Souichi Shiratori

ZAPS is a potent stimulator of signaling mediated by the RNA helicase RIG-I during antiviral responses

The poly(ADP-ribose) polymerases (PARPs) participate in many biological and pathological processes. Here we report that the PARP-13 shorter isoform (ZAPS), rather than the full-length protein (ZAP), was selectively induced by 5′-triphosphate–modified RNA (3pRNA) and functioned as a potent stimulator of interferon responses in human cells mediated by the RNA helicase RIG-I. ZAPS associated with RIG-I to promote the oligomerization and ATPase activity of RIG-I, which led to robust activation of IRF3 and NF-κB transcription factors. Disruption of the gene encoding ZAPS resulted in impaired induction of interferon-α (IFN-α), IFN-β and other cytokines after viral infection. These results indicate that ZAPS is a key regulator of RIG-I signaling during the innate antiviral immune response, which suggests its possible use as a therapeutic target for viral control.

A Retrospective Analysis of Allogeneic Hematopoietic Stem Cell Transplantation for Adult T Cell Leukemia/Lymphoma (ATL): Clinical Impact of Graft-versus-Leukemia/Lymphoma Effect

Adult T cell leukemia/lymphoma (ATL) is a highly aggressive T cell malignancy, and has a poor prognosis. Recently, allogeneic-hematopoietic stem cell transplantation (allo-HSCT) has been suggested to improve the outcome. We retrospectively analyzed 15 patients with ATL who had received allo-HSCT in 2 institutions in Hokkaido, Japan. The median age of the patients was 57 years. The estimated 3-year overall survival (OS) and progression-free survival (PFS) rates were 73.3% and 66.7%, respectively. Calcineurin inhibitor dosage was reduced and administration was discontinued abruptly in 6 of the 15 patients for disease control; as a result, 4 (66.7%) of the 6 patients achieved complete response (CR) or partial response. Therefore, a graft-versus-leukemia/lymphoma (GVL) effect might be induced by discontinuation of immunosuppression. Thirteen of the 15 patients were followed up by monitoring HTLV-1 proviral DNA levels. In 10 of the 11 patients with positive HTLV-1 proviral DNA before allo-HSCT, HTLV-1 proviral DNA became undetectable at least once after allo-HSCT, and only 1 of the 5 patients in whom HTLV-1 proviral DNA became detectable after allo-HSCT relapsed. Compared to the results of past studies, these results show that allo-HSCT greatly improved the prognosis of ATL and suggest a contribution of the induction of a GVL effect.

Hepatitis B virus reactivation with a rituximab-containing regimen

Rituximab is currently used not only in the treatment of B-cell lymphoma but also for various other diseases, including autoimmune diseases, post-transplant graft vs host disease, and rejection following kidney transplants. Due to rituximabs widespread use, great progress has been made regarding research into complications that arise from its use, one of the most serious being the reactivation of hepatitis B virus (HBV), and efforts continue to establish guidelines for preventive treatment against this occurrence. This report discusses preventive measures against rituximab-induced HBV reactivation and future objectives.

Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation

Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution. In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P = .0427 compared with patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P = .012), and flow cytometric analyses revealed lower numbers of CD19(+) B cells and a significantly increased CD4 to CD8 ratio (P = .0002) in these patients. Our data, for the first time to our knowledge, summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients.

Expansion of NK cells from cord blood with antileukemic activity using GMP-compliant substances without feeder cells.

Expansion of NK cells from cord blood with antileukemic activity using GMP-compliant substances without feeder cells

Efficacy of folinic acid in preventing oral mucositis in allogeneic hematopoietic stem cell transplant patients receiving MTX as prophylaxis for GVHD

As the safety of folinic acid administration and its efficacy for reducing the toxicity of MTX remain controversial, we assessed the effect of folinic acid administration after MTX treatment for GVHD prophylaxis on the incidence of oral mucositis and acute GVHD. We retrospectively analyzed data for 118 patients who had undergone allogeneic hematopoietic SCT and had received MTX for GVHD prophylaxis. Multivariate analysis showed that systemic folinic acid administration significantly reduced the incidence of severe oral mucositis (odds ratio (OR)=0.13, 95% confidence interval (CI) 0.04–0.73, P=0.014). There was also a tendency for a lower incidence of severe oral mucositis in patients who received folinic acid mouthwash (OR=0.39, 95%CI 0.15–1.00, P=0.051). No significant difference was observed in the incidence of acute GVHD between patients who received systemic folinic acid administration and those who did not (P=0.88). Systemic folinic acid administration and mouthwash appear to be useful for reducing the incidence of severe oral mucositis in patients who have received allogeneic hematopoietic SCT using MTX as GVHD prophylaxis.

