Development of donor‐specific chimerism and tolerance in composite tissue allografts under αβ‐T‐cell receptor monoclonal antibody and cyclosporine a treatment protocols

Abstract

Recently, we induced donor-specific tolerance to rat hindlimb allografts under a 35-day course of alphabeta-T-cell receptor monoclonal antibody (alphabeta-TCR mAb) and cyclosporine A (CsA). In this report, we investigated the role of shorter alphabeta-TCR/CsA protocols on tolerance induction. We performed 52 hindlimb transplantations, between Lewis-Brown-Norway (LBN, F1) donors and Lewis recipients to test the impact of 21-, 7-, and 5-day protocols of combined alphabeta-TCR/CsA treatment on tolerance induction. Donor-specific tolerance and immunocompetence were tested by mixed lymphocyte reaction (MLR) in vitro and by standard skin grafting in vivo. The efficacy of immunosuppressive protocol and donor-specific chimerism was assessed by flow cytometry. All transplants under 5, 7, and 21 days of combined alphabeta-TCR/CsA therapy survived over 350 days. Clinical tolerance and immunocompetence were confirmed by skin grafting in vivo and MLR in vitro. Flow cytometry revealed a high level of donor chimerism in the peripheral blood of long-term survivors. The extension of survival of limb allografts and allo-unresponsiveness were directly associated with the development of stable chimerism in the tolerant recipients.

Living Bone Allotransplants Survive by Surgical Angiogenesis Alone: Development of a Novel Method of Composite Tissue Allotransplantation

“…Tissue survival associated with donor-specific tolerance has only recently been satisfactorily demonstrated in studies that made use of rat hind limb and vascularized skin transplant models, monoclonal ab T-cell receptor antibodies, and a short course of either FK-506 or cyclosporine A [50][51][52] . Although mixed chimerism has been considered a promising method of tolerance induction, the method remains problematic for nonlife-critical transplants 53 .…”

Applications of Bilateral Vascularized Femoral Bone Marrow Transplantation for Chimerism Induction Across the Major Histocompatibility (MHC) Barrier

“…17 Next, we tested short-term protocol of combined ␣␤ T-cell receptor monoclonal antibody and cyclosporine A (␣␤-TCRmAb/CsA) for tolerance induction in semiallogenic and fully major histocompatibility (MHC) mismatched limb transplants. 18,19 In both models, limb transplants served as a source of VBMT, and indefinite survival and tolerance were confirmed by skin grafting and MLR assay.…”

Immunologic Approaches to Composite Tissue Allograft

“…75,108 Furthermore, it was also shown that these mAbs decreased the expression of the TCR on the surface of the T cell. 109,110 Initial studies using anti-TCR mAbs on an experimental cardiac allograft model demonstrated that they abrogated accelerated rejection (in a hamster-to-rat model) and prolonged cardiac allograft survival in a dose-dependent fashion. 111 Recently, several studies used anti-TCR mAbs in CTA.…”