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

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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IL-11 inhibits CD4-mediated GVHD while preserving both CD4- and CD8-medi...
IL-11 inhibits CD4-mediated GVHD while preserving both CD4- and CD8-mediated GVL effects. (a) Survival in control-treated recipients of TCD BM alone (thin dotted line; n = 5), CD4-depleted T cells (thick dotted line; n = 8), and CD8-depleted T cells (broken dotted line; n = 8); and in IL-11–treated recipients of CD8-depleted T cells (solid line; n = 8) after BMT. Lethally irradiated (15 Gy) B6D2F1 mice were transplanted with 5 × 106 TCD BM, alone or with 1 × 106 CD4- or CD8-depleted T cells from B6 donors. *P < 0.0001 vs. control-treated recipients of CD4-depleted T cells or IL-11–treated animals receiving CD8-depleted T cells. (b, c, and d) Leukemic mortality. B6D2F1 mice were transplanted as described above after 11 Gy TBI. Five thousand P815 cells were injected intravenously on day 0. GVHD deaths were not counted. (b) Leukemic mortality in animals treated with control (thick dotted line; n = 20) and IL-11 (solid line; n = 20) after allogeneic BMT, and in animals treated with control (thin dotted line; n = 12) and IL-11 (broken dotted line; n = 8) after allogeneic TCD BMT. (c) Leukemic mortality in animals treated with control (thick dotted line; n = 20) and IL-11 (solid line; n = 24) after CD4-depleted BMT. (d) Leukemic mortality in animals treated with control (thick dotted line; n = 8) and IL-11 (solid line; n = 8) after CD8-depleted BMT.