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Blood, 15 April 2008, Vol. 111, No. 8, pp. 4392-4402. Prepublished online as a Blood First Edition Paper on September 24, 2007; DOI 10.1182/blood-2007-08-104471. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-08-104471v1 blood-2007-08-104471v2 111/8/4392    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Mielke, S. Articles by Barrett, A. J. PubMed PubMed Citation Articles by Mielke, S. Articles by Barrett, A. J. Related Collections Transplantation Immunotherapy Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  TRANSPLANTATION A clinical-scale selective allodepletion approach for the treatment of HLA-mismatched and matched donor-recipient pairs using expanded T lymphocytes as antigen-presenting cells and a TH9402-based photodepletion technique Stephan Mielke1, Raquel Nunes1, Katayoun Rezvani1, Vicki S. Fellowes2, Annie Venne3, Scott R. Solomon1, Yong Fan2, Emma Gostick4, David A. Price4, Christian Scotto3, Elizabeth J. Read2, and A. John Barrett1 1 Allotransplantation Section, Hematology Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD; 2 Cell Processing Section, Department of Transfusion Medicine, NIH, Bethesda, MD; 3 Kiadis Pharma (formerly Celmed), Saint-Laurent, QC; and 4 Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom Selective allodepletion is a strategy to eliminate host-reactive donor T cells from hematopoietic stem cell allografts to prevent graft-versus-host disease while conserving useful donor immune functions. To overcome fluctuations in activation-based surface marker expression and achieve a more consistent and effective allodepletion, we investigated a photodepletion process targeting activation-based changes in p-glycoprotein that result in an altered efflux of the photosensitizer TH9402. Expanded lymphocytes, generated using anti-CD3 and IL-2, were cocultured with responder cells from HLA-matched or -mismatched donors. Optimal results were achieved when cocultured cells were incubated with 7.5 µM TH9402, followed by dye extrusion and exposure to 5 Joule/cm2 light energy at 5 x 106 cells/mL. In mismatched stimulator-responder pairs, the median reduction of alloreactivity was 474-fold (range, 43-fold to 864-fold) compared with the unmanipulated responder. Third-party responses were maintained with a median 1.4-fold (range, 0.9-fold to 3.3-fold) reduction. In matched pairs, alloreactive helper T-lymphocyte precursors were reduced to lower than 1:100 000, while third-party responses remained higher than 1:10 000. This establishes a clinical-scale process capable of highly efficient, reproducible, selective removal of alloreactive lymphocytes from lymphocyte transplant products performed under current Good Manufacturing Practice. This procedure is currently being investigated in a clinical trial of allotransplantation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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