ArticleAmerican journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons2017
The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques.
Article in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 24 citations in OpenAlex.
- Article
- Cytomegalovirus latency-the sum of subtleties.Journal of virology · 2025Review
- Efficient long-term multilineage engraftment of CD33-edited hematopoietic stem/progenitor cells in nonhuman primates.Molecular therapy. Methods & clinical development · 2023Article
- Helical TomoTherapy Total Lymphoid Irradiation and Hematopoietic Cell Transplantation for Kidney Transplant Tolerance in Rhesus Macaques.Transplant international : official journal of the European Society for Organ Transplantation · 2023Article
- Graft-versus-host disease: teaching old drugs new tricks at less cost.Frontiers in immunology · 2023Review
- Apoptotic Donor Cells in Transplantation.Frontiers in immunology · 2021Review
- MCMV Dissemination from Latently-Infected Allografts Following Transplantation into Pre-Tolerized Recipients.Pathogens (Basel, Switzerland) · 2020Article
- Murine cytomegalovirus dissemination but not reactivation in donor-positive/recipient-negative allogeneic kidney transplantation can be effectively prevented by transplant immune tolerance.Kidney international · 2020Article
- Impact of CMV Reactivation, Treatment Approaches, and Immune Reconstitution in a Nonmyeloablative Tolerance Induction Protocol in Cynomolgus Macaques.Transplantation · 2020Article
- Long-term tolerance of islet allografts in nonhuman primates induced by apoptotic donor leukocytes.Nature communications · 2019Article
- Therapeutically relevant engraftment of a CRISPR-Cas9-edited HSC-enriched population with HbF reactivation in nonhuman primates.Science translational medicine · 2019Article
- Transplant research in nonhuman primates to evaluate clinically relevant immune strategies in organ transplantation.Transplantation reviews (Orlando, Fla.) · 2019Review
- Advancing the technology for head transplants: From immunology to peripheral nerve fusion.Surgical neurology international · 2019Article
- Animal Models for Preclinical Development of Allogeneic Hematopoietic Cell Transplantation.ILAR journal · 2018Article
- Evidence for persistence of the SHIV reservoir early after MHC haploidentical hematopoietic stem cell transplantation.Nature communications · 2018Article
- Apoptotic cell-based therapies for promoting transplantation tolerance.Current opinion in organ transplantation · 2018Review
- CD28 blockade controls T cell activation to prevent graft-versus-host disease in primates.The Journal of clinical investigation · 2018Article
- Allogeneic stem cell transplantation in fully MHC-matched Mauritian cynomolgus macaques recapitulates diverse human clinical outcomes.Nature communications · 2017Article
- Combined OX40L and mTOR blockade controls effector T cell activation while preserving TScience translational medicine · 2017Article
- Chimerism-based tolerance in organ transplantation: preclinical and clinical studies.Clinical and experimental immunology · 2017Review
Corrections and comments
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Authors and funding
19 authors at 6 institutions in 1 country.
Funding
Abstract
Although stable mixed-hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC-matched nonhuman primates (NHPs), a busulfan plus combined belatacept and anti-CD154-based regimen could induce long-lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected, and tolerance to skin allografts was not achieved. Here, we describe an adaptation of this strategy, with the addition of low-dose total body irradiation to our conditioning regimen. This strategy has successfully induced multilineage hematopoietic chimerism in MHC-matched transplants that was stable for as long as 24 months posttransplant, the entire length of analysis. High-level T cell chimerism was achieved and associated with significant donor-specific prolongation of skin graft acceptance. However, we also observed significant infectious toxicities, prominently including cytomegalovirus (CMV) reactivation and end-organ disease in the setting of functional defects in anti-CMV T cell immunity. These results underscore the significant benefits that multilineage chimerism-induction approaches may represent to transplant patients as well as the inherent risks, and they emphasize the precision with which a clinically successful regimen will need to be formulated and then validated in NHP models.
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