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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Persistence of host-reactive T cells in long-term GVHD survivors. (a) In...
Persistence of host-reactive T cells in long-term GVHD survivors. (a) In naive B6 and GVHD-surviving mice (more than 60 days), spleen and LNs were stained with anti-CD3 and anti-CD62L mAb’s and examined for CD62L expression of CD3-positive cells. (b) Sublethally irradiated B6 or BDF1 recipient mice received 4 × 107 LN cells from 2C TCR transgenic mice on day 0. BDF1 recipients were treated with anti-CD40L (100 μg, on day 0) and LTβR-Ig (100 μg on days 0, 3, and 6), whereas control Ig was injected into B6 recipients. More than 60 days later, recipient spleen cells were stained with anti-CD8, 1B2, and anti-CD62L mAb’s. CD62L expression of CD8+1B2+ double-positive cells was examined. Numbers in the figure represent the percentage of 2C T cells (b) and the percentage of CD62Llow cells (a and b).