Evaluation of the impact of conventional immunosuppressant on the establishment of murine transplantation tolerance – an experimental study

Abstract

Summary Regulatory T cells (Tregs) play a significant role in immune tolerance. Since Treg function deeply depends on Interleukin‐2 signaling, calcineurin inhibitors could affect their suppressive potentials, whereas mammalian target of rapamycin (mTOR) inhibitors may have less impact, as mTOR signaling is not fundamental to Treg proliferation. We previously reported a novel mixed hematopoietic chimerism induction regimen that promotes Treg proliferation by stimulating invariant natural killer T cells under CD40 blockade. Here, we use a mouse model to show the impact of tacrolimus (TAC) or everolimus (EVL) on the establishment of chimerism and Treg proliferation in the regimen. In the immunosuppressive drug‐dosing phase, peripheral blood chimerism was comparably enhanced by both TAC and EVL. After dosing was discontinued, TAC‐treated mice showed gradual graft rejection, whereas EVL‐treated mice sustained long‐term robust chimerism. Tregs of TAC‐treated mice showed lower expression of both Ki67 and cytotoxic T lymphocyte antigen‐4 (CTLA‐4), and lower suppressive activity in vitro than those of EVL‐treated mice, indicating that TAC negatively impacted the regimen by interfering with Treg proliferation and activation. Our results suggest that the usage of calcineurin inhibitors should be avoided if utilizing the regimen to induce Tregs in vivo for the establishment of mixed hematopoietic chimerism.

Chimerism through the activation of invariant natural killer T cells prolongs graft survival after transplantation of induced pluripotent stem cell–derived allogeneic cardiomyocytes

“…RGI-2001 activated iNKT cells, which are innate lymphocytes that produce a variety of cytokines and bridge the innate and adaptive immune systems [ 26 ] and induce the proliferation of CD4 + CD25 + Foxp3 - preTregs, which differentiate into CD4 + CD25 + Foxp3 + Tregs upon IL-2 stimulation [ 27 ]. This is consistent with previous reports stating that the use of a calcineurin inhibitor, which inhibits IL-2 transcription, failed to induce Treg expansion [ 28 ].…”

IL-2 receptor engineering enhances regulatory T cell function suppressed by calcineurin inhibitor

“…Although both PBS and ortho IL‐2‐treated groups showed mixed chimerism at the induction phase, 71.4% of the PBS group eventually rejected chimerism and failed to establish heart transplant tolerance. This result is consistent with the previous report that showed tacrolimus administration reduced the proportion and the suppressive function of Tregs and resulted in the failure of transplantation tolerance 17 . In contrast, the mice treated with ortho IL‐2 sustained donor cell chimerism and tolerance by d180, indicating that ortho IL‐2 treatment can reverse the negative impact of CNIs on Tregs.…”

“…This result is consistent with the previous report that showed tacrolimus administration reduced the proportion and the suppressive function of Tregs and resulted in the failure of transplantation tolerance. 17 In contrast, the mice treated with ortho IL-2 sustained donor cell chimerism and tolerance by d180, indicating that ortho IL-2 treatment can reverse the negative impact of CNIs on Tregs.…”

Selective expansion of regulatory T cells using an orthogonal IL-2/IL-2 receptor system facilitates transplantation tolerance

“…We demonstrated here that transducing the ortho IL-2Rβ into host-derived Tregs followed by treatment with the ortho IL-2 cytokine enables the selective stimulation and expansion of Tregs without off-target effects. The selective proliferation of Tregs improved alloengraftment, which was followed by establishment of organ mAb, anti-L-2 mAb (54-56), or tacrolimus that abrogates Treg function (57) in the induction phase precluded HSC engraftment, implying that Tregs play a nonredundant role in the induction phase of mixed chimerism when clonal deletion is not completed. This Treg function is not dependent on MHC recognition because adoptively transferred Tregs that were obtained from or primed by a third party retained the ability to facilitate alloengraftment (58) (43).…”