Dasatinib enhances the expansion of CD56+CD3− NK cells from cord blood

To the editor: Dasatinib can inhibit T-cell activation through inhibition of the Scr family of tyrosine kinases such as p56 (Lck).[1][1] It has been reported that some chronic myeloid leukemia (CML) patients who were treated with dasatinib developed chronic large-granular lymphocytosis (LGL) with

Increased number of CD16+CD56dim NK cells in peripheral blood mononuclear cells after allogeneic cord blood transplantation

In the present study, we investigated subpopulations of natural killer (NK) cells and the expression of stimulatory and inhibitory NK receptors after adult blood and bone marrow transplantation (BBMT) and cord blood transplantation (CBT). There were significant increases in CD16(+)CD56(dim) cell proportion and in absolute number in peripheral blood mononuclear cells (PBMC) during a period of 4-9 months after CBT compared with these in normal PBMC, cord blood (CB), and in PBMC after BBMT. Also, increased numbers of CD16(+)CD56(dim) NK cells were sustained in some patients until 4 years after CBT. This CD16(+)CD56(dim) cell subset after CBT exhibited decreased expression of NKG2A compared with that in CB and increased expression of NKG2C. Purified CD16(+)CD56(dim) cells from patients 8-9 months after CBT exhibited significantly higher levels of cytolytic activity against K562 than did purified CD16(+)CD56(bright) cells and also whole PBMC. The CD16(+)CD56(dim) cell subset with a high level of cytolytic activity significantly increased after CBT, and these cells may be responsible for NK cell-mediated immunity after CBT.

Increased risk of bacterial infection after engraftment in patients treated with allogeneic bone marrow transplantation following reduced-intensity conditioning regimen

A. Shigematsu, S. Yamamoto, J. Sugita, T. Kondo, M. Onozawa, K. Kahata, T. Endo, S. Shiratori, S. Ota, K. Yamaguchi, K. Wakasa, M. Takahata, H. Goto, S. Ito, R. Takemura, J. Tanaka, S. Hashino, M. Nishio, T. Koike, M. Asaka, M. Imamura. Increased risk of bacterial infection after engraftment in patients treated with allogeneic bone marrow transplantation following reduced‐intensity conditioning regimen.
Transpl Infect Dis 2010: 12: 412–420. All rights reserved

Differential effects of interleukin-12 and interleukin-15 on expansion of NK cell receptor-expressing CD8+ T cells

The cytolytic activity of cells expressing natural killer cell receptors (NKRs) depends on the balance between stimulatory and inhibitory signals. We investigated both inhibitory NK receptor (CD94/NKG2A) expression and stimulatory NKR (NKG2D) expression on T cells after stimulation with cytokines (IL-12 or IL-15). Cytolytic NKR-expressing CD8+ T cells were expanded from normal adult peripheral blood mononuclear cells using anti-CD3 monoclonal antibody and cytokines (IL-12 or IL-15). The proportion and absolute number of CD94/NKG2A-expressing T cells expanded by IL-12 were significantly larger than those of the cells expanded by IL-15. On the other hand, the proportion and absolute number of NKG2D-expressing T cells expanded by IL-15 were significantly larger than those of the cells expanded by IL-12. The proportions of NKG2D and intracellular granzyme A expression in CD94-expressing cells were much more increased in PBMCs cultured with IL-15 than those of cells cultured with IL-12. A real-time polymerase chain reaction assay showed that there was a 1.68-fold increase in NKG2D mRNA expression level and a 1.37-fold increase in DAP10 mRNA expression level in CD94-expressing cells expanded by IL-15 compared with those of the cells expanded by IL-12. The cytolytic activity levels of purified CD94-expressing cells from 8-day culture with IL-15 tested against 51Cr-labeled K562 cells by standard 4-h 51Cr release assays without prior sensitization were much higher than those of cells from 8-day culture with IL-12. IL-15 appears to be able to enhance the cytolytic activity of CD94/NKG2A-expressing cells through induction of NKG2D and intracellular granzyme expression much more efficiently than does IL-12.