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 Blood, 1 January 2007, Vol. 109, No. 1, pp. 365-373.
Prepublished online as a Blood First Edition Paper on August 24, 2006; DOI 10.1182/blood-2006-04-014100.

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TRANSPLANTATION

Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines

Thomas C. Wehler1, Marion Nonn1, Britta Brandt1, Cedrik M. Britten1, Mark Gröne1, Mariya Todorova1, Irina Link1, Shamsul A. Khan1, Ralf G. Meyer1, Christoph Huber1, Udo F. Hartwig1,, and Wolfgang Herr1,

1 Department of Medicine III, Hematology, and Oncology, Johannes Gutenberg-University of Mainz, Mainz, Germany

In HLA-incompatible hematopoietic stem cell transplantation, alloreactive donor T cells recognizing recipient mismatch HLA cause severe graft-versus-host disease (GVHD). Strategies allowing the selective depletion of alloreactive T cells as well as the enhancement of graft-versus-malignancy immunity would be beneficial. We generated donor CD8 T-cell lines in vitro using allogeneic recipient cells mismatched at a single HLA class I allele or haplotype as stimulators. Recipient cells were obtained from acute myeloid leukemias, renal-cell carcinomas, and CD40L-induced B lymphoblasts. Resulting alloreactive T cells were activated by incubating day 21 T-cell cultures with HLA-mismatch transfected K562 cells or recipient-derived fibroblasts. Selective allodepletion (SAD) was subsequently performed by a newly developed immunomagnetic depletion approach targeting the tumor necrosis factor receptor molecule CD137 (4-1BB). Compared with other activation-induced antigens, CD137 showed a superior performance based on a consistently low baseline expression and a rapid up-regulation following alloantigen stimulation. In 15 different SAD experiments, the frequency of alloreactive CD8 T cells was reduced to a median of 9.5% compared with undepleted control populations. The allodepleted T-cell subsets maintained significant antitumor and antiviral CD8 responses. In vitro expansion of tumor-reactive T cells followed by CD137-mediated SAD might enhance the antitumor efficacy of T-cell allografts with lower risk of inducing GVHD.


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