Treg-therapy allows mixed chimerism and transplantation tolerance without cytoreductive conditioning.
Establishment of mixed chimerism through transplantation of allogeneic donor bone marrow (BM) into sufficiently conditioned recipients is an effective experimental approach for the induction of transplantation tolerance. Clinical translation, however, is impeded by the lack of feasible protocols devoid of cytoreductive conditioning (i.e. irradiation and cytotoxic drugs/mAbs). The therapeutic application of regulatory T cells (Tregs) prolongs allograft survival in experimental models, but appears insufficient to induce robust tolerance on its own. We thus investigated whether mixed chimerism and tolerance could be realized without the need for cytoreductive treatment by combining Treg therapy with BM transplantation (BMT). Polyclonal recipient Tregs were cotransplanted with a moderate dose of fully mismatched allogeneic donor BM into recipients conditioned solely with short-course costimulation blockade and rapamycin. This combination treatment led to long-term multilineage chimerism and donor-specific skin graft tolerance. Chimeras also developed humoral and in vitro tolerance. Both deletional and nondeletional mechanisms contributed to maintenance of tolerance. All tested populations of polyclonal Tregs (FoxP3-transduced Tregs, natural Tregs and TGF-beta induced Tregs) were effective in this setting. Thus, Treg therapy achieves mixed chimerism and tolerance without cytoreductive recipient treatment, thereby eliminating a major toxic element impeding clinical translation of this approach.
Division of Transplantation, Department of Surgery, Medical University of Vienna, Austria.
N
N
Pilat
Division of Transplantation, Department of Surgery, Medical University of Vienna, Austria.
U
U
Baranyi
Division of Transplantation, Department of Surgery, Medical University of Vienna, Austria.
C
C
Klaus
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany.
E
E
Jaeckel
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany.
N
N
Mpofu
Institute of Clinical Pathology, Medical University of Vienna, Austria.
F
F
Wrba
Transplantation Centre and Transplantation Immunopathology Laboratory, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University, Lausanne, Switzerland.
D
D
Golshayan
Division of Transplantation, Department of Surgery, Medical University of Vienna, Austria.
F
F
Muehlbacher
Division of Transplantation, Department of Surgery, Medical University of Vienna, Austria.
T
T
Wekerle
D056704:Adaptive Immunity; D000818:Animals; D001483:Base Sequence; D017690:Cell Transplantation; D002678:Chimera; D017931:DNA Primers; D005260:Female; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008815:Mice, Inbred Strains; D016133:Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D019172:Transplantation Conditioning
D017931:DNA Primers