Abstract
BackgroundIn this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model.Methodology/Principal FindingsMixed lymphocyte reactions were used to determine the in vitro effects of curcumin. Treatment with curcumin attenuated alloreactive T cell proliferation and inhibited the production of interferon (IFN)-γ and interleukin (IL)-17. In a murine acute GVHD model, transplantation of curcumin-treated allogeneic splenocytes into irradiated recipient mice significantly reduced the clinical severity scores of acute GVHD manifested in the liver, skin, colon and lung as compared with animals receiving vehicle-treated splenocytes. c-Fos and c-Jun expression levels in the skin and intestine, which are major target organs, were analyzed using immunohistochemical staining. Expression of both proteins was reduced in epithelial tissues of skin and intestine from curcumin-treated GVHD animals. The IFN-γ-expressing CD4+ splenocytes and IFN-γ-expressing lymph node cells were dramatically decreased in curcumin-treated mice. In contrast, CD4+Foxp3+ splenocytes were increased in the curcumin-treated acute GVHD animals. Flow cytometric analysis revealed that animals transplanted with curcumin-treated allogeneic splenocytes showed increased populations of CD4+ regulatory T cells (Tregs) as well as CD8+ Treg cells, compared to animals administered vehicle-treated splenocytes. Curcumin-treated acute GVHD animals could have a change in B cell subpopulations.Conclusion/SignificanceIn the present study, we investigated the efficacy and mechanism of action of curcumin treatment against acute GVHD. The acute GVHD mice administered with curcumin-treated splenocytes showed significantly reduced severity of acute GVHD. Curcumin exerted in vivo preventive effects on acute GVHD by reciprocal regulation of T helper 1 (Th1) and Treg (both CD4+ and CD8+ Treg) cell lineages as well as B cell homeostasis.
Highlights
Allogenic hematopoietic stem cell transplantation (HSCT) is the only curative therapy with proven efficacy for the management of many hematologic malignancies and other life-threatening hematological diseases
The results indicated that the treatment with curcumin and DSMO at various concentrations did not induce apoptosis or affect cell viability
To determine whether in vitro curcumin treatment can regulate the T helper 1 (Th1) and Th2 balance, B6 splenic T cells incubated with irradiated B6 splenic T cells or BALB/c splenic T cells in the absence of presence of curcumin (2.5 mM) were analyzed by intracellular staining for IL-4, IFN-c, IL-17, and Foxp3 (Fig. 1C)
Summary
Allogenic hematopoietic stem cell transplantation (HSCT) is the only curative therapy with proven efficacy for the management of many hematologic malignancies and other life-threatening hematological diseases. The development of graft-versus-host disease (GVHD), which is the main complication of HSCT, is a significant obstacle of allogenic HSCT [1]. The development of GVHD requires escalated and prolonged immunosuppressive therapy with increased risk of infectious complications. GVHD increases the risk of fatal morbidities and moralities in HSCT recipients. Acute GVHD (grades II–IV) occurs in 30–60% of patents after allogenic HSCT from human leukocyte antigen (HLA)-identical sibling donors [2]. Following the development of GVHD, complete remission has been observed in only 30 to 50% of patients with acute GVHD [3,4]. In this study we examined the in vivo and in vitro effects and mechanisms of action of curcumin on the development of acute graft-versus-host disease (GVHD) using a murine model
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