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A clinically relevant CTLA4-Ig-based regimen induces chimerism and tolerance to heart grafts
S Li1, M Thanikachalam, M Pang
1Division of Cardiothoracic Surgery, University of Miami School of Medicine, Florida 33136, USA.
Insights
A novel CTLA4-Ig conditioning regimen induced mixed chimerism and donor-specific tolerance in simultaneous heart and bone marrow transplants. This approach shows promise for clinical applications in transplantation tolerance.
Area of Science:
- Immunology
- Transplantation Biology
- Regenerative Medicine
Background:
- Investigating strategies to induce immune tolerance in organ transplantation.
- Evaluating the efficacy of CTLA4-Ig in combination with bone marrow transplantation.
Purpose of the Study:
- To determine if a CTLA4-Ig-based conditioning regimen can achieve mixed chimerism and donor-specific tolerance during simultaneous heart and bone marrow transplantation.
Main Methods:
- Utilized fully mismatched rat strain combinations for transplantation.
- Administered total-body irradiation, bone marrow, and cardiac allografts on day 0.
- Applied a conditioning regimen including CTLA4-Ig, tacrolimus, and antilymphocyte serum post-transplant.
Main Results:
- All bone marrow recipients achieved mixed chimerism (25% at 1 year) and permanent cardiac allograft acceptance (>375 days).
- Animals receiving conditioning but no bone marrow rejected cardiac allografts within 51 days.
- Successful heart graft recipients also accepted donor-specific skin grafts but rejected third-party grafts.
Conclusions:
- A non-toxic CTLA4-Ig-based regimen effectively induces mixed chimerism and donor-specific tolerance in simultaneous heart and bone marrow transplantation.
- This conditioning strategy holds potential for future clinical use in transplantation.
Background:
We determined whether a nontoxic CTLA4-Ig-based conditioning regimen effected mixed chimerism and donor-specific tolerance when heart and bone marrow were transplanted simultaneously.
Methods:
Fully mismatched rat strain combinations were used. Recipients received total-body irradiation (300 centigrays), bone marrow (10(8) cells), and cardiac transplants from the donor on day 0. Subsequently, recipient animals received CTLA4-Ig (2 mg/kg, every other day, x 5 doses), tacrolimus (1 mg/kg/day; days 0 to 9), and one dose (10 mg) of antilymphocyte serum on day 10.
Results:
All bone marrow recipients (n = 7) developed mixed chimerism (mean = 25% +/- 9% at 1 year) and accepted cardiac allografts permanently (> 375 +/- 32 days). Recipients that received conditioning regimen but no bone marrow (n = 5) rejected donor hearts within 51 +/- 13 days (p < 0.01). Recipients that accepted heart grafts also permanently accepted (> 180 days) donor-specific skin grafts, but rapidly rejected (< 10 days) third-party skin grafts.
Conclusions:
A nontoxic CTLA4-Ig-based conditioning regimen effects mixed chimerism and donor-specific tolerance when heart and bone marrow are transplanted simultaneously. This regimen may have clinical application.
