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Blockade of individual Notch ligands and receptors controls graft-versus-host disease
Ivy T. Tran, … , Christian W. Siebel, Ivan Maillard
Ivy T. Tran, … , Christian W. Siebel, Ivan Maillard
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(4):1590-1604. https://doi.org/10.1172/JCI65477.
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Research Article Immunology Article has an altmetric score of 47

Blockade of individual Notch ligands and receptors controls graft-versus-host disease

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Abstract

Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation. Current strategies to control GVHD rely on global immunosuppression. These strategies are incompletely effective and decrease the anticancer activity of the allogeneic graft. We previously identified Notch signaling in T cells as a new therapeutic target for preventing GVHD. Notch-deprived T cells showed markedly decreased production of inflammatory cytokines, but normal in vivo proliferation, increased accumulation of regulatory T cells, and preserved anticancer effects. Here, we report that γ-secretase inhibitors can block all Notch signals in alloreactive T cells, but lead to severe on-target intestinal toxicity. Using newly developed humanized antibodies and conditional genetic models, we demonstrate that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T cells during GVHD, with dominant roles for Notch1 and Delta-like4. Notch1 inhibition controlled GVHD, but led to treatment-limiting toxicity. In contrast, Delta-like1/4 inhibition blocked GVHD without limiting adverse effects while preserving substantial anticancer activity. Transient blockade in the peritransplant period provided durable protection. These findings open new perspectives for selective and safe targeting of individual Notch pathway components in GVHD and other T cell–mediated human disorders.

Authors

Ivy T. Tran, Ashley R. Sandy, Alexis J. Carulli, Christen Ebens, Jooho Chung, Gloria T. Shan, Vedran Radojcic, Ann Friedman, Thomas Gridley, Amy Shelton, Pavan Reddy, Linda C. Samuelson, Minhong Yan, Christian W. Siebel, Ivan Maillard

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Figure 1

Efficient Notch inhibition in alloreactive T cells but severe intestinal toxicity of GSIs after BM transplantation.

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Efficient Notch inhibition in alloreactive T cells but severe intestinal...
Lethally irradiated (9 Gy) BALB/c mice were transplanted with B6 TCD BM (5 × 106 cells) with or without WT or DNMAML (DN) B6 T cells (10 × 106 splenocytes). The GSI DBZ was administered daily as compared with vehicle (i.p., 10 μmol/kg) (28). (A) Cytokine production by donor-derived H2Kb+H2Kd– CD4+ spleen T cells at day 5 after allo-BMT. Representative flow cytometry plots show intracellular IFN-γ and IL-2 after anti-CD3/CD28 restimulation. (B) Relative abundance of transcripts for Ifng, Il2, and the Notch target gene Dtx1 in day-5 donor-derived CD4+ T cells after anti-CD3/CD28 restimulation. (C) Short survival of DBZ-treated mice after allo-BMT, even upon transplantation of TCD BM only (P < 0.01, WT vehicle vs. WT DBZ; P < 0.0001, TCD vehicle vs. TCD DBZ). In contrast, DNMAML expression in donor T cells led to markedly prolonged survival (P < 0.0001, WT vs. DNMAML vehicle) (n = 14 for vehicle-treated, n = 6 for DBZ-treated groups). (D) H&E sections and quantification of villus atrophy in the ileum of DBZ-treated mice at day 5 after allo-BMT (n = 5–6/group). (E) Markedly decreased BrdU incorporation upon DBZ treatment (n = 3/group). Scale bars: 100 μm. Bar graphs represent mean ± SD. **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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