Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official VSports app下载. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely V体育官网. .

Comparative Study
. 1999 Aug;104(4):459-67.
doi: 10.1172/JCI6896.

Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia

G R Hill  1 , T Teshima, A Gerbitz, L Pan, K R Cooke, Y S Brinson, J M Crawford, J L Ferrara
Affiliations
Comparative Study

Differential roles of IL-1 and TNF-alpha on graft-versus-host disease and graft versus leukemia

G R Hill et al. J Clin Invest. 1999 Aug.

Abstract

We demonstrate an increase in graft-versus-host disease (GVHD) after experimental bone marrow transplant (BMT) when cyclophosphamide (Cy) is added to an otherwise well-tolerated dose (900 cGy) of total body irradiation (TBI). Donor T cell expansion on day +13 was increased after conditioning with Cy/TBI compared with Cy or TBI alone, although cytotoxic T lymphocyte (CTL) function was not altered. Histological analysis of the gastrointestinal tract demonstrated synergistic damage by Cy/TBI and allogeneic donor cells, which permitted increased translocation of LPS into the systemic circulation. TNF-alpha and IL-1 production in response to LPS was increased in BMT recipients after Cy/TBI conditioning. Neutralization of IL-1 significantly reduced serum LPS levels and GVHD mortality, but it did not affect donor CTL activity. By contrast, neutralization of TNF-alpha did not prevent GVHD mortality but did impair CTL activity after BMT VSports手机版. When P815 leukemia cells were added to the bone marrow inoculum, allogeneic BMT recipients given the TNF-alpha inhibitor relapsed at a significantly faster rate than those given the IL-1 inhibitor. To confirm that the role of TNF-alpha in graft versus leukemia (GVL) was due to effects on donor T cells, cohorts of animals were transplanted with T cells from either wild-type mice or p55 TNF-alpha receptor-deficient mice. Recipients of TNF-alpha p55 receptor-deficient T cells demonstrated a significant impairment in donor CTL activity after BMT and an increased rate of leukemic relapse compared with recipients of wild-type T cells. These data highlight the importance of conditioning in GVHD pathophysiology, and demonstrate that TNF-alpha is critical to GVL mediated by donor T cells, whereas IL-1 is not. .

