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IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation
Takanori Teshima, … , Kenneth R. Cooke, James L.M. Ferrara
Takanori Teshima, … , Kenneth R. Cooke, James L.M. Ferrara
Published August 1, 1999
Citation Information: J Clin Invest. 1999;104(3):317-325. https://doi.org/10.1172/JCI7111.
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Article

IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation

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Abstract

We recently showed that IL-11 prevents lethal graft-versus-host disease (GVHD) in a murine bone marrow transplantation (BMT) model of GVHD directed against MHC and minor antigens. In this study, we have investigated whether IL-11 can maintain a graft-versus-leukemia (GVL) effect. Lethally irradiated B6D2F1 mice were transplanted with either T cell–depleted (TCD) bone marrow (BM) alone or with BM and splenic T cells from allogeneic B6 donors. Animals also received host-type P815 mastocytoma cells at the time of BMT. Recipients were injected subcutaneously with recombinant human IL-11 or control diluent twice daily, from 2 days before BMT to 7 days after BMT. TCD recipients all died from leukemia by day 23. All control- and IL-11–treated allogeneic animals effectively rejected their leukemia, but IL-11 also reduced GVHD-related mortality. Examination of the cellular mechanisms of GVL and GVHD in this system showed that IL-11 selectively inhibited CD4-mediated GVHD, while retaining both CD4- and CD8-mediated GVL. In addition, IL-11 treatment did not affect cytolytic effector functions of T cells after BMT either in vivo or in vitro. Studies with perforin-deficient donor T cells demonstrated that the GVL effect was perforin dependent. These data demonstrated that IL-11 can significantly reduce CD4-dependent GVHD without impairing cytolytic function or subsequent GVL activity of CD8+ T cells. Brief treatment with IL-11 shortly after BMT may therefore represent a novel strategy for separating GVHD and GVL.

Authors

Takanori Teshima, Geoffrey R. Hill, Luying Pan, Yani S. Brinson, Marcel R.M. van den Brink, Kenneth R. Cooke, James L.M. Ferrara

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Figure 1

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Characteristics of leukemic cell lines. (a) P210 and P815 cells were sta...
Characteristics of leukemic cell lines. (a) P210 and P815 cells were stained with H-2Kk and H-2Dd, respectively, to determine MHC I expression (A, D), and with I-Ak and I-Ad (B, E), respectively, to determine MHC II expression. Expression of membrane-bound Fas on cell surfaces was also determined (C, F, G). Each graph shows staining with the indicated antibody (filled histograms) compared with the isotype control (dotted histograms). (b) Apoptosis induced by cross-linking with anti-Fas antibodies. Cells were incubated in 96-well plates coated with anti-Fas antibodies at 37°C in 5% atmospheric CO2 for 20 hours. Apoptotic cells were analyzed by flow cytometry after staining with hypotonic propidium iodide solution, and are presented as apoptotic percentage of total cells.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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