Effect of mTORC1/mTORC2 inhibition on T cell function: potential role in graft‐versus‐host disease control

Abstract

The mechanistic target of rapamycin (mTOR) pathway is crucial for the activation and function of T cells, which play an essential role in the development of graft-versus-host disease (GvHD). Despite its partial ability to block mTOR pathway, the mTORC1 inhibitor rapamycin has shown encouraging results in the control of GvHD. Therefore, we considered that simultaneous targeting of both mTORC1 and mTORC2 complexes could exert a more potent inhibition of T cell activation and, thus, could have utility in GvHD control. To assess this assumption, we have used the dual mTORC1/mTORC2 inhibitors CC214-1 and CC214-2. In vitro studies confirmed the superior ability of CC214-1 versus rapamycin to block mTORC1 and mTORC2 activity and to reduce T cell proliferation. Both drugs induced a similar decrease in Th1/Th2 cytokine secretion, but CC214-1 was more efficient in inhibiting naïve T cell activation and the expression of T-cell activation markers. In addition, CC214-1 induced specific tolerance against alloantigens, while preserving anti-cytomegalovirus response. Finally, in a mouse model of GvHD, the administration of CC214-2 significantly improved mice survival and decreased GvHD-induced damages. In conclusion, the current study shows, for the first time, the immunosuppressive ability of CC214-1 on T lymphocytes and illustrates the role of CC214-2 in the allogeneic transplantation setting as a possible GvHD prophylaxis agent.

Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression

“…It is notable that DLL1 correlated with MIT 1 year post-HTx for both study groups (n = 28, r = 0.40, P = .003) ( Figures 4D,E), and a similar finding was also found between DLL1 and PAV (r = 0.36, P = .057). T cell production of Th1/Th2 cytokines, 36 Figure S1B) in a pattern similar to DLL1 and sCD25, supporting a link between mTOR complex (mTORC) signaling and DLL1 release. T cell production of Th1/Th2 cytokines, 36 Figure S1B) in a pattern similar to DLL1 and sCD25, supporting a link between mTOR complex (mTORC) signaling and DLL1 release.…”

“…31 A total of 70 patients (CNI, n = 34; EVR, n = 36) with plasma collected at ≥3 timepoints: 7-11 weeks (i.e., baseline), 6 months, 1 year, and 3 years post-HTx, were included in the present follow-up substudy. The 2 regimens were initiated no later than the fifth postoperative day.…”

“…After the 1-year trial, immunosuppression was according to the investigator's preference, and the patients were reassessed at 3 years post-HTx. 31 A total of 70 patients (CNI, n = 34; EVR, n = 36) with plasma collected at ≥3 timepoints: 7-11 weeks (i.e., baseline), 6 months, 1 year, and 3 years post-HTx, were included in the present follow-up substudy.…”

“…E, correlation between maximal intimal thickness (MIT) and DLL1 mRNA 1 year after heart transplantation (showed as ln transformed values). Experiments were run in duplicates [Color figure can be viewed at wileyonlinelibrary.com]T cell production of Th1/Th2 cytokines,36 and it is important to note that the lower doses are relevant to targeted concentrations of EVR in the HTx patients (6-10 ng/mL in the SCHEDULE and 3-8 ng/mL in the NOCTET study). Stimulation of activated T cells with the mTOR inhibitor sirolimus, but not the CNI CsA, dampened the DLL1 and sCD25 release in a pattern similar to EVR, whereas CNI reduced sCD25 release dose dependently at 72 hours (Figure S2).…”

Glycolytic metabolism of pathogenic T cells enables early detection of GvHD by13C-MRI

“…Finally, therapeutic targeting of upregulated glycolysis is a promising strategy for modulating overactive immunity that characterizes GvHD and other T cell-mediated conditions. Multiple steps in the glycolytic pathway have already been inhibited to augment T cell function in auto-and alloimmune diseases 49,50,55,68,69 and 13 C-pyruvate imaging can be used to detect responses to glycolytic inhibitors 70,71 . Non-invasive and non-radioactive approaches to guide clinical decisions are needed, and this methodology offers a promising new tool for the post-HSCT setting.…”