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Development of Donor-Specific Chimerism and Tolerance in Composite Tissue Allografts Under abT-Cell Receptor Monoclonal Antibody and Cyclosporine-A Treatment Protocols

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ABSTRACT

A donor-specific tolerance was induced in rat hind limb allografts across major histocompatibility complex (MHC) barrier over a 35-day course of abT-cell receptor (abTCR) monoclonal antibody (mAb) and cyclosporine-A (CsA) therapy. The shorter course of immunomodulating protocol on the development of donor-specific lymphoid chimerism and tolerance induction was investigated.

Fifty-two hind limb transplantations across major histocompatibility complex barrier between Lewis-Brown-Norway donors (LBN, RT1^l+n) and Lewis recipients (LEW, RT1^l) were performed to test the impact of 21-, 7-, and 5-day protocols of combined α ßTCR mAb/CsA treatment on tolerance induction. The monotherapies of CsA and T-cell receptor served as controls. Donor-specific tolerance and immunocompetence were tested by mixed lymphocyte reaction in vitro and by standard skin grafting in vivo. The efficacy of immunosuppressive protocol and donor-specific chimerism was assessed by flow cytometry.

Without immunosuppression, allografts were rejected at day 7. Monotherapy with CsA and abTCR prolonged survival up to 21 and 13 days, respectively. All transplants under 5, 7, and 21 days of combined abTCR mAb/CsA therapy survived >350 days without rejection. At post-transplant day 100, clinical tolerance and immunocompetence were confirmed by skin graft acceptance from the donor and rejection of the third-party alloantigen. Mixed lymphocyte reaction in vitro revealed unresponsiveness to the host and donor antigens but strong reactivity against third-party alloantigens. Donor chimerism ranged between 10% and 12% for CD4⁺/RT1ⁿ⁺ and 6% and 9% for CD8⁺/RT1ⁿ⁺ cells.

The allo-unresponsiveness was directly associated with the development of stable, multilineage chimerism in the tolerated recipients of limb allografts.