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 promotes overall survival after BMT by reducing the mortality of G...
IL-11 promotes overall survival after BMT by reducing the mortality of GVHD while retaining GVL activity. (a) Survival in control-treated (thick dotted line; n = 25) and IL-11–treated (solid line; n = 22) animals after allogeneic BMT and allogeneic TCD BMT (thin dotted line; n = 16). B6D2F1 mice were transplanted with 5 × 106 BM and 1 × 106 splenic T cells from allogeneic B6 donors after 15 Gy TBI. P815 cells (2,000 per mouse) were also given intravenously on day 0. *P < 0.001 vs. control-treated allogeneic animals. (b) Survival in control-treated (thick dotted line; n = 16) and IL-11–treated (solid line; n = 16) animals after allogeneic BMT and allogeneic TCD BMT (thin dotted line; n = 12). C3FeB6F1 mice were transplanted with 5 × 106 BM and 2 × 106 splenic T cells from B6 donors after 15 Gy TBI. Five hundred P210 cells were given intravenously on day 0. *P < 0.01 vs. control-treated allogeneic animals. In both experiments, all recipients of allogeneic BM and T cells died from GVHD; all recipients of TCD BM died from leukemia.