The influence of immunosuppressive drugs on tolerance induction through bone marrow transplantation with costimulation blockade

被引:146
作者
Blaha, P
Bigenzahn, S
Koporc, Z
Schmid, M
Langer, F
Selzer, E
Bergmeister, H
Wrba, F
Kurtz, J
Kiss, C
Roth, E
Muehlbacher, F
Sykes, M
Wekerle, T
机构
[1] Univ Vienna, Vienna Gen Hosp, Dept Surg 21A, Div Transplantat, A-1010 Vienna, Austria
[2] Univ Vienna, Vienna Gen Hosp, Dept Radiotherapy & Radiobiol, A-1010 Vienna, Austria
[3] Univ Vienna, Vienna Gen Hosp, Inst Biomed Res, A-1010 Vienna, Austria
[4] Univ Vienna, Vienna Gen Hosp, Inst Clin Pathol, A-1010 Vienna, Austria
[5] Univ Vienna, Vienna Gen Hosp, Surg Res Labs, A-1010 Vienna, Austria
[6] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA USA
关键词
D O I
10.1182/blood-2002-10-3014
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
We recently developed a murine protocol for the induction of allogeneic mixed chimerism and tolerance employing nonmyeloablative total body irradiation (TBI), standard-dose bone marrow transplantation (BMT), and costimulation blockade (cobl) with an anti-CD154 monoclonal antibody (mAb) plus CTLA4Ig. We now evaluated whether a short course (1 month) of immunosuppressive drugs, which would be ethically required in the clinical setting of organ transplantation to prevent graft loss in case tolerance is not achieved, interferes with tolerance induced with this regimen. Our results show that calcineurin inhibitors (cyclosporin A [CyA] or tacrolimus [FK]) inhibit development of long-term chimerism and abrogate tolerance induction in this model. Rapamycin (rapa), methylprednisolone (MP), FTY720, and mycophenolate mofetil (MMF), in contrast, have no negative effect on chimerism or tolerance development. Peripheral deletion of donor-reactive T cells, which usually occurs in the weeks following BMT in this model, is blocked by CyA and FK, but not by the other drugs tested. Furthermore, we found that the additional use of compatible immunosuppressive drugs (rapa plus MMF plus MP) allows the dose of TBI to be reduced, so that mixed chimerism and donor skin-graft acceptance can be achieved with 1 Gy using clinically feasible cell numbers. Thus, this protocol of BMT with costimulation blockade can be safely combined with a clinically tested immunosuppressive regimen to permit success with a lower dose of irradiation. These results should facilitate clinical application of this tolerance strategy.
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页码:2886 / 2893
页数:8
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