Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders

Jing Ouyang, Przemyslaw Juszczynski, Scott J. Rodig, Michael R Green, Evan O'Donnell, Treeve Currie, Myriam Armant, Kunihiko Takeyama, Stefano Monti, Gabriel A. Rabinovich, Jerome Ritz, Jeffery L. Kutok, Margaret A. Shipp

Research output: Contribution to journalArticle

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Abstract

Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBV-driven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid B-cell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydrate-binding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4 + Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)-mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8 + T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.

Original languageEnglish (US)
Pages (from-to)4315-4322
Number of pages8
JournalBlood
Volume117
Issue number16
DOIs
StatePublished - Apr 21 2011

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Galectin 1
Lymphoproliferative Disorders
Human Herpesvirus 4
B-Lymphocytes
T-cells
Membrane Proteins
Cells
T-Lymphocytes
Cell Line
Apoptosis
Immune Evasion
Th17 Cells
Th1 Cells
Proteins
Chemotherapy
Graft Rejection
Immunosuppressive Agents
Hematopoietic Stem Cells
Combination Drug Therapy
Stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Ouyang, J., Juszczynski, P., Rodig, S. J., Green, M. R., O'Donnell, E., Currie, T., ... Shipp, M. A. (2011). Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders. Blood, 117(16), 4315-4322. https://doi.org/10.1182/blood-2010-11-320481

Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders. / Ouyang, Jing; Juszczynski, Przemyslaw; Rodig, Scott J.; Green, Michael R; O'Donnell, Evan; Currie, Treeve; Armant, Myriam; Takeyama, Kunihiko; Monti, Stefano; Rabinovich, Gabriel A.; Ritz, Jerome; Kutok, Jeffery L.; Shipp, Margaret A.

In: Blood, Vol. 117, No. 16, 21.04.2011, p. 4315-4322.

Research output: Contribution to journalArticle

Ouyang, J, Juszczynski, P, Rodig, SJ, Green, MR, O'Donnell, E, Currie, T, Armant, M, Takeyama, K, Monti, S, Rabinovich, GA, Ritz, J, Kutok, JL & Shipp, MA 2011, 'Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders', Blood, vol. 117, no. 16, pp. 4315-4322. https://doi.org/10.1182/blood-2010-11-320481
Ouyang J, Juszczynski P, Rodig SJ, Green MR, O'Donnell E, Currie T et al. Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders. Blood. 2011 Apr 21;117(16):4315-4322. https://doi.org/10.1182/blood-2010-11-320481
Ouyang, Jing ; Juszczynski, Przemyslaw ; Rodig, Scott J. ; Green, Michael R ; O'Donnell, Evan ; Currie, Treeve ; Armant, Myriam ; Takeyama, Kunihiko ; Monti, Stefano ; Rabinovich, Gabriel A. ; Ritz, Jerome ; Kutok, Jeffery L. ; Shipp, Margaret A. / Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders. In: Blood. 2011 ; Vol. 117, No. 16. pp. 4315-4322.
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