Abstract
Immunological rejection is an important factor resulting in allograft dysfunction, and more valid therapeutic methods need to be explored to improve allograft outcomes. Many researches have indicated that artemisinin and its derivative exhibits immunosuppressive functions, apart from serving as a traditional anti-malarial drug. In this assay, we further explored the therapeutic effects of artemisinin for transplant rejection in a rat cardiac transplantation model. We found that it markedly attenuated allograft rejection and histological injury and significantly prolonged the survival of allograft. Upon further exploring the mechanism, we demonstrated that artemisinin not only attenuated T cell-mediated rejection (TCMR) by reducing effector T cell infiltration and inflammatory cytokine secretion and increasing regulatory T cell infiltration and immunoregulatory cytokine levels, but also attenuated antibody-mediated rejection (ABMR) through inhibition of B cells activation and antibody production. Furthermore, artemisinin also reduced macrophage infiltration in allografts, which was determined to be important for TCMR and ABMR. Moreover, we demonstrated that artemisinin significantly inhibited the function of pure T cells, B cells, and macrophages in vitro. All in all, this study provide evidence that artemisinin significantly attenuates TCMR and ABMR by targeting multiple effectors. Therefore, this agent might have potential for use in clinical settings to protect against transplant rejection.
Highlights
Cardiac transplantation has become the gold-standard long-term medical treatment for end-stage heart failure and has achieved remarkable success [1]
Recipients treated with ART had longer graft survival than controls (17.33 ± 4.89 vs 6.83 ± 0.75 days); approximately 66% of grafts in the ART group survived over 2 weeks, while survival time of grafts were less than 8 day in the control group (Figure 1A)
Allografts were harvested on day 5 after cardiac transplantation
Summary
Cardiac transplantation has become the gold-standard long-term medical treatment for end-stage heart failure and has achieved remarkable success [1]. Immune responses could result in the rejection to cardiac allografts, which including chronic rejection (CR) and acute rejection (AR). Transplant rejection mainly consists of T cell-mediated rejection (TCMR) and antibody-mediated. Immunosuppression has achieved good results for TCMR therapy, side effects such as infection and graft toxicities are likely to be a significant impact on patient prognosis [4]. ABMR, caused by donorspecific antibodies (DSAs), has emerged as an important immunological barrier to successful transplantation [5, 6]. Current therapeutic strategies for ABMR focus on removing the generated antibodies in the peripheral blood, or eliminating B cells to inhibit the generation of antibodies, but these strategies are not as effective as expected [7]. More effective and safe strategies must be explored to improve transplant outcomes
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