The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Zheng, HB; Watkins, B; Tkachev, V; Yu, S; Tran, D; Furlan, S; Zeleski, K; Singh, K; Hamby, K; Hotchkiss, C; Lane, J; Gumber, S; Adams, AB; Cendales, L; Kirk, AD; Kaur, A; Blazar, BR; Larsen, CP; Kean, LS

Published Date

  • March 2017

Published In

Volume / Issue

  • 17 / 3

Start / End Page

  • 657 - 670

PubMed ID

  • 27500470

Pubmed Central ID

  • PMC5338742

Electronic International Standard Serial Number (EISSN)

  • 1600-6143

Digital Object Identifier (DOI)

  • 10.1111/ajt.14006


  • eng

Conference Location

  • United States