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

• Published in: Blood 2013-02, Vol.121 (7), p.1220-1228
• Main Authors: Ophir, Eran, Or-Geva, Noga, Gurevich, Irina, Tal, Orna, Eidelstein, Yaki, Shezen, Elias, Margalit, Raanan, Lask, Assaf, Shakhar, Guy, Hagin, David, Bachar-Lustig, Esther, Reich-Zeliger, Shlomit, Beilhack, Andreas, Negrin, Robert, Reisner, Yair
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Transplantation - immunology; CD8-Positive T-Lymphocytes - immunology; Female; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Hematologic Diseases - immunology; Hematologic Diseases - therapy; Humans; Immunologic Memory; Immunosuppressive Agents - administration & dosage; Isoantigens; Lymph Nodes - immunology; Lymphocyte Depletion; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Sirolimus - administration & dosage; Skin Transplantation - immunology; T-Lymphocytes - immunology; Tissue Donors; Transplantation; Transplantation Chimera - immunology; Transplantation Conditioning - methods
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2012-07-441493

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 donor-derived 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. •A new approach to achieving immune tolerance and mixed chimerism with relevance for hematopoietic stem cell and organ transplantation.•Anti–third-party central memory T cells support engraftment with nonablative conditioning by sequestering and deleting anti-donor T cells.