Tracking ex vivo-expanded CD4+CD25+ and CD8+CD25+ regulatory T cells after infusion to prevent donor lymphocyte infusion-induced lethal acute graft-versus-host disease.
Donor bone marrow (BM)-derived CD4+ CD25+ regulatory T cells, maturing in the host thymus, are critical in inhibiting graft-versus-host disease (GVHD) after donor lymphocyte infusion (DLI) in murine BM chimeras. Data presented here demonstrate that fresh CD25+ cells isolated from donor-type mice can be expanded ex vivo by a variety of methods. Ex vivo-expanded CD4+ CD25+ and CD8+ CD25+ cells were potent suppressors of donor response to host alloantigens in mixed lymphocyte reaction assays. Both fresh and ex vivo-expanded CD4+ CD25+ cells persisted long-term in vivo and effectively prevented DLI-induced GVHD in CD25-/- BM chimeras. Importantly, co-infused CD4+ CD25+ cells with DLI cells migrated to peripheral lymphoid organs and survived long-term in DLI-treated CD25-/- chimeras, but not in DLI-treated CD25+/+ chimeras, indicating homeostatic control of CD25+ cells and an available niche required for their long-term persistence. Furthermore, maintenance of CD25 expression seemed necessary for suppressive function, because only the CD25+ cell fraction, but not the CD25- fraction isolated after adoptive transfer, was suppressive in vitro. Ex vivo-expanded CD8+ CD25+ cells weakly prevented GVHD, apparently because of a rapid disappearance of these cells after adoptive transfer. Taken together, these data suggest that the therapeutic use of ex vivo-expanded CD4+ CD25+ cells may be a feasible, nontoxic modality for controlling GVHD in the clinic. Because of strict homeostatic control, an available niche may be required for long-term persistence of infused regulatory T cells.
Xia
Guliang
G
Department of Pediatrics, Medical College of Wisconsin, and Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Kovochich
Mike
M
Truitt
Robert L
RL
Johnson
Bryon D
BD
D000818:Animals; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000637:transplantation; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D017710:Lymphocyte Transfusion; D051379:Mice; D015375:Receptors, Interleukin-2
D015375:Receptors, Interleukin-2