Blockade of LIGHT/LTβ and CD40 signaling induces allospecific T cell anergy, preventing graft-versus-host disease
Koji Tamada, … , Bruce R. Blazar, Lieping Chen
Koji Tamada, … , Bruce R. Blazar, Lieping Chen
Published February 15, 2002
Citation Information: J Clin Invest. 2002;109(4):549-557. https://doi.org/10.1172/JCI13604.
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Article

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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Synergistic effect of LTβR-Ig and anti-CD40L mAb in amelioration of GVHD...
Synergistic effect of LTβR-Ig and anti-CD40L mAb in amelioration of GVHD and inhibition of anti-host CTL activity. (a–c) B6 splenocytes (7 × 107 cells) were injected into sublethally irradiated BDF1 mice and treated with either anti-CD40L (open circles), LTβR-Ig (filled squares), or both (filled circles). Hamster IgG and human IgG1 were injected as control (open squares). (a) Survival of recipients was examined daily, and pooled data from four independent experiments are presented. Treatment with both anti-CD40L and LTβR-Ig significantly prolonged survival compared to other treatments (P < 0.05). (b) Average body weight. Symbols same as for a. (c) The CTL activity of recipient spleen cells against P815 (H-2d) and EL4 (H-2b) was examined on day 7 without in vitro restimulation. Results are expressed as the mean ± SD of triplicate wells. (d) Purified B6 CD8+ T cells (1 × 106 cells) were injected into sublethally irradiated bm1 mice followed by treatment with LTβR-Ig (filled squares) or control Ig (open squares) as described in Methods. Recipients of LTβR-Ig had a significantly (P = 0.0002) higher survival rate than did control-treated recipients. The reduction in GVHD lethality by LTβR-Ig treatment was estimated to be approximately equivalent to that resulting in control-treated mice from a threefold lower number (3 × 105) of CD8+ cell transfer (open circles, P > 0.1). (e) Purified B6 CD4+ T cells (1 × 105 cells) were injected into sublethally-irradiated bm12 mice followed by treatment with LTβR-Ig (filled squares) or control Ig (open squares) as described in Methods. No significant difference (P > 0.1) was noted between these two groups.