Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease
Koji Tamada, Hideto Tamura, Dallas Flies, Yang-Xin Fu, Esteban Celis, Larry R. Pease, Bruce R. Blazar, Lieping Chen
Koji Tamada, Hideto Tamura, Dallas Flies, Yang-Xin Fu, Esteban Celis, Larry R. Pease, Bruce R. Blazar, Lieping Chen
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Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease

Abstract

Previous studies have shown that blockade of LIGHT, a T cell costimulatory molecule belonging to the TNF superfamily, by soluble lymphotoxin β receptor–Ig (LTβR-Ig) inhibits the cytotoxic T lymphocyte (CTL) response to host antigenic disparities and ameliorates lethal graft-versus-host disease (GVHD) in a B6 to BDF1 mouse model. Here, we demonstrate that infusion of an mAb against CD40 ligand (CD40L) further increases the efficacy of LTβR-Ig, leading to complete prevention of GVHD. We further demonstrate that alloantigen-specific CTLs become anergic upon rapid expansion, and persist in the tolerized mice as a result of costimulatory blockade. Transfer of anergic CTLs to secondary F1 mice fails to induce GVHD despite the fact that anergic CTLs can be stimulated to proliferate in vitro by antigens and cytokines. Our study provides a potential new approach for the prevention of lethal GVHD.

Authors

Koji Tamada, Hideto Tamura, Dallas Flies, Yang-Xin Fu, Esteban Celis, Larry R. Pease, Bruce R. Blazar, Lieping Chen

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In vivo tolerance of host-reactive T cells in GVHD-surviving recipients....
In vivo tolerance of host-reactive T cells in GVHD-surviving recipients. Spleen cells (5 × 107 cells) from recipient mice that survived GVHD for more than 60 days due to the combined treatment were injected intravenously into secondary BDF1 recipient mice on day 0 (open squares). In some mice, 50,000 IU of IL-2 was injected daily intraperitoneally from day 0 to day 10 (filled squares). As control, either naive B6 spleen cells (open circles) or spleen cells from B6 BM–reconstituted BDF1 mice (filled circles) were injected into BDF1 recipients. (a) After 10 days of cell transfer, recipient spleen cells were examined for CTL activity against P815 and EL4 cells without in vitro culture. Results are expressed as the mean ± SD of triplicate wells. (b) After 10 days of transfer of spleen cells from either naive B6 mice (left panel), GVHD-surviving mice (center panel), or B6 BM–reconstituted BDF1 mice (right panel), spleen cells of recipient mice were stained with mAb’s against indicated antigens. Numbers in figure represent the percentage of lymphocytes located in that quadrant.