Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

Abstract

Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans.Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells. Keywords: Clonal deletion Mixed chimerism Nonmyeloablative conditioning Transplantation tolerance Treg cells IntroductionLong-term outcome after organ transplantation has improved little in the past few decades and remains suboptimal [1]. Grafts are still lost to immunological damage that is not prevented by current immunosuppressive drug regimens [2], which in addition cause severe adverse effects, including increased risks of malignancy and infection. Therefore, immunological tolerance -i.e., a state of specific nonresponsiveness to donor antigens -remains the "Holy Grail" in clinical organ transplantation. Among the Correspondence: Dr. Thomas Wekerle e-mail: Thomas.Wekerle@meduniwien.ac.at numerous strategies that have been tested over time, chimerismbased tolerance induction appears particularly promising [3,4]. This concept is based on the cotransplantation of donor hematopoietic stem cells (HSCs) (contained in bone marrow (BM) or mobilized peripheral blood stem cells (mPBSCs)) into the organ transplant recipient who has been sufficiently preconditioned, either with radiation or cytotoxic drugs, to permit HSC engraftment. If engraftment is achieved, multilineage chimerism ensues, which is termed "mixed" chimerism if donor representation is clearly detectable (by flow cytometry, for instance) but is less than 100% (which would constitute "full" chimerism) and can be achieved with less extensive recipient conditioning.In 1945 Ray Owen described a naturally occur...

Minor Antigen Disparities Impede Induction of Long Lasting Chimerism and Tolerance through Bone Marrow Transplantation with Costimulation Blockade

“…Peripheral and central clonal deletion are important mechanisms for the induction and maintenance of tolerance in models of mixed chimerism induced by BMT plus CB [20]. Notably not all mice become chimeric with such a protocol and not all chimeric mice accept donor skin grafts indefinitely.…”

Irradiation before and donor splenocyte infusion immediately after transplantation induce tolerance to lung, but not heart allografts in miniature swine

“…Other groups have likewise described the importance of this, often transient, leucocyte chimerism and its role for the onset of operational tolerance towards allografts, in recent years .…”

Donor-Specific Regulatory T Cells Acquired from Tolerant Mice Bearing Cardiac Allograft Promote Mixed Chimerism and Prolong Intestinal Allograft Survival

“…Similar results were found in peripheral blood, which strongly suggests achievement of immune tolerance in these recipient mice. Besides, clonal deletion is considered the backbone of tolerance through chimerism (40), and most groups investigating tolerance associated with chimerism-inducing strategies have reported deletion of donor-reactive CD4 + T cells (11). We also observed significant deletion of Vβ5 + and Vβ11 + MMTV-reactive CD4 + and CD8 + T cells in DSTreg-cell-induced chimeras.…”