Induction of Tolerance Across Fully Mismatched Barriers by a Nonmyeloablative Treatment Excluding Antibodies or Irradiation Use

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Induction of Tolerance Across Fully Mismatched Barriers by a Nonmyeloablative Treatment Excluding Antibodies or Irradiation Use

Published Article
Cell transpantation


A mixed-chimerism approach is a major goal to circumvent sustained immunosuppression, but most of the proposed protocols need antibody treatment or host irradiation. Another promising experience involves bu-sulfan combined with cyclophosphamide treatment. Additionally, recent publications demonstrated that, differing from busulfan, treosulfan administration does not present severe organ or hemato toxicities. Currently, Duchenne muscular dystrophy (DMD) patients are treated with chronic immunosuppression for muscle precursor cell transplantation (MT). We have developed a safe tolerance approach within this cellular allotrans-plantation therapy background. Thus, we have conditioned, prior to a donor BALB/c MT, the dystrophic mouse model C57Bl10J mdx/mdx, with our treatment based on a donor-specific transfusion, then a treosul-fan treatment combined with single cyclophosphamide dose, and finally a donor bone marrow transplantation (TTCB). A first MT was performed in all mixed chimeric mice resulting from the TTCB treatment in the left tibialis anterior (TA) muscles. A second MT from the same donor strain was performed 100 days later in the right TA without any additional therapy. Results show that all treated mice developed permanent mixed chimerism. Long-lasting donor-positive fibers were present in both TAs of the mice, which received MT after the TTCB treatment. Only a basal level of infiltration was observed around donor fibers and mixed chimeric mice rejected third-party haplotype skin grafts. Thus, mixed chimerism development with this TTCB conditioning regimen promotes donor-specific stable tolerance, avoiding costimulatory blockade anti-bodies or irradiation use and side effects of sustained immunosuppressive treatments. This protocol could be eventually applied for MT to DMD patients or others tissue transplantations. INTRODUCTION lished, leading to the absence of both graft-versus-host and host-versus-graft diseases (44,61). Many protocols to induce mixed chimerism have been investigated, but Rejection of organ or cell allotransplantation is currently prevented with immunosuppressive drugs such as most of them required antibody treatment or irradiation of the host (9,12,28). An interesting protocol based on cyclosporine, FK506, mycophenolate mofetil, etc. Although these drugs are very effective for this purpose, stable multilineage chimerism involved a nonmyeloabla-tive treatment with susulfan (Busilvex) in mice primed their nonspecific immunosuppression increases the re-cipient's risks of developing opportunistic infections and with allogeneic spleen cells followed by a single dose of an immunosuppressive drug, cyclophosphamide (Pro-malignancies. Moreover, their use is associated with some toxicities (6,14,15,37,38,54). In addition, chronic cytox) (56). However, busulfan administration is associated with severe organ and hematotoxicity, which may rejection is not well controlled by these immunosuppres-sive agents. An alternative approach to permit graft ac-not be avoided, even after reduced intensity conditioning (31,40,42,51,53). ceptance by the host immune system is to induce im-munological tolerance. The establishment of mixed A busulfan analog already used in clinics is treosul-fan (Ovastat), a prodrug of a bifunctional alkylating hematopoietic chimerism has several advantages over other tolerance-inducing methods. In mixed chimeras, cytotoxic agent. It is indicated for oral or IV treatment of human advanced ovarian cancer (13,16,35,36). Re-tolerance to both host and donor is permanently estab

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