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TISSUE-SPECIFIC STEM CELLS

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

^a Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services, Bethesda, Maryland;
^b Immunology Laboratory,
^c Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Department of Health and Human Services, Bethesda, Maryland;
^d Hematopathology Section, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland;
^e Division of Biostatistics, University of Minnesota, Twin Cities, Minnesota

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

Correspondence: Cynthia E. Dunbar, M.D., Hematology Branch, National Heart, Lung, and Blood Institute, NIH, Department of Health and Human Services, Building 10, Clinical Research Center, Room 4-5140, 10 Center Drive, Mail Stop Code 1202, Bethesda, Maryland 20892-1202, USA. Telephone: (301) 496-1434; Fax: (301) 496-8396; e-mail: dunbarc{at}nhlbi.nih.gov

Received September 15, 2005; accepted for publication February 12, 2006.

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.

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