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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Intact T cell responses to nominal antigen in the combined therapy. Subl...
Intact T cell responses to nominal antigen in the combined therapy. Sublethally irradiated BDF1 mice received a mixture of OT-I LN cells (3 × 107 cells) and either 3 × 107 BDF1 spleen cells (open circles) or B6.Ly5.1 spleen cells (filled circles) on day 0. Recipients of transferred OT-I LN cells and B6.Ly5.1 cells received anti-CD40L (100 μg, on day 0) and LTβR-Ig (100 μg on days 0, 3, and 6). On day 8, cell populations negative for both Ly5.1 and H-2Kd were enriched from recipient spleen cells by magnetic cell sorting. The purified cells (1.5 × 106 cells/ml) were stimulated with 10 ng/ml OVA peptide in the presence of irradiated B6 spleen cells (1.5 × 106 cells/ml) for 4 days. The CTL activity against nonpulsed EL4 cells, EL4 cells pulsed with 10 μg/ml of antigenic OVA peptide (EL4/pep), and E.G7 cells was assessed by 51Cr release assay. Results are expressed as mean ± SD.