“The 77th of Stem Cell Biology and Regenerative Medicine Forum”
Date：Jan 29th (Thu) 2015
Time : 18:30 〜 20:00
Place：Auditorium in 1st Building at Institute of Medical Science in Univ. of Tokyo------------------------------------------------------------------------------------------------------------------------------------（Internal Speaker）
18:30-19:00
Yukie Tanaka (Division of Molecular Therapy, IMSUT, Division ofHematology, Saitama Medical Center, Jichi Medical University)
Investigation of redirected T-cell immunotherapy against HTLV-1 Tax（External Speaker）
19:00-20:00
Yoshinobu Maeda (Department of Hematology and Oncology, Okayama
University Hospital)
Mouse Models for Understanding the Pathogenesis of Chronic
Graft-versus-Host Disease-------------------------------------------------------------------------------------------------------------------------------------

Hosted by Center for Stem Cell Biology and Regenerative Medicine---Information--＊ Please register attendance at the reception desk.

＊ Next forum（the78th）will be held on

Mar. 4th（Wed）17:00〜 at Auditorium in 1st Building.

＊ Please contact tatsu-m@ims.u-tokyo.ac.jp, for Forum speaker recommendations

Investigation of redirected T-cell immunotherapy against HTLV-1 Tax
Yukie Tanaka (Division of Molecular Therapy, IMSUT, Division ofHematology, Saitama Medical Center, Jichi Medical University)
Adult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human
T cell lymphotropic virus type 1 (HTLV-1) infection. Tax is the most important
regulatory protein of HTLV-1, and is also a major target antigen for CD8+ cytotoxic
T-cells (CTLs). Immunological studies of ATL patients who underwent allogeneic
hematopoietic stem cell transplantation (allo-HSCT) showed that donor
Tax-specific CTL might contribute to control of HTLV-1 replication after
allo-HSCT. We previously analyzed T cell receptor (TCR) repertoire of HTLV-1
Tax301-309-specific CTLs of ATL patients underwent allo-HSCT at single-cell levels,and reported that a particular amino acid sequence motif (P-D-R) in CDR3 ofTCR-β was conserved among predominant Tax-specific CTLs. Moreover, thePDR-motif+ Tax-specific CTLs with sufficient activities persistently existed inlong-term ATL survivors after HSCT. Based on these observations, we consideredthat PDR-motif+ TCR-gene could be a promising candidate for TCR-gene
immunotherapy against HTLV-1 Tax. Therefore, PDR-motif+ TCRα/β gene wasintroduced into donor T-cells by retroviral vector system. The redirected T-cells
selectively killed HTLV-1 infected-cells without any reaction against normal cells
in vitro. Now, we are testing the cytotoxic performances in vivo using mousemodels.

Mouse Models for Understanding the Pathogenesis of Chronic
Graft-versus-Host Disease
Yoshinobu Maeda (Department of Hematology and Oncology, Okayama
University Hospital)
Allogeneic stem cell transplantation (SCT) is a widely performed therapy for manyhematologic malignancies, although graft-versus-host disease (GVHD) remains
potentially lethal complications after allogeneic SCT. Based on differences inclinical manifestations and histopathology, GVHD can be divided into acute andchronic types. The clinical manifestations of acute GVHD occur in the skin,gastrointestinal tract, and liver. Several convergent lines of experimental data havedemonstrated that donor T cells and donor and/or host antigen-presenting cells areimportant in the induction of acute GVHD.
Chronic GVHD often presents with clinical manifestations that resemble thoseobserved in autoimmune diseases, and is a major cause of late death and morbidity
after allogeneic SCT. However, the pathophysiology and treatment strategy ofchronic GVHD remain poorly defined. Initially, chronic GVHD was considered tobe a Th2-mediated disease, based on results from the non-irradiated parent into F1mouse GVHD model. However, chronic GVHD has not fit neatly into the Th2paradigm. Firstly, we evaluated the kinetics of regulatory T cell (Treg)
reconstitution in mouse allogeneic SCT model. Next, we showed that Th1 cell andTh17 cell expansion occurred during chronic GVHD and contributed to chronic
GVHD progression using a mouse model. We also identified a population ofdonor-derived IFN-17 double-positive cells following only allogeneictransplantation, not syngeneic transplantation, suggesting that this population isgenerated by allogeneic stimulation.
In this talk, we discuss the pathophysiology of chronic GVHD, focusing on four
aspects: (a) Tregs, (b) Th1 cell and Th17 cell, (c) the IL-12/IL-23 pathway and (d)the PD-1 pathway. Finally, we present a new strategy for the treatment of chronic
GVHD.