Targeting CD137 Can Selectively Delete Alloreactive T Cells During BMTs

[Guest guest]

Blood First Edition Paper, prepublished online August 24, 2006

Submitted April 7, 2006

Accepted August 12, 2006

Targeting the activation-induced antigen CD137 can selectively deplete

alloreactive T cells from anti-leukemic and anti-tumor donor T-cell lines

C. Wehler, n Nonn, Britta Brandt, Cedrik M. Britten, Mark

Grone, Mariya Todorova, Irina Link, Shamsul A Khan, Ralf G Meyer,

Christoph Huber, Udo F Hartwig, and Wolfgang Herr*

Dept. of Hematology & Oncology, University School of Medicine,

Johannes Gutenberg-University Mainz

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 allo-depletion (SAD) was subsequently performed by a newly

developed immunomagnetic depletion approach targeting the tumor

necrosis factor receptor molecule CD137 (4-1BB). Compared to 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 to undepleted control

populations. The allo-depleted T-cell subsets maintained significant

anti-tumor and anti-viral CD8 responses.

In vitro expansion of tumor-reactive T cells followed by

CD137-mediated SAD might enhance the anti-tumor efficacy of T-cell

allografts with lower risk of inducing GVHD.