Induction of chimerism in rhesus macaques through stem cell transplant and costimulation blockade-based immunosuppression

L. S. Kean, A. B. Adams, E. Strobert, R. Hendrix, S. Gangappa, T. R. Jones, N. Shirasugi, M. R. Rigby, K. Hamby, J. Jiang, H. Bello, D. Anderson, K. Cardona, M. M. Durham, T. C. Pearson, C. P. Larsen

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

A strategy for producing high-level hematopoietic chimerism after non-myeloablative conditioning has been established in the rhesus macaque. This strategy relies on hematopoietic stem cell transplantation after induction with a non-myeloablative dose of busulfan and blockade of the IL2-receptor in the setting of mTOR inhibition with sirolimus and combined CD28/CD154 costimulation blockade. Hematopoietic stem cells derived from bone marrow and leukopheresis products both were found to be successful in inducing high-level chimerism. Mean peripheral blood peak donor chimerism was 81% with a median chimerism duration of 145 days. Additional immune modulation strategies, such as pre-transplant CD8 depletion, donor-specific transfusion, recipient thymectomy or peritransplant deoxyspergualin treatment did not improve the level or durability of chimerism. Recipient immunologic assessment suggested that chimerism occurred amidst donor-specific down-regulation of alloreactive T cells, and the reappearance of vigorous T-mediated alloreactivity accompanied rejection of the transplants. Furthermore, viral reactivation constituted a significant transplant-related toxicity and may have negatively impacted the ability to achieve indefinite survival of transplanted stem cells. Nevertheless, this chimerism-induction regimen induced amongst the longest-lived stem cell chimerism reported to date for non-human primates and thus represents a platform upon which to evaluate emerging tolerance-induction strategies.

Original languageEnglish (US)
Pages (from-to)320-335
Number of pages16
JournalAmerican Journal of Transplantation
Volume7
Issue number2
DOIs
StatePublished - Feb 2007
Externally publishedYes

Keywords

  • Chimerism
  • Costimulation
  • Non-human primate
  • Nonmyeloablative
  • Tolerance
  • Transplant

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