title: Murine anti-third-party central-memory CD8(+) T cells promote hematopoietic chimerism under mild conditioning: lymph-node sequestration and deletion of anti-donor T cells.
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 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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Ophir
authors.forename: Noga
authors.initials: N
authors.lastname: Or-Geva
authors.forename: Irina
authors.initials: I
authors.lastname: Gurevich
authors.forename: Orna
authors.initials: O
authors.lastname: Tal
authors.forename: Yaki
authors.initials: Y
authors.lastname: Eidelstein
authors.forename: Elias
authors.initials: E
authors.lastname: Shezen
authors.forename: Raanan
authors.initials: R
authors.lastname: Margalit
authors.forename: Assaf
authors.initials: A
authors.lastname: Lask
authors.forename: Guy
authors.initials: G
authors.lastname: Shakhar
authors.forename: David
authors.initials: D
authors.lastname: Hagin
authors.forename: Esther
authors.initials: E
authors.lastname: Bachar-Lustig
authors.forename: Shlomit
authors.initials: S
authors.lastname: Reich-Zeliger
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.forename: Robert
authors.initials: R
authors.lastname: Negrin
authors.forename: Yair
authors.initials: Y
authors.lastname: Reisner
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control; D006402:Hematologic Diseases / Q000276:immunology / Q000628:therapy; D006801:Humans; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007519:Isoantigens; D008198:Lymph Nodes / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D020123:Sirolimus / Q000008:administration & dosage; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014019:Tissue Donors; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D007166:Immunosuppressive Agents; D007519:Isoantigens; D020123:Sirolimus