T-regulatory cell treatment prevents chronic rejection of heart allografts in a murine mixed chimerism model.
BACKGROUND
The mixed chimerism approach induces donor-specific tolerance in both pre-clinical models and clinical pilot trials. However, chronic rejection of heart allografts and acute rejection of skin allografts were observed in some chimeric animals despite persistent hematopoietic chimerism and tolerance toward donor antigens in vitro. We tested whether additional cell therapy with regulatory T cells (Tregs) is able to induce full immunologic tolerance and prevent chronic rejection.


METHODS
We recently developed a murine "Treg bone marrow (BM) transplantation (BMT) protocol" that is devoid of cytoreductive recipient pre-treatment. The protocol consists of a moderate dose of fully mismatched allogeneic donor BM under costimulation blockade, together with polyclonal recipient Tregs and rapamycin. Control groups received BMT under non-myeloablative irradiation and costimulation blockade without Treg therapy. Multilineage chimerism was followed by flow cytometry, and tolerance was assessed by donor-specific skin and heart allografts.


RESULTS
Durable multilineage chimerism and long-term donor skin and heart allograft survival were successfully achieved with both protocols. Notably, histologic examination of heart allografts at the end of follow-up revealed that chronic rejection is prevented only in chimeras induced with the Treg protocol.


CONCLUSIONS
In a mouse model of mixed chimerism, additional Treg treatment at the time of BMT prevents chronic rejection of heart allografts. As the Treg-chimerism protocol also obviates the need for cytoreductive recipient treatment it improves both efficacy and safety over previous non-myeloablative mixed chimerism regimens. These results may significantly impact the development of protocols for tolerance induction in cardiac transplantation.
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna.
Nina
N
Pilat
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna.
Andreas M
AM
Farkas
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna.
Benedikt
B
Mahr
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna.
Christoph
C
Schwarz
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna.
Lukas
L
Unger
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna.
Karin
K
Hock
Department of Visceral, Transplant, and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University, Innsbruck.
Rupert
R
Oberhuber
Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
Klaus
K
Aumayr
Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
Fritz
F
Wrba
Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna. Electronic address: thomas.wekerle@meduniwien.ac.at.
Thomas
T
Wekerle
D064591:Allografts; D000818:Animals; D016026:Bone Marrow Transplantation; D002908:Chronic Disease; D005260:Female; D016027:Heart Transplantation; D051379:Mice; D008815:Mice, Inbred Strains; D020123:Sirolimus / Q000494:pharmacology; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation*; D018183:Transplantation Chimera / Q000276:immunology*; D014181:Transplantation Immunology / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology*
D020123:Sirolimus
chronic rejection; costimulation blockade; heart transplantation; mixed chimerism; regulatory T cells; tolerance