Chimerism and immunological tolerance in solid organ transplantation

Abstract

In solid organ transplantation, chimerism inevitably occurs via the coexistence of donor-derived cells from the graft and host cells throughout the recipient. However, long-term immunosuppressive treatment is needed to suppress host immune responses to the foreign organ graft. The deliberate induction of stable mixed bone marrow chimerism to achieve donor-specific immunological tolerance in solid organ graft recipients is an ambitious goal that may significantly contribute to the long-term survival of solid organ grafts and their recipients. While this strategy has been effectively established in laboratory animals and some promising clinical case series have been reported, widespread clinical application is still limited by the toxicity of the necessary conditioning regimens. On the other hand, the naturally occurring chimeric state resulting from the bidirectional transplacental cell trafficking during pregnancy, the so-called feto-maternal microchimerism, can also induce immune tolerance and thus influence the outcome of mother-to-child or child-to-mother organ transplantation. This review provides an overview of the field's historical development, clinical results, and underlying principles of (micro) chimerism-based tolerance.

Keywords: Chimerism; Donor; Feto-maternal microchimerism; Organ transplantation; Recipient; Tolerance.

Fig. 1

Milestones in preclinical and early clinical development of chimerism-based tolerance induction to solid organ grafts. NHPs = non-human primates

Fig. 2

Overview of clinical protocols for tolerance induction in kidney transplantation. KTX = kidney transplantation, BMT = bone marrow transplantation, HSCs = hematopoietic stem cells, FCs = facilitating cells, mAB = monoclonal antibody, ATG = anti-thymocyte globulin, MMF = mycophenolate mofetil

Fig. 3

Mechanism of tolerance induction in mixed chimerism. Donor-derived cells and tissues are depicted in red, host-derived cells in blue. After recipient preconditioning and the transfer of donor-derived hematopoietic stem cells (HSCs), both donor- and host-derived cells co-exist in the recipient bone marrow. Engraftment of donor-derived dendritic cells in the recipient thymus enables the mutual negative selection of newly developing host- and donor-reactive T cells. Peripheral tolerance mechanisms, such as the deletion of host- and donor-reactive T cell clones and the presence of regulatory T cells (T_reg) of both donor and recipient origin, also contribute to the long-term acceptance of the donor organ

Fig. 4

Feto-maternal microchimerism and organ transplantation. The bidirectional transplacental cell trafficking during pregnancy shapes a microchimeric state for both mother and offspring, with maternal (MMc) and fetal microchimeric cells (FMc) residing in fetal and offspring tissues, respectively, for a long time after birth. Such an early and prolonged exposure of the offspring to these maternal cells promotes immune tolerance to maternal antigens, which may influence the transplantation outcome in cases of mother-to-child organ donation