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Murine anti-3rd-party central-memory CD8+ T-cells promote hematopoietic-chimerism under mild conditioning: lymph-node sequestration and deletion of anti-donor T-cells

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 Negrin, Yair Reisner

Abstract

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 non-malignant hematologic-disorders and can mediate immune tolerance to subsequent organ transplantation. However, overcoming TDBM rejection following reduced-conditioning remains a challenge. Here, we address this barrier using donor-derived central-memory CD8+T-cells (Tcm), directed against 3rd-party antigens. Our results show that fully allogeneic or (hostXdonor)F1-Tcm, support donor chimerism (>6 months) in sublethaly 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, while third-party skin was rejected. Tracking of host-anti-donor T-cells (HADTC), that mediate TDBMT rejection, in a novel bioluminescence-imaging model revealed that Tcm both induce accumulation and eradicate HADTC in the LNs, concomitant with their elimination from other organs, including the BM. Further analysis with 2-photon microcopy revealed that Tcm form conjugates with HADTC, resulting in decelerated and confined movement of HADTC within the LNs in an antigen-specific manner. Thus, anti-3rd-party Tcm support TDBMT engraftment under reduced-conditioning through lymph-node sequestration and deletion of HADTC, offering a novel and potentially safe approach for attaining stable hematopoietic chimerism.

  • Submitted July 6, 2012.
  • Accepted November 12, 2012.