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The Knife’s Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism But With A Significant Risk of CMV Reactivation and Disease in Rhesus Macaques
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September 19 2016
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Source: Am J Transplant. 17(3):657-670
[PDF-1.91 MB]
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Alternative Title:Am J Transplant
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Description: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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Pubmed ID:27500470
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Pubmed Central ID:PMC5338742
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Funding:R01 HL095791/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; P01 AI056299/NIAID NIH HHS/National Institute of Allergy and Infectious Diseases Extramural Activities/United States ; P51 OD011132/ODCDC CDC HHS/Office of the Director/United States ; R01 HL118979/NHLBI NIH HHS/National Heart, Lung, and Blood Institute/United States ; U19 AI051731/NIAID NIH HHS/National Institute of Allergy and Infectious Diseases Extramural Activities/United States
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