Tolerance induction with donor hematopoietic stem cell infusion in kidney transplantation: a single-center experience in China with a 10-year follow-up

Abstract

Background: Immunosuppressive therapy after life-saving kidney transplantation increases the risk of infection, cardiovascular diseases, metabolic diseases, and cancer. To date, four centers (three in the USA and one in South Korea) have reported clinical tolerance trials in kidney transplantation. We performed the first Chinese clinical trial in which kidney transplantation was combined with donor hematopoietic stem cell (DHSC) infusion to induce tolerance. This study summarizes the 10-year follow-up results.Methods: From 2009 to 2017, 11 donor/recipient pairs underwent living-related kidney transplantation combined with DHSC infusion. Two of the pairs were human leukocyte antigen (HLA)-matched, and nine were HLA-mismatched. DHSCs were mobilized using granulocyte colony-stimulating factor (G-CSF) and harvested 1 day before transplantation. The recipients received consecutive total lymphoid irradiation (TLI) for 3 days before kidney transplantation. The induction drug was anti-thymocyte globulin (ATG).DHSCs were infused on days 2, 4, and 6 post surgery. All patients were followed-up until Dec 2019. Routine laboratory examinations, chimerism, biopsies, and mixed lymphocyte reactions were performed.Results: One HLA-matched recipient had 30-50% chimerism, while the other patients had less than 1% chimerism. Recipients had donor-specific hyporesponsiveness (DSH) while sustaining normal reactivity to non-donors in mixed lymphocyte reactions. All recipients were followed up for 717-3,918 days. One recipient lost allograft function, and 10 recipients had stable renal function. None of the 11 recipients developed myelosuppression or graft-versus-host disease (GVHD) post transplantation. Our protocol did not increase the risk of infection. Allograft biopsy confirmed that one patient had mild rejection with Banff grade IA, while the other ten recipients did not develop rejection. Five patients were able to reduce the dose of their immunosuppressive therapy.Conclusions: Our immune tolerance induction protocol, which used DHSC infusion and TLI, achieved low dose immunosuppression with long-term stable kidney allograft survival in Chinese patients.

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapeutic Strategy for Acute Kidney Injury

“…Among these, mesenchymal stem cells (MSCs) are considered to be one of the most promising types of cells for cellular therapy because of their ease of harvesting, low immunogenicity, and ability to be stored and expanded in vitro (15,16). Notably, numerous preclinical and clinical studies have confirmed the potential role of MSCs in kidney protection and repair (17)(18)(19)(20)(21)(22). However, the mechanisms by which MSCs exert their therapeutic effects remain controversial.…”

“…However, the mechanisms by which MSCs exert their therapeutic effects remain controversial. Researchers previously believed that MSCs replaced injured cells through differentiation after introduction into the body, but this view was challenged by the fact that MSCs disappeared from the injured kidney and other organs within 72 h after administration, suggesting that differentiation and replacement of damaged cells by stem cells is probably a rare and late event in AKI in vivo (22,23).…”