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Functional characterization of alloreactive T cells identifies CD25 and CD71 as optimal targets for a clinically applicable allodepletion strategy

Samarasinghe, S; Mancao, C; Pule, M; Nawroly, N; Karlsson, H; Brewin, J; Openshaw, P; ... Amrolia, PJ; + view all (2010) Functional characterization of alloreactive T cells identifies CD25 and CD71 as optimal targets for a clinically applicable allodepletion strategy. BLOOD , 115 (2) 396 - 407. 10.1182/blood-2009-08-235895.

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Abstract

Immunotherapy with allodepleted donor T cells (ADTs) improves immunity after T cell-depleted stem cell transplantation, but infection/relapse remain problematic. To refine this approach, we characterized the expression of surface markers/cytokines on proliferating alloreactive T cells (ATs). CD25 was expressed on 83% of carboxyfluorescein diacetate succinimidyl ester(dim) ATs, confirming this as an excellent target for allodepletion. Seventy percent of CD25(-) ATs expressed CD71 (transferrin receptor), identifying this as a novel marker to target ATs persisting after CD25 depletion. Comparison of residual alloreactivity after combined CD25/71 versus CD25 immunomagnetic depletion showed enhanced depletion of alloreactivity to host with CD25/71 depletion in both secondary (2 degrees) mixed lymphocyte reactions (P < .01) and interferon-gamma enzyme-linked immunospot assays (P < .05) with no effect on third-party responses. In pentamer/interferon-gamma enzyme-linked immunospot assays, antiviral responses to cytomegalovirus, Epstein-Barr virus, and adenovirus were preserved after CD25/71 allodepletion. CD25/71 ADTs can be redirected to recognize leukemic targets through lentiviral transfer of a chimeric anti-CD19 zeta T-cell receptor. Finally, we have established conditions for clinically applicable CD25/71 allodepletion under European Union Good Manufacturing Practice conditions, resulting in highly effective, reproducible, and selective depletion of ATs (median residual alloreactivity to host in 2 degrees mixed lymphocyte reaction of 0.39% vs third-party response of 62%, n = 5). This strategy enables further clinical studies of adoptive immunotherapy with larger doses of ADTs to enhance immune reconstitution after T cell-depleted stem cell transplantation. (Blood. 2010; 115: 396-407)

Type: Article
Title: Functional characterization of alloreactive T cells identifies CD25 and CD71 as optimal targets for a clinically applicable allodepletion strategy
DOI: 10.1182/blood-2009-08-235895
Keywords: VERSUS-HOST-DISEASE, BONE-MARROW-TRANSPLANTATION, EPSTEIN-BARR-VIRUS, SELECTIVE DEPLETION, ADOPTIVE IMMUNOTHERAPY, IMMUNE RECONSTITUTION, ADENOVIRAL INFECTIONS, LENTIVIRAL VECTORS, GRAFT, LYMPHOCYTES
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Infect, Imm, Infla. and Physio Med
URI: http://discovery.ucl.ac.uk/id/eprint/163369
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