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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.

Publication ,  Journal Article
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 ...
Published in: Am J Transplant
March 2017

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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Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

March 2017

Volume

17

Issue

3

Start / End Page

657 / 670

Location

United States

Related Subject Headings

  • Virus Activation
  • Transplantation, Homologous
  • Transplantation Tolerance
  • Transplantation Conditioning
  • Transplantation Chimera
  • T-Lymphocytes
  • Surgery
  • Skin Transplantation
  • Macaca mulatta
  • Hematopoietic Stem Cell Transplantation
 

Citation

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Zheng, H. B., Watkins, B., Tkachev, V., Yu, S., Tran, D., Furlan, S., … Kean, L. S. (2017). The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques. Am J Transplant, 17(3), 657–670. https://doi.org/10.1111/ajt.14006
Zheng, H. B., B. Watkins, V. Tkachev, S. Yu, D. Tran, S. Furlan, K. Zeleski, et al. “The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques.Am J Transplant 17, no. 3 (March 2017): 657–70. https://doi.org/10.1111/ajt.14006.
Zheng HB, Watkins B, Tkachev V, Yu S, Tran D, Furlan S, et al. The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques. Am J Transplant. 2017 Mar;17(3):657–70.
Zheng, H. B., et al. “The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques.Am J Transplant, vol. 17, no. 3, Mar. 2017, pp. 657–70. Pubmed, doi:10.1111/ajt.14006.
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. The Knife's Edge of Tolerance: Inducing Stable Multilineage Mixed Chimerism but With a Significant Risk of CMV Reactivation and Disease in Rhesus Macaques. Am J Transplant. 2017 Mar;17(3):657–670.
Journal cover image

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

March 2017

Volume

17

Issue

3

Start / End Page

657 / 670

Location

United States

Related Subject Headings

  • Virus Activation
  • Transplantation, Homologous
  • Transplantation Tolerance
  • Transplantation Conditioning
  • Transplantation Chimera
  • T-Lymphocytes
  • Surgery
  • Skin Transplantation
  • Macaca mulatta
  • Hematopoietic Stem Cell Transplantation