July 2019
Volume 60, Issue 9
Free
ARVO Annual Meeting Abstract  |   July 2019
The purinergic receptor antagonist oxidized adenosine triphosphate promotes corneal allograft survival without expanding regulatory T cells
Author Affiliations & Notes
  • William Foulsham
    Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, United States
  • Sharad Mittal
    Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, United States
  • Takeshi Nakao
    Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, United States
  • Giulia Coco
    Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, United States
  • Yukako Taketani
    Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, United States
  • Sunil Chauhan
    Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, United States
  • Reza Dana
    Massachusetts Eye and Ear/Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   William Foulsham, None; Sharad Mittal, None; Takeshi Nakao, None; Giulia Coco, None; Yukako Taketani, None; Sunil Chauhan, None; Reza Dana, None
  • Footnotes
    Support  NIH Grant EY12963
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 884. doi:
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      William Foulsham, Sharad Mittal, Takeshi Nakao, Giulia Coco, Yukako Taketani, Sunil Chauhan, Reza Dana; The purinergic receptor antagonist oxidized adenosine triphosphate