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. 1999 Aug;104(3):317-25.
doi: 10.1172/JCI7111.

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

T Teshima  1 , G R Hill, L Pan, Y S Brinson, M R van den Brink, K R Cooke, J L Ferrara
Affiliations

"VSports最新版本" IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation

T Teshima (V体育官网入口) et al. J Clin Invest. 1999 Aug.

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 VSports手机版. 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. .

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Figures

Figure 1
Figure 1
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.
Figure 2
Figure 2
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.
Figure 3
Figure 3
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.
Figure 4
Figure 4
IL-11 treatment preserves CTL function after BMT. Splenocytes harvested from allogeneic animals on day 14 of BMT were pooled (n = 3) and used immediately in a 51Cr release assay. (a) CTL activity against P815 in control-treated (open circles) and IL-11–treated (filled circles) recipients of wild-type donor T cells, and in control-treated (open squares) and IL-11–treated (filled squares) recipients of pfp–/– donor T cells after 7 hours in culture. (b) CTL activity against LK35.2 in control-treated (open circles) and IL-11–treated (filled circles) recipients of wild-type donor T cells, and in control-treated (open squares) and IL-11–treated (filled squares) recipients of pfp–/– donor T cells after 7 hours in culture. (c) CTL against YAC-1 in control-treated (open circles) and IL-11–treated (filled circles) recipients of wild-type donor T cells, and in control-treated (open squares) and IL-11–treated (filled squares) recipients of pfp–/– donor T cells after 4 hours in culture.
Figure 5
Figure 5
IL-11 inhibits GVHD in a perforin-independent fashion, but retains the perforin-dependent GVL effect. (a) Lethally irradiated (15 Gy) B6D2F1 mice were transplanted with 5 × 106 BM and 1 × 106 splenic T cells from wild-type B6 (wt) or pfp–/– donors. Survival in control-treated (thin dotted line; n = 8) and IL-11–treated (broken dotted line; n = 8) recipients of T cells from pfp–/– donors, and in control-treated recipients of T cells from wild-type donors (solid line; n = 6) after BMT. (b) B6D2F1 mice were transplanted as described above after 11 Gy TBI. Two thousand P815 cells were injected intravenously on day 0. Leukemic mortality after BMT in control- or IL-11–treated recipients of T cells from wild-type donors (solid line; n = 16), in control-treated (thick dotted line; n = 8) and IL-11–treated (broken dotted line; n = 8) recipients of pfp–/– T cells, and in control-treated animals receiving TCD BMT (thin dotted line; n = 4). *P < 0.01 vs. recipients of either TCD BM or T cells from wild-type B6 donors.
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References

    1. Bortin M, Rimm A, Saltzstein E. Graft-versus-leukemia: Quantification of adoptive immunotherapy in murine leukemia. Science. 1973;173:811–813. - "VSports在线直播" PubMed
    1. Truitt RJ, Johnson BD. Principles of graft versus leukemia reactivity. Bone Marrow Transplant. 1995;1:61–68. - PubMed
    1. Barrett AJ. Mechanisms of the graft-versus-leukemia reaction. Stem Cells. 1997;15:248–258. - PubMed
    1. Barnes D, Corp M, Loutit J, Neal F. Treatment of murine leukaemia with x-rays and homologous bone marrow: preliminary communication. Br Med J. 1956;2:626–630. - "V体育官网入口" PMC - PubMed
    1. Horowitz MM, et al. Graft-verus-leukemia reactions after bone marrow transplantation. Blood. 1990;75:555–562. - PubMed

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