Original article: cardiovascularA clinically relevant CTLA4-Ig-based regimen induces chimerism and tolerance to heart grafts
Section snippets
Animals
Six- to 8-week-old major histocompatibility complex (MHC) and minor antigen-mismatched Wistar Furth (WF; RT1.Au), August Copenhagen Irish (ACI; RT1.Aa), and Lewis (RT1.A1) rats were purchased from Harlan Sprague Dawley (Indianapolis, IN) and housed in a pathogen-free facility. All animals were treated in compliance with the Principles of Laboratory Animal Care, formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals, prepared by the
Stable mixed hematopoietic chimerism and robust donor-specific tolerance to heart allografts
One hundred percent (7 of 7) of animals conditioned with the CTLA4-Ig-based regimen developed MC. The MC was stable with a mean donor chimerism of 25% ± 9% at 1 year (Table 1). There was no conditioning-related morbidity or mortality. None of the animals showed clinical or histological evidence for acute or chronic GVHD. All bone marrow recipients (n = 7) exhibited donor-specific tolerance to cardiac allografts (mean graft survival time: > 375.0 ± 32.0 days; Table 1, group 3). In contrast, all
Comment
In this study, we have demonstrated that a nontoxic CTLA4-Ig-based conditioning regimen effects mixed chimerism and donor-specific tolerance when heart and bone marrow are transplanted simultaneously. The conditioning regimen consists of CTLA4-Ig (which blocks the CD28:B7 costimulatory pathway), tacrolimus, antithymocyte globulin, and low-dose (300 cGy) total-body irradiation. This conditioning regimen was well tolerated by the animal. No animal developed acute or chronic GVHD. All animals that
Acknowledgements
This work was supported in part by grants from the American Heart Association (National Center; 960144590) and the Thoracic Surgery Research Foundation Fellowship Award to Mohan Thanikachalam.
References (20)
- et al.
Mixed allogeneic chimerism as an approach to transplantation tolerance
Immunol Today
(1988) - et al.
Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation
Blood
(1997) - et al.
Combined host-conditioning with CTLA4-Ig, tacrolimus, anti-lymphocyte serum and low dose radiation leads to stable mixed hematopoietic chimerism in rats
Exp Hematol
(2001) Costimulation of T lymphocytesthe role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy
Cell
(1992)- et al.
T-cell depletion of allogeneic bone marrow using anti-alphabetaTCR monoclonal antibodyprevention of graft-versus-host disease without affecting engraftment potential in rats
Exp Hematol
(1999) - et al.
T cell depletion for graft-versus-host disease prophylaxis. A perspective on engraftment in mice and humans
Transplantation
(1989) - et al.
Tacrolimus-based partial conditioning produces stable mixed lymphohematopoietic chimerism and tolerance for cardiac allografts
Circulation
(1998) - et al.
Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts
Nature
(1984) - et al.
Establishment of stable multilineage hematopoietic chimerism and donor-specific tolerance without irradiation
Transplantation
(2000) - et al.
Anti-CD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hematopoietic chimerism and tolerance
Transplantation
(1999)
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