PubMed Disclaimer

Figures

Figure 1
Figure 1
GVHD severity is significantly increased after a Cy/TBI conditioning regimen. B6D2F1 recipients received allogeneic B6 donor bone marrow and T cells after 1 of 3 conditioning regimens: Cy (dotted line; n = 11), TBI (900 cGy; dashed line; n = 10), or Cy/TBI (solid line; n = 35). Syngeneic recipients received B6D2F1 bone marrow and T cells after Cy/TBI (dashed line broken by dots; n = 15). (a) Mortality was significantly (P < 0.0001) greater in allogeneic Cy/TBI group than in all others. (b) GVHD severity was determined by clinical score (as described in Methods) and was significantly greater (P < 0.001) after Cy/TBI conditioning than after all other regimens. Allogeneic groups were significantly different (P < 0.001) from syngeneic recipients from day 14 forward. Results are from 3 similar experiments.
Figure 2
Figure 2
Cy/TBI conditioning accelerates T-cell expansion. (a) Thirteen days after BMT, the numbers of CD4+ and CD8+ cells were determined in the spleens of allogeneic BMT recipients after conditioning with Cy (dotted bars; n = 9), TBI (filled bars; n = 10), or Cy/TBI (hatched bars; n = 13). CD4+ and CD8+ numbers (×106) in syngeneic BMT recipients after Cy/TBI (n = 6) were 3.2 ± 0.7 and 1.8 ± 0.3, respectively (P < 0.03 for Cy/TBI vs. Cy and TBI allogeneic and Cy/TBI syngeneic groups). (b) CTL activity of splenic T cells 13 days after BMT subsequent to conditioning with Cy (dotted line), TBI (dashed line), or Cy/TBI (solid line). Spleens from 3–4 animals in each allogeneic group were pooled and used as effectors in standard 5-hour 51Cr release assays against host-type P815 targets (top curves) or donor-type EL4 targets (bottom curves). Results represent average curves from 3 similar experiments.
Figure 3
Figure 3
Cy/TBI conditioning enhances GVHD of the GI tract and subsequent endotoxemia. (a) GI tract injury was determined 7 days after BMT by a semiquantitative histological scoring system as described in Methods. The severity of injury was significantly increased (P < 0.02) in allogeneic BMT recipients after Cy/TBI conditioning (hatched bars; n = 13) compared with recipients transplanted with syngeneic marrow after Cy/TBI conditioning (open bars; n = 6) or allogeneic recipients transplanted after TBI alone (filled bars; n = 8). (b) Serum LPS levels 7 days after BMT were significantly increased (P < 0.03) in allogeneic BMT recipients after Cy/TBI conditioning (n = 17) compared with recipients transplanted with syngeneic marrow after Cy/TBI conditioning (n = 9) or allogeneic recipients transplanted after TBI alone (n = 23). (c) Elevated levels of serum LPS 7 days after BMT correlate with the severity of GI tract injury (P < 0.01). Cy/TBI allogeneic: filled squares (n = 13); Cy/TBI syngeneic: filled circles (n = 3); TBI allogeneic: open circles (n = 2).
Figure 4
Figure 4
Cy/TBI conditioning amplifies macrophage TNF-α and IL-1β responses to LPS. Peritoneal macrophages were pooled from 4 animals per group and stimulated in vitro with 0.1 μg/mL of LPS. TNF-α (a) and IL-1β (b) were determined in the supernatant by ELISA at 4 and 48 hours, respectively, after conditioning with Cy (stippled bars), TBI (filled bars), or Cy/TBI (hatched bars). Results are expressed as mean ± SD of quadruplicate wells and represent 1 of 3 similar experiments. Macrophages from syngeneic BMT recipients transplanted after Cy/TBI conditioning produced 484 ± 41 pg of TNF-α and 8 ± 1 pg of IL-1β. P < 0.05 for Cy/TBI vs. Cy and TBI.
Figure 5
Figure 5
Cy/TBI conditioning amplifies IL-1–mediated GVHD mortality. Animals were transplanted with allogeneic bone marrow and T cells after Cy/TBI conditioning as in Figure 1. (a) Animals received TNF blockade (dashed line; n = 19) with 100 μg/dose of recombinant human TNFR:Fc on days –3, –2, –1, and 0 and then on alternate days to day +16. (b) Animals received IL-1 blockade (dotted line; n = 19) with 200 μg/dose of the hamster anti-mouse IL-1 receptor antibody (anti–IL-1R) in the same dose schedule. Control-treated animals (solid line; n = 19) received 200 μg/dose of human or hamster IgG. P < 0.01 for IL-1 blockade vs. control; P = 0.70 for TNF blockade vs. control. All control-treated syngeneic BMT recipients survived the period of observation (data not shown). Data are pooled from 2 similar experiments.
Figure 6
Figure 6
TNF-α blockade impairs GVL activity after allogeneic BMT. Allogeneic BMT recipients were transplanted with TNF (dashed line; n = 30) or IL-1 blockade (dotted line; n = 19) as in Figure 5, with the addition of 5 × 104 host-type P815 leukemic cells to the donor inoculum. Syngeneic BMT recipients (dashed line broken by dots; n = 15) were used as positive controls. (a) Overall survival; (b) leukemic relapse. P < 0.002 and P < 0.05 for survival and relapse between allogeneic arms.
Figure 7
Figure 7
Optimal CTL generation after allogeneic BMT requires TNF-α signaling through the TNF p55 receptor. (a) Spleen lytic activity (LU20) was determined 14 days after BMT in animals transplanted with wild-type T-cell–depleted bone marrow and either wild-type T cells (hatched bar) or p55 TNFR–/– T cells (solid bar). Results are from 3 experiments. P < 0.05 between groups. (b) The rate of relapse was determined after allogeneic BMT with 5 × 104 P815 cells and wild-type T-cell–depleted bone marrow and wild-type T cells (solid line; n = 30), or wild-type T-cell–depleted bone marrow and p55 TNFR–/– T cells (dashed line; n = 20). P < 0.001 between groups.
See this image and copyright information in PMC

References

    1. Truitt, R., Johnson, B., and McCabe, C. 1997. Graft versus leukemia. Marcel Dekker Inc. New York, NY. 385–424.
    1. Krenger W, Hill G, Ferrara J. Cytokine cascades in acute graft-versus-host disease. Transplantation. 1997;64:553–558. - VSports最新版本 - PubMed
    1. Kichian K, Nestel FP, Kim D, Ponka P, Lapp WS. IL-12 p40 messenger RNA expression in target organs during acute graft-versus-host disease. J Immunol. 1996;157:2851–2856. - PubMed
    1. Nestel FP, Price KS, Seemayer TA, Lapp WS. Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med. 1992;175:405–413. - PMC (VSports在线直播) - PubMed
    1. Hill GR, Krenger W, Ferrara JLM. The role of cytokines in acute graft-versus-host disease. Cytokines Cell Mol Ther. 1997;3:257–265. - PubMed

"V体育安卓版" Publication types

MeSH terms (VSports)

VSports最新版本 - Substances