Induction of Tolerance through Mixed Chimerism

Abstract

"Mixed chimerism" refers to a state in which the lymphohematopoietic system of the recipient of allogeneic hematopoietic stem cells comprises a mixture of host and donor cells. This state is usually attained through either bone marrow or mobilized peripheral blood stem cell transplantation. Although numerous treatment regimens have led to transplantation tolerance in mice, the induction of mixed chimerism is currently the only treatment modality that has been successfully extended to large animals and to the clinic. Here we describe and compare the use of mixed chimerism to establish transplantation tolerance in mice, pigs, monkeys, and in the clinic. We also attempt to correlate the mechanisms involved in achieving tolerance with the nature of the tolerance that has resulted in each case.

The role of donor-derived veto cells in nonmyeloablative haploidentical HSCT

“…This state of mixed chimerism, has largely been associated with improved immunity and central tolerance. [35][36][37][38][39] The major advantage of RIC is also its main caveat, while sparing much of the host immunity improves immune reconstitution; it also allows a robust host-versus-graft response, which increases the chances of graft rejection.…”

Tolerance--Is It Worth It?

“…A promising approach developed by several groups makes use of strategies to induce mixed chimerism (Sachs et al 2013). This is accomplished by a stem-cell infusion in combination with a transplant from the same donor.…”

Innate Immune Cell Collaborations Instigate Transplant Tolerance

“…The induction of a similar robust tolerant state clinically would remove the recipient's need for toxic immunosuppressants and provide freedom from acute and chronic rejection. Indeed, when comparable regimens are tried clinically, they have shown promise by inducing transplant tolerance in a subset of patients and often enable recipient tapering off immunosuppression (1). Yet there has been a failure to fully recapitulate the consistent and robust immunological tolerance observed experimentally.…”

“…Yet there has been a failure to fully recapitulate the consistent and robust immunological tolerance observed experimentally. Recipient chimerism tends to be transient and cellular and antibody-mediated rejection often thwarts successful immunosuppression withdrawal (1). Thus, a better understanding of the precise immunological mechanisms that consistently mediate tolerance in animals will hopefully lead to uniform and robust tolerance induction in the clinic.…”

“…Total lymphoid irradiation (TLI), T cell depletion and donor bone marrow transplantation (BMT) consistently induces mixed chimerism and a state of donor-specific immunological tolerance to allografts in laboratory animals (1). The induction of a similar robust tolerant state clinically would remove the recipient's need for toxic immunosuppressants and provide freedom from acute and chronic rejection.…”