Induction of tolerance to bone marrow allografts by donor-derived host nonreactive ex vivo-induced central memory CD8 T cells.
Enabling engraftment of allogeneic T cell-depleted bone marrow (TDBM) under reduced-intensity conditioning represents a major challenge in bone marrow transplantation (BMT). Anti-third-party cytotoxic T lymphocytes (CTLs) were previously shown to be endowed with marked ability to delete host antidonor T cells in vitro, but were found to be less effective in vivo. This could result from diminished lymph node (LN) homing caused by the prolonged activation, which induces a CD44(+)CD62L(-) effector phenotype, and thereby prevents effective colocalization with, and neutralization of, alloreactive host T cells (HTCs). In the present study, LN homing, determined by imaging, was enhanced upon culture conditions that favor the acquisition of CD44(+)CD62L(+) central memory cell (Tcm) phenotype by anti-third-party CD8(+) cells. These Tcm-like cells displayed strong proliferation and prolonged persistence in BM transplant recipients. Importantly, adoptively transferred HTCs bearing a transgenic T-cell receptor (TCR) with antidonor specificity were efficiently deleted only by donor-type Tcms. All these attributes were found to be associated with improved efficacy in overcoming T cell-mediated rejection of TDBM, thereby enabling high survival rate and long-term donor chimerism, without causing graft-versus-host disease. In conclusion, anti-third-party Tcms, which home to recipient LNs and effectively delete antidonor T cells, could provide an effective and novel tool for overcoming rejection of BM allografts.
Ophir
Eran
E
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Eidelstein
Yaki
Y
Afik
Ran
R
Bachar-Lustig
Esther
E
Reisner
Yair
Y
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007156:Immunologic Memory / Q000276:immunology / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D014019:Tissue Donors; D019172:Transplantation Conditioning / Q000379:methods; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D015854:Up-Regulation / Q000276:immunology