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Tolerogenic dendritic cells inhibit antiphospholipid syndrome derived effector/memory CD4+ T cell response to β2GPI
  1. Honorio Torres-Aguilar1,2,3,4,
  2. Miri Blank1,2,3,
  3. Shaye Kivity1,5,
  4. Mudi Misgav6,
  5. Jacob Luboshitz7,
  6. Silvia S Pierangeli8,
  7. Yehuda Shoenfeld1,5
  1. 1Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  2. 2Department of Medicine A & C, Sheba Medical Center, Tel-Hashomer, Israel
  3. 3Department of Microbiology and Clinical Immunology, Sackler Faculty of Medicine Tel-Aviv University, Tel-Aviv, Israel
  4. 4The National Center of Blood Transfusion, Mexico city, Mexico
  5. 5Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Tel-Aviv University, Israel
  6. 6Institute of Thrombosis and Hemostasis, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
  7. 7National Hemophilia Center, Sheba Medical Center affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
  8. 8Department of Internal Medicine, Division of Rheumatology, University of Texas Medical Branch, Galveston, Texas, USA
  1. Correspondence to Professor Yehuda Shoenfeld, Zabludowiz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 52621, Israel; shoenfel{at}post.tau.ac.il

Abstract

Objectives The importance of β2-glycoprotein I (β2GPI)-specific CD4+ T cells in the development of pathogenic processes in patients with antiphospholipid syndrome (APS) and APS mouse models is well established. Therefore, our objective is to manipulate the β2GPI specific CD4+ T cells using tolerogenic dendritic cells (tDCs) to induce tolerance. We aim to evaluate the capability of tDCs to induce antigen-specific tolerance in effector/memory T cells from patients with APS and to elucidate the involved mechanism.

Methods DCs and tDCs were produced from patients with APS peripheral-blood-monocytes, using specific cytokines. β2GPI-specific tolerance induction was investigated by coculturing control DC (cDC) or tDC, β2GPI-loaded, with autologous effector/memory T cells, evaluating the proliferative response, phenotype, cytokines secretion, viability and regulatory T cells.

Results Human monocyte-derived DCs treated with interleukin (IL)-10 and transforming growth factor β-1 (10/TGF-DC) induced β2GPI-specific-unresponsiveness in effector/memory CD4+ T cells (46.5%±26.0 less proliferation) in 16 of 20 analysed patients with APS, without affecting the proliferative response to an unrelated candidin. In five analysed patients, 10/TGF-DC-stimulated T cells acquired an IL-2lowinterferon γlowIL-10high cytokine profile, with just a propensity to express higher numbers of Foxp3+CTLA-4+ cells, but with an evident suppressive ability. In four of 10 analysed patients, 10/TGF-DC-stimulated T cell hyporesponsiveness could not be reverted and showed higher percentages of late apoptosis, p<0.02.

Conclusions The inherent tolerance induction resistance of activated T cells present during the development of autoimmune diseases has delayed the application of tDC as an alternative therapy. This study highlights the 10/TGF-DC feasibility to induce antigen-specific unresponsiveness in autoreactive T cells generated in patients with APS by inducing apoptosis or T cells with regulatory abilities.

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Footnotes

  • Funding HTA was supported by a grant from ICyTDF (BI09-532). This study was supported by The Binational USA-Israel Foundation number 2009099.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethical approval was obtained from the Sheba Medical Center Helsinki Committee.

  • Provenance and peer review Not commissioned; externally reviewed.

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