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

• Published in: Biology of blood and marrow transplantation 2004-11, Vol.10 (11), p.748-760
• Main Authors: Xia, Guliang, Kovochich, Mike, Truitt, Robert L., Johnson, Bryon D.
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Transplantation; CD4 +CD25; CD4-Positive T-Lymphocytes - transplantation; CD8 +CD25; CD8-Positive T-Lymphocytes - transplantation; Donor lymphocyte infusion; Graft vs Host Disease - etiology; Graft vs Host Disease - prevention & control; Graft-versus-host disease; Lymphocyte Transfusion; Mice; Receptors, Interleukin-2; Regulatory T cells
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2004.07.004

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.