Assaf Lask
Weizmann Institute of Science
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Featured researches published by Assaf Lask.
Blood | 2012
Lior Zangi; Yael Zlotnikov Klionsky; Liran Yarimi; Esther Bachar-Lustig; Yaki Eidelstein; Elias Shezen; David Hagin; Yumi Ito; Toshiyuki Takai; Shlomit Reich-Zeliger; Assaf Lask; Oren Milstein; Steffen Jung; Vera Shinder; Yair Reisner
Immature dendritic cells (imDCs) can have a tolerizing effect under normal conditions or after transplantation. However, because of the significant heterogeneity of this cell population, it is extremely difficult to study the mechanisms that mediate the tolerance induced or to harness the application of imDCs for clinical use. In the present study, we describe the generation of a highly defined population of imDCs from hematopoietic progenitors and the direct visualization of the fate of TCR-transgenic alloreactive CD4(+) and CD8(+) T cells after encountering cognate or noncognate imDCs. Whereas CD4(+) T cells were deleted via an MHC-independent mechanism through the NO system, CD8(+) T-cell deletion was found to occur through a unique MHC-dependent, perforin-based killing mechanism involving activation of TLR7 and signaling through Triggering Receptor-1 Expressed on Myeloid cells (TREM-1). This novel subpopulation of perforin-expressing imDCs was also detected in various lymphoid tissues in normal animals and its frequency was markedly enhanced after GM-CSF administration.
Blood | 2013
Eran Ophir; Noga Or-Geva; Irina Gurevich; Orna Tal; Yaki Eidelstein; Elias Shezen; Raanan Margalit; Assaf Lask; Guy Shakhar; David Hagin; Esther Bachar-Lustig; Shlomit Reich-Zeliger; Andreas Beilhack; Robert S. Negrin; Yair Reisner
Transplantation of T cell-depleted BM (TDBM) under mild conditioning, associated with minimal toxicity and reduced risk of GVHD, offers an attractive therapeutic option for patients with nonmalignant hematologic disorders and can mediate immune tolerance to subsequent organ transplantation. However, overcoming TDBM rejection after reduced conditioning remains a challenge. Here, we address this barrier using donorderived central memory CD8(+) T cells (Tcms), directed against third-party antigens. Our results show that fully allogeneic or (hostXdonor)F1-Tcm, support donor chimerism (> 6 months) in sublethally irradiated (5.5Gy) mice, without GVHD symptoms. Chimerism under yet lower irradiation (4.5Gy) was achieved by combining Tcm with short-term administration of low-dose Rapamycin. Importantly, this chimerism resulted in successful donor skin acceptance, whereas third-party skin was rejected. Tracking of host anti-donor T cells (HADTCs), that mediate TDBMT rejection, in a novel bioluminescence-imaging model revealed that Tcms both induce accumulation and eradicate HADTCs in the LNs,concomitant with their elimination from other organs, including the BM. Further analysis with 2-photon microcopy revealed that Tcms form conjugates with HADTCs, resulting in decelerated and confined movement of HADTCs within the LNs in an antigen-specific manner. Thus, anti-third-party Tcms support TDBMT engraftment under reduced-conditioning through lymph-node sequestration and deletion of HADTCs, offering a novel and potentially safe approach for attaining stable hematopoietic chimerism.
Journal of Immunology | 2011
Assaf Lask; Polina Goichberg; Adva Cohen; Rinat Goren-Arbel; Oren Milstein; Shraga Aviner; Ilan Feine; Eran Ophir; Shlomit Reich-Zeliger; David Hagin; Tirza Klein; Arnon Nagler; Alain Berrebi; Yair Reisner
We previously demonstrated that anti–third-party CTLs (stimulated under IL-2 deprivation against cells with an MHC class I [MHC-I] background different from that of the host and the donor) are depleted of graft-versus-host reactivity and can eradicate B cell chronic lymphocytic leukemia cells in vitro or in an HU/SCID mouse model. We demonstrated in the current study that human allogeneic or autologous anti–third-party CTLs can also efficiently eradicate primary non-Hodgkin B cell lymphoma by inducing slow apoptosis of the pathological cells. Using MHC-I mutant cell line as target cells, which are unrecognizable by the CTL TCR, we demonstrated directly that this killing is TCR independent. Strikingly, this unique TCR-independent killing is induced through lymphoma MHC-I engagement. We further showed that this killing mechanism begins with durable conjugate formation between the CTLs and the tumor cells, through rapid binding of tumor ICAM-1 to the CTL LFA-1 molecule. This conjugation is followed by a slower second step of MHC-I–dependent apoptosis, requiring the binding of the MHC-I α2/3 C region on tumor cells to the CTL CD8 molecule for killing to ensue. By comparing CTL-mediated killing of Daudi lymphoma cells (lacking surface MHC-I expression) to Daudi cells with reconstituted surface MHC-I, we demonstrated directly for the first time to our knowledge, in vitro and in vivo, a novel role for MHC-I in the induction of lymphoma cell apoptosis by CTLs. Additionally, by using different knockout and transgenic strains, we further showed that mouse anti–third-party CTLs also kill lymphoma cells using similar unique TCR-independence mechanism as human CTLs, while sparing normal naive B cells.
Blood | 2013
Assaf Lask; Eran Ophir; Noga Or-Geva; Adva Cohen-Fredarow; Ran Afik; Yaki Eidelstein; Shlomit Reich-Zeliger; Bar Nathansohn; Matthias Edinger; Robert S. Negrin; David Hagin; Yair Reisner
Generation of T cells endowed with graft-versus-leukemia (GVL) and depleted of graft-versus-host (GVH) activity represents a highly desirable goal in bone marrow transplantation (BMT). Here, we demonstrate that donor anti-third-party CD8 T cells with central memory phenotype (Tcm) exhibit marked GVL reactivity through a unique T-cell receptor-independent mechanism. Thus, in a residual disease mouse model, Tcm therapy following autologous BMT led to significant survival prolongation, with 30% to 40% of the treated mice displaying long-term tumor-free survival. A more impressive finding was that infusion of donor Tcm in an allogeneic model rapidly eliminated residual lymphoma cells and led to long-term survival of 100% in the absence of GVH disease. Collectively, the strong GVL reactivity of anti-third-party Tcm, coupled with their demonstrated enhancement of bone marrow allografting, suggests that the use of Tcm therapy in conjunction with allogeneic T-cell-depleted BMT could be of particular benefit in patients with B-cell malignancies who cannot tolerate intensive myeloablative conditioning.
Blood | 2011
Oren Milstein; David Hagin; Assaf Lask; Shlomit Reich-Zeliger; Elias Shezen; Eran Ophir; Yaki Eidelstein; Ran Afik; Yaron E. Antebi; Michael L. Dustin; Yair Reisner
Blood | 2010
Assaf Lask; Eran Ophir; Noga Or-Geva; Adva Cohen; Ran Afik; Yaki Eidelstein; Robert S. Negrin; Arnon Nagler; Alain Berrebi; David Hagin; Yair Reisner
Archive | 2012
Yair Reisner; Yaki Eidelstein; Eran Ophir; Assaf Lask; Ran Afik; Noga Or-Geva; Esther Bachar-Lustig
Archive | 2011
Yair Reisner; Assaf Lask; Eran Ophir; Noga Or-Geva; Adva Cohen; Ran Afik; Esther Bachar-Lustig; Yaki Eidelstein
Best Practice & Research Clinical Haematology | 2011
Eran Ophir; Yaki Eidelstein; Esti Bachar-Lustig; David Hagin; Noga Or-Geva; Assaf Lask; Yair Reisner
Blood | 2007
Oren Milstein; Assaf Lask; Shlomit Reich-Zeliger; Yair Reisner