Murine models of transplantation tolerance through mixed chimerism: advances and roadblocks

Abstract

Organ transplantation is the treatment of choice for patients with end-stage organ failure, but chronic immunosuppression is taking its toll in terms of morbidity and poor efficacy in preventing late graft loss. Therefore, a drug-free state would be desirable where the recipient permanently accepts a donor organ while remaining otherwise fully immunologically competent. Mouse studies unveiled mixed chimerism as an effective approach to induce such donor-specific tolerance deliberately and laid the foundation for a series of clinical pilot trials. Nevertheless, its widespread clinical implementation is currently prevented by cytotoxic conditioning and limited efficacy. Therefore, the use of mouse studies remains an indispensable tool for the development of novel concepts with potential for translation and for the delineation of underlying tolerance mechanisms. Recent innovations developed in mice include the use of pro-apoptotic drugs or regulatory T cell (T_reg ) transfer for promoting bone marrow engraftment in the absence of myelosuppression and new insight gained in the role of innate immunity and the interplay between deletion and regulation in maintaining tolerance in chimeras. Here, we review these and other recent advances in murine studies inducing transplantation tolerance through mixed chimerism and discuss both the advances and roadblocks of this approach.

Keywords: rodent; tolerance/suppression/anergy; transplantation.

Figure 1

Mechanisms maintaining tolerance in mixed chimeras: the following mechanisms contribute to tolerance after donor stem cells have engrafted in a recipient's bone marrow niches, leading to hematopoietic mixed chimerism. Donor‐derived antigen‐presenting cells (APCs) (dendritic cells and B cells) invade the thymus to eliminate developing donor‐reactive T cells (central clonal deletion). Pre‐existing alloreactive T cells and those escaping central deletion are either eliminated in the periphery (peripheral clonal deletion) or suppressed by regulatory T cells (T_regs) (peripheral regulation). Peripheral regulation can either occur in secondary lymphoid organs or in the allograft itself (intragraft regulation). Natural killer (NK) cells adapt to donor cells by reshaping their receptor repertoire (NK cell education).

Figure 2

Factors influencing the translational relevance of mouse studies for chimerism‐based tolerance: Several factors make mouse protocols more relevant for potential clinical translation. With regard to patient safety, conditioning should ideally be non‐cytotoxic and drugs tested should be clinically available or at least under development. The donor and recipient pairs should be mismatched in major (MHC) and minor antigens (miHag), as is typically the case in clinical transplantation. A clinically realistic dose of donor bone marrow should be deployed and recipients of different ages should be tested. Different types of donor grafts (e.g. heart and skin) should be evaluated to test for tolerance in order to allow assessment of acute and chronic immunological damage and to include a range of tissue‐specific antigens. Mice not kept under specific pathogen‐free conditions should be evaluated as recipients, as heterologous immunity constitutes a considerable barrier to tolerance induction.