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Early preservation of effector functions followed by eventual T-cell memory depletion: A model for Thiopurines' delayed onset of effect
  1. Shomron Ben-Horin (sben-horin{at}013.net.il)
  1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
    1. Itamar Goldstein (itamar.goldstein{at}sheba.health.gov.il)
    1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
      1. Ella Fudim (ella.fudim{at}sheba.health.gov.il)
      1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
        1. Orit Picard (orit.picard{at}sheba.health.gov.il)
        1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
          1. Zohar Yerushalmi (zohar.yerushalmi{at}sheba.health.gov.il)
          1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
            1. Iris Barshack (barshack{at}sheba.health.gov.il)
            1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
              1. Ilan Bank (ibank{at}post.tau.ac.il)
              1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
                1. Yifat Goldschmid (yifat.goldschmid{at}sheba.health.gov.il)
                1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
                  1. Simon Bar-Meir (barmeirs{at}yahoo.com)
                  1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel
                    1. Lloyd Mayer (lloyd.mayer{at}mssm.edu)
                    1. Immunology Institute, The Mount Sinai School of Medicine, New York, New York, United States
                      1. Yehuda Chowers (yehuda.chowers{at}sheba.health.gov.il)
                      1. Sheba Medical Center & Sackler School of Medicine, Tel-Aviv University, Israel

                        Abstract

                        Objective: The onset of effect of Thiopurines is delayed for several months. The aim of this study was to investigate immune mechanisms for this delay.

                        Methods: The effects of Thiopurines on human peripheral blood T-cells and on lamina propria lymphocytes were investigated for apoptosis induction by Annexin-V/PI and for cytokine secretion by intra-cellular staining and ELISA assays. To investigate Thiopurines' mechanism of effect in vivo, Balb/C mice were co-immunized with HEL/OVA antigens, and then repeatedly challenged by HEL only, while being treated by Mercaptopurine or vehicle alone for either 4 or 20 weeks. The memory response of CD4+ splenocytes towards HEL/OVA was then determined by CFSE-dilution.

                        Results: Thiopurines arrested the proliferation of stimulated T-cells but did not enhance the apoptosis of either resting T-cells or activated T-cells until day 5 post-stimulation. Despite the proliferation arrest, stimulated T-cells successfully differentiated into effector cells, as evidenced by their capacity for pro-inflammatory cytokine secretion, potent adhesion and cytotoxicity. Prolonged Mercaptopurine treatment of mice for 20 weeks selectively reduced the CD4+-memory response to a repeatedly encountered HEL antigen, but did not affect the T-cell memory pool to the previously exposed OVA antigen. A shorter, 4 weeks, treatment with Mercpatopurine did not inhibit the memory response to either antigen.

                        Conclusions: These data propose a model whereby despite Thiopurine treatment, cycle-arrested T-cells can still differentiate into potent effector cells capable of propagating tissue inflammation. However, recurrent antigen encounters result in incremental depletion of specific T-cell memory that may herald the eventual anti-inflammatory activity of Thiopurines

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