Preclinical and clinical studies on kidney allograft tolerance via hematopoietic chimerism

In current clinical practice, successful kidney transplantation requires lifelong immunosuppression to prevent graft rejection, which is unfortunately associated with significant morbidity, mortality, and reduced quality of life. Over the past 2 decades, there has been growing interest and encouraging progress in clinical therapeutic approaches to transplantation tolerance, defined as stable allograft acceptance in the absence of chronic immunosuppression. To date, these advances have largely been based on the concept of hematopoietic chimerism, achieved by bone marrow or hematopoietic stem cell transplantation performed at the time of solid organ transplant. Recipients undergo a conditioning regimen prior to combined kidney and bone marrow transplantation that allows donor-derived hematopoietic cells to expand persistently or transiently. These clinical trials were based on foundational concepts developed over half a century of preclinical work in mice and large animal models. Preclinical models have also proven essential in addressing unforeseen challenges that arise during clinical trials. In this review, we discuss the foundational basic studies in murine models and preclinical work in large animal models and the current clinical efforts to achieve allograft tolerance in kidney transplantation.