Fluvastatin Promotes Treg Cell Production in Allogeneic Immune Reaction and Suppresses Inflammatory Response

Introduction: Statins, a class of HMG-CoA reductase inhibitors, exhibit prophylactic benefits against immune rejection induced by allogeneic hematopoietic stem cell transplantation (allo-HSCT). Despite the protective function is confirmed, the precise mechanism to induce immune tolerance of statin in the initial stages of transplantation remains incompletely understood. Given that Treg cells play a critical role in preventing graft versus host response and Foxp3 as a transcription factor of Treg can be induced by statins, we hypothesize that the immunosuppressive effects of statins are partially mediated through regulation of Treg cells expansion.

Methods: T cells were stimulated in vitro under anti-CD3/anti-CD28/IL-2/TGF-β condition or allo-reactive system with or without the addition of statins. The induction of Tregs were detected using flow cytometry. Allo-HSCT models were established by transferring donor cells alone or combined with recipient treated by fluvastatin. The proportions of Treg and phenotypes of effector T cells were identified. Cytokine secretion and antigen-presenting cell (APC) function were tested in irradiated mice.

Results: Statins induced higher Treg production in classical and allogeneic cell co-culture conditions in vitro. In the early stage of models treated with fluvastatin only in donors or combined treatment of donors and recipients, a similar phenomenon was observed with elevated levels of Foxp3⁺ Treg along with increased expression of CCR7, CD62L, and S1P1 on allo-reactive T cells. Fluvastatin treatment suppressed the secretion of pro-inflammatory cytokines IFN-γ and TNF-α by CD4⁺ and CD8⁺ T cells in irradiated mice. Furthermore, fluvastatin also contributed to restraining the numbers and activation of APCs, including dentritic cells (DCs) and macrophages in vitro and in vivo.

Conclusion: Our finding demonstrated that statin exposure modulates immune responses during the initial phase of allo-HSCT by promoting Treg expansion and suppressing inflammatory reactions, which supply a promising strategy for aGVHD prevention.