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Donor-specific tolerance induction in composite tissue allografts

R D Foster1, L Fan, M Neipp

  • 1Division of Plastic and Reconstructive Surgery, University of California at San Francisco, USA.

American Journal of Surgery
|January 5, 1999
PubMed
Summary

This study developed a rat model for composite tissue allograft (CTA) tolerance without long-term immunosuppression. Stable mixed allogeneic chimerism led to rejection-free survival of hindlimb allografts.

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Area of Science:

  • Transplantation immunology
  • Regenerative medicine
  • Immunosuppression strategies

Background:

  • Prolonged composite tissue allograft (CTA) survival is possible with immunosuppressive drugs in animals.
  • Long-term immunosuppression for CTAs is clinically unacceptable for most patients.
  • Need for a reliable CTA tolerance induction model in adult rats across MHC mismatch without long-term immunosuppression.

Purpose of the Study:

  • To develop a reliable model for composite tissue allograft (CTA) tolerance induction.
  • To achieve CTA tolerance in adult rats with a strong MHC mismatch.
  • To eliminate the need for long-term immunosuppression in CTA survival.

Main Methods:

  • Preparation of rat chimeras using WF (RT1Au) + ACI (RT1Aa) strains with MHC incompatibility.

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  • T-cell depleted syngeneic and allogeneic bone marrow (BM) injection into irradiated recipients.
  • Administration of a single dose of anti-lymphocyte serum (ALS) and short-term tacrolimus.

    • Main Results:

    • Stable mixed allogeneic chimerism (WF/ACI) achieved in 10/13 animals for over 12 months.
    • Multilineage chimerism confirmed engraftment of pluripotent rat stem cells.
    • Animals with >60% donor chimerism showed no limb rejection; those with <20% showed rejection.
    • Successful gross motor and sensory reinnervation observed in 6/9 rats.

    Conclusions:

    • Stable mixed allogeneic chimerism is achievable in a rat hindlimb composite tissue allotransplantation model.
    • Hindlimb allografts in mixed allogeneic chimeras demonstrate prolonged, rejection-free survival.
    • This study presents the first reliable model for rejection-free CTA survival in adult animals without long-term immunosuppression across a strong MHC mismatch.