Intragraft Th17 Infiltrate Promotes Lymphoid Neogenesis and Hastens Clinical Chronic Rejection

Abstract

To evaluate the influence of intragraft inflammatory infiltrate on the course of chronic rejection, 11 human renal grafts, detransplanted for terminal failure, were analyzed. Samples were divided into two groups according to their graft survival (> or ≤8 y). In both groups, the main cell population infiltrating the graft interstitia was T lymphocytes. The extent of the lymphocytic infiltration and the distribution of naive and memory, CD4+ and CD8+ T cells, were similar in both groups. Although all types of Th polarization profiles can lead to terminal chronic rejection, a correlation between shorter graft survival and the presence of Th17 cells that produce IL-17 and IL-21 was observed. In contrast, grafts infiltrated by regulatory T cells survived significantly longer. The correlation between the expressions of activation-induced cytidine deaminase (the key enzyme of the germinal center reaction) and IL-21 suggests that Th17 could exert their deleterious effect by promoting lymphoid neogenesis, namely, the organization of inflammatory effectors into ectopic germinal centers in which a local humoral immune response is elicited. Further studies will determine whether Th17 infiltration can be used as a prognosis tool and whether theTh17 subset constitutes a therapeutic target for slowing down chronic rejection.

Th-17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell–Mediated Rejection

“…In cardiac and lung transplantation models, IL-17 deficiency is associated with high numbers of regulatory cells and prolonged graft survival (26) and activation of the Th17 pathway strongly promotes chronic rejection (27). In kidney transplantation, Th17 cells within the explanted kidney allograft are associated with rapidly progressing chronic rejection (28). The effect of this Th17-mediated response during acute rejection in recipients of a marginal kidney will require follow-up biopsies after the initial TCMR episode.…”

Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A

“…It has been shown that IL-17A-expressing CD4 + T cells, more than IFN-g-producing CD4 + Th1 cells, play an important role in rejection and vasculopathy in clinical solid organ transplantation [21][22][23]. Twelve-month transplant specimens from CsA-treated patients showed important mononuclear cell infiltrates in which IL-17A-producing CD4 + T cells were clearly evident, even in the absence of acute rejection criteria; this process was accompanied by fibrosis and hyaline material.…”

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…Through control of lymphoid chemokine production in epithelial and fibroblastic stromal cells, IL‐22 also drives lymphoid neogenesis in mice following salivary gland cannulation with adenovirus 23. Podoplanin and IL‐17 have also been linked with ectopic lymphoneogenesis in human diseases 21, 24, 25…”