acute ABMR attack [ 38 ]. After 5 days of transplantation, we found marked linear circumferential C4d depositions on peritubular capillaries (CD34 + cells) in transplanted allografts ( Figure 3(a) ), consistent with findings from previous investigations on ABMR [ 39 ]. Weak C4d signals were found in isografts, and they correlate with complement activation and C5b-9 formation by ischemia/reperfusion injury during surgery [ 40 ].…”

Adenovirus-IL-10 relieves chronic rejection after mouse heart transplantation by inhibiting miR-155 and activating SOCS5

“…High IL-21 level has been found to maintain immune homeostasis after transplantation. [30] IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype after lung transplantation. [31] In heart transplantation model, allografts survival could be significantly prolonged in the IL-21R deficient recipients.…”

Extracorporeal Photopheresis Reduces Fibrotic and Inflammatory Transcriptomic Biological Marker of Chronic Antibody-mediated Kidney Rejection

“…Indeed, in a kidney transplant mouse model, injection of exogenous IL-21 increases C4d deposition, glomerulitis, tubulitis, and interstitial inflammation in the graft. 24 Lowering IL-21 could therefore be beneficial in cases of allograft rejection. Our results support this hypothesis as other B-cell markers, such as CD19 and PAX5 mRNA expressions were significantly decreased after ECP.…”

“…The anti-inflammatory effect of ECP was expected; after reinjection of apoptotic cells following their irradiation, ECP treatment is known to be associated with a switch from T helpers 1 (Th1) to Th2, an increase in Th1 cytokines and interleukin-12, a switch from dendritic cells 1 to 2, and it induces tolerance through induction of regulatory T cells. 24 This switch towards type 2 immune response could be a key to the regulation of tissue regeneration. 25 This anti-inflammatory effect could also have an impact on preventing the development of fibrotic lesions.…”