In vitro culture during retroviral transduction improves thymic repopulation and output after total body irradiation and autologous peripheral blood progenitor cell transplantation in rhesus macaques

Karin Loré, Ruth Seggewiss, F. Javier Guenaga, Stefania Pittaluga, Robert E. Donahue, Allen Krouse, Mark E. Metzger, Richard A. Koup, Cavan S Reilly, Daniel C. Douek, Cynthia E. Dunbar

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Immunodeficiency after peripheral blood progenitor cell (PBPC) transplantation may be influenced by graft composition, underlying disease, and/or pre-treatment. These factors are difficult to study independently in humans. Ex vivo culture and genetic manipulation of PBPC grafts may also affect immune reconstitution, with relevance to gene therapy applications. We directly compared the effects of three clinically relevant autologous graft compositions on immune reconstitution after myeloblative total body irradiation in rhesus macaques, the first time these studies have been performed in a large animal model with direct clinical relevance. Animals received CD34+ cell dose-matched grafts of either peripheral blood mononuclear cells, purified CD34+ PBPCs, or purified CD34+ PBPCs expanded in vitro and retrovirally transduced. We evaluated the reconstitution of T, B, natural killer, dendritic cells, and monocytes in blood and lymph nodes for up to 1 year post-transplantation. Animals receiving selected-transduced CD34+ cells had the fastest recovery of T-cell numbers, along with the highest T-cell-receptor gene rearrangement excision circles levels, the fewest proliferating Ki-67+ T-cells in the blood, and the best-preserved thymic architecture. Selected-transduced CD34+ cells may therefore repopulate the thymus more efficiently and promote a higher output of naïve T-cells. These results have implications for the design of gene therapy trials, as well as for the use of expanded PBPCs for improved T-cell immune reconstitution after transplantation.

Original languageEnglish (US)
Pages (from-to)1539-1548
Number of pages10
JournalSTEM CELLS
Volume24
Issue number6
DOIs
StatePublished - Jun 2006

Keywords

  • Autologous
  • In vitro expansion
  • Peripheral blood progenitor cell
  • Retroviral gene transfer
  • Rhesus macaque
  • T-cell immune reconstitution
  • Thymus
  • Transplantation

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