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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 18, 2007September 24, 2007; DOI 10.1182/blood-2007-08-104471.
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Submitted August 2, 2007
Accepted September 12, 2007
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 Mielke*, Raquel Nunes, Katayoun Rezvani, Vicki S Fellowes, Annie Venne, Scott R Solomon, Yong Fan, Emma Gostick, David A Price, Christian Scotto, Elizabeth J Read, and A John Barrett
Allotransplantation Section, Hematology Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, United States
Cell Processing Section, Department of Transfusion Medicine, National Institutes of Health (NIH), Bethesda, MD, United States
Research Group, Kiadis Pharma Inc., Saint-Laurent, QC, Canada
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
* Corresponding author; email: mielkes{at}nhlbi.nih.gov.
Selective allodepletion (SD) is a strategy to eliminate host-reactive donor T-cells from hematopoietic stem cell allografts to prevent graft-versus-host disease (GvHD) 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 (PD) 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 co-cultured with responder cells from HLA-matched or mismatched donors. Optimal results were achieved when co-cultured cells were incubated with 7.5 µM TH9402, followed by dye-extrusion and exposure to 5 Joule/cm2 light energy at 5x106 cells/ml. In mismatched stimulator-responder pairs, the median reduction of allo-reactivity was 474-fold (range, 43-864) when compared to the unmanipulated responder. Third-party responses were maintained with a median 1.4-fold (range, 0.9-3.3) reduction. In matched pairs alloreactive helper T-lymphocyte precursors (HTLps) were reduced below 1:100,000 while third party responses remained above 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 (cGMP). This procedure is currently being investigated in a clinical trial of allo-transplantation.
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