Chimerism-based tolerance in organ transplantation: preclinical and clinical studies

Abstract

Induction of allograft tolerance has been considered the ultimate goal in organ transplantation. Although numerous protocols to induce allograft tolerance have been reported in mice, a chimerism-based approach through donor haematopoietic stem cell transplantation has been the only approach to date that induced allograft tolerance reproducibly following kidney transplantation in man. Renal allograft tolerance has been achieved by induction of either transient mixed chimerism or persistent full donor chimerism. Although the risk of rejection may be low in tolerance achieved via durable full donor chimerism, the development of graft-versus-host disease (GVHD) has limited the wider clinical application of this approach. In contrast, tolerance induced by transient mixed chimerism has not been associated with GVHD, but the risk of allograft rejection is more difficult to predict after the disappearance of haematopoietic chimerism. Current efforts are directed towards the development of more clinically feasible and reliable approaches to induce more durable mixed chimerism in order to widen the clinical applicability of these treatment regimens.

Keywords: GVHD; NHP; TBI; TI; TLI; chimerism; cyclophosphamide; durable mixed chimerism; full donor chimerism; haematopoietic stem cell transplantation; living-donor kidney transplantation; persistent mixed chimerism; transient mixed chimerism; transplantation tolerance induction.

Figure 1

Three pilot studies of renal allograft tolerance induction in human living‐donor kidney transplantation at Stanford, Northwestern and Massachusetts General Hospital (MGH). Stanford human leucocyte antigen (HLA)‐matched conditioning protocol consists of total lymphoid irradiation (TLI) (120 cGy/day, 10 daily doses starting on postoperative day 1) and rabbit anti‐thymocyte globulin (rATG) (1·5 mg/kg/day, five daily doses starting intra‐operatively). Following the last dose of TLI, CD34⁺‐enriched donor peripheral blood stem cells are infused. The recipients are then maintained on calcineurin inhibitor (CNI)/mycophenolate mofetil (MMF)/steroid therapy until weaning was attempted several months later (a). Northwestern protocol consists of Fludarabine (30 mg/kg on days −4, −3 and −2), cyclophosphamide (CP) (50 mg/kg on days −3 and +3) and total body irradiation (TBI) (200 cGy) on day −1. This is followed by kidney transplantation (KTx), then donor haematopoietic stem cell transplantation (HSCT) on day +1. Immunosuppression consists of MMF and tacrolimus starting on day 0 and tapered off slowly by 1 year. In addition, the Northwestern regimen includes infusion of a unique ‘facilitating cell’ [a mixture of CD8⁺/T cell receptor (TCR^–)] in the attempt to enhance engraftment and reduce further the risk of graft‐versus‐host disease (GVHD) (b). The initial MGH conditioning regimen for human leucocyte antigen (HLA)‐mismatched KTx included CP, TI anti‐CD2 monoclonal antibody (mAb) and post‐transplant CNI administration. To prevent donor‐specific antibody (DSA) development, we add rituximab therapy subsequently around the peri‐transplant period. As acute kidney injury had not been observed in the non‐human primate (NHP) studies that utilized TBI rather than CP in the conditioning regimen, a revised regimen in which low‐dose TBI replaced CP, has been evaluated recently in three recipients (c). Open circles indicate host haematopoietic cells and closed circles indicate donor haematopoietic cells.