Effects of decitabine on allogeneic immune reactions of donor lymphocyte infusion via activation of dendritic cells
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Experimental Hematology & Oncology Open Access
RESEARCH
Effects of decitabine on allogeneic immune reactions of donor lymphocyte infusion via activation of dendritic cells Yong‑Rim Kwon1†, Hye Joung Kim1†, Min‑Jung Sohn1†, Ji‑Young Lim1, Kyung‑Shin Park2, Seok Lee1,3,4, Nack‑Gyun Chung3,4,5, Dae‑Chul Jeong5, Chang‑Ki Min1,3,4 and Yoo‑Jin Kim1,3,4*
Abstract Background: Successful prevention of post-transplantation relapse after donor lymphocyte infusion (DLI) depends on its capability to mediate an effective graft-versus-leukemia (GVL) response while minimizing DLI-related toxicity, including graft-versus-host disease (GVHD). Methods: We assessed the effects of decitabine (DEC), a hypomethylating agent, upon allogeneic immune reaction in a murine model of DLI. Results: Significantly greater tumor growth retardation and survival prolongation occurred in mice administered with 1.0 mg/kg DEC for 5 days (DEC-1.0) than in control or DEC-0.1 mice. Upon prompt DEC and DLI co-administra‑ tion, dendritic cells (DCs) were activated; DEC-1.0/DLI induced severe GVHD, and survival was significantly lower than with DLI alone or DEC-0.1/DLI treatments. IFN-γ and CD28 levels were higher in splenic DCs of DEC-1.0 mice than in those of control mice. Assessment of delayed DLI co-administration with DEC, when IFN-γ levels were normalized to control levels, revealed that DEC-1.0/DLI successfully facilitated tumor management without causing severe GVHD. Conclusions: Our results suggest that DEC primes allogeneic immune reactions of DLI via DC activation, and GVHD and GVL effects are separable through optimal DLI timing based on DEC-induced increase in IFN-γ expression levels. Keywords: Donor lymphocyte infusion, Decitabine, Graft-versus-host disease, Graft-versus-leukemia effect, Dendritic cells Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option for selected patients with hematological malignancies. The recent improvement in long-term survival after transplantation may result from a reduction in treatment-related mortality due to organ damage, infection, and severe *Correspondence: [email protected] † Yong-Rim Kwon, Hye Joung Kim, Min-Jung Sohn contributed equally to this work 4 Seoul St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo‑daero, Seocho‑gu, Seoul 06591, Republic of Korea Full list of author information is available at the end of the article
acute graft-versus-host disease (GVHD) [1]; however, relapse remains the major cause of transplantation failure. Accordingly, various strategies to decrease post-transplantation relapse have been attempted, and incorporation of novel agents such as tyrosine kinase inhibitors (TKIs) or hypomethylating agents (HMAs) into pre- or post-HSCT settings is regarded as the most promising and feasible option. For example, a combination of TKIs and conventional chemotherapy in Philadelphia chromosome-positive acute lymphoblastic leukemia patients induced more pronounced molecular responses at t
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