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Bone marrow chimerism and tolerance induced by single-dose cyclophosphamide.
Junji Okayama1, Saiho Ko, Hiromichi Kanehiro
1First Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan.
The Journal of Surgical Research
|June 3, 2004
Summary
A single dose of cyclophosphamide (CYP) can induce hematopoietic chimerism and organ transplant tolerance across major histocompatibility complex (MHC) barriers. The optimal dose of 150 mg/kg establishes tolerance without causing graft-versus-host disease (GVHD).
Area of Science:
- Transplantation immunology
- Immunosuppression strategies
- Hematopoietic stem cell transplantation
Background:
- Hematopoietic chimerism is crucial for donor-specific transplant tolerance.
- Safer preclinical methods for inducing chimerism are needed for clinical translation.
- Cyclophosphamide (CYP) is evaluated as a simple pretreatment regimen for tolerance induction.
Purpose of the Study:
- To assess the efficacy of a cyclophosphamide (CYP)-based protocol for inducing hematopoietic chimerism.
- To determine the optimal CYP dose for achieving organ transplant tolerance across major histocompatibility complex (MHC) barriers in a rat model.
- To evaluate the safety profile, specifically the incidence of graft-versus-host disease (GVHD), associated with different CYP doses.
Main Methods:
- Rats received bone marrow cells from donors across MHC barriers post-single-dose CYP pretreatment.
- Various doses of CYP (50, 100, 150, 200 mg/kg) were administered prior to bone marrow infusion.
- Hematopoietic chimerism was quantified using flow cytometry.
- Donor-specific (BN) and third-party (BUF) heart allografts were transplanted to assess tolerance.
Main Results:
- A CYP dose of 150 mg/kg induced significant donor chimerism (36.5%) without GVHD, leading to acceptance of donor-specific heart allografts (>100 days).
- Higher dose (200 mg/kg) resulted in high chimerism but severe GVHD, causing mortality in most recipients.
- Lower doses (100 and 50 mg/kg) led to transient or no chimerism and allograft rejection.
- Third-party allografts were rejected, indicating specific donor tolerance.
Conclusions:
- A single dose of cyclophosphamide effectively induces hematopoietic chimerism and donor-specific organ transplant tolerance across MHC barriers.
- The dose of 150 mg/kg cyclophosphamide represents an optimal balance for achieving tolerance without significant graft-versus-host disease.
- This regimen shows promise as a safer pretreatment strategy for clinical transplantation.