Levy-Barazany Hilit, Shachnai-Pinkas Liat, Rodionov Galina, Saar Alex, Rosenzwaig Michal, Gez Liron, Rodin Anastasia, Marelly Nitzan, Abraham Michal, Mishalian Inbal, Wildbaum Hila, Katz Tamar, Baar Yuval, Yarkoni Shai, Bakimer-Kleiner Ronit, Peled Amnon, Zuckerman Tsila, Stein Jerry
Cellect Biotherapeutics Ltd., Kfar-Saba, Israel.
Goldyne Savad Institute of Gene Therapy, Hebrew University of Jerusalem, Jerusalem, Israel.
Bone Marrow Transplant. 2020 Jul;55(7):1305-1316. doi: 10.1038/s41409-020-0941-2. Epub 2020 May 20.
Graft versus host disease (GvHD) remains a limiting factor for successful hematopoietic stem cell transplantation (HSCT). T cells and antigen-presenting cells (APCs) are major components of the hematopoietic G-CSF mobilized peripheral blood cell (MPBC) graft. Here we show that a short incubation (2 h) of MPBCs with hexameric Fas ligand (FasL) selectively induces apoptosis of specific donor T cell subsets and APCs but not of CD34 cells. FasL treatment preferentially induces apoptosis in mature T cell subsets which express high levels of Fas (CD95), such as T stem cell memory, T central memory, and T effector memory cells, as well as T1 and T17 cells. Anti-CD3/CD28 stimulated T cells derived from FasL-treated-MPBCs express lower levels of CD25 and secrete lower levels of IFN-γ as compared to control cells not treated with FasL. FasL treatment also induces apoptosis of transitional, naïve, memory and plasmablastoid B cells leading to a reduction in their numbers in the graft and following engraftment in transplanted mice. Most importantly, ex vivo treatment of MPBCs with FasL prior to transplant in conditioned NOD-scid IL2Rγ (NSG) mice prevented GvHD while preserving graft versus leukemia (GvL) effects, and leading to robust stem cell engraftment.
移植物抗宿主病（GvHD）仍然是成功进行造血干细胞移植（HSCT）的一个限制因素。T细胞和抗原呈递细胞（APC）是造血生长集落刺激因子动员的外周血细胞（MPBC）移植物的主要成分。在此我们表明，MPBC与六聚体Fas配体（FasL）短时间孵育（2小时）可选择性诱导特定供体T细胞亚群和APC凋亡，但不会诱导CD34细胞凋亡。FasL处理优先诱导表达高水平Fas（CD95）的成熟T细胞亚群凋亡，如T干细胞记忆细胞、T中央记忆细胞和T效应记忆细胞，以及T1和T17细胞。与未用FasL处理的对照细胞相比，源自FasL处理的MPBC的抗CD3/CD28刺激的T细胞表达较低水平的CD25，分泌较低水平的干扰素-γ。FasL处理还诱导过渡性、幼稚、记忆和浆母细胞样B细胞凋亡，导致移植物中以及移植到小鼠体内并植入后其数量减少。最重要的是，在将条件性NOD- scid IL2Rγ（NSG）小鼠移植前对MPBC进行FasL体外处理可预防GvHD，同时保留移植物抗白血病（GvL）效应，并导致强大的干细胞植入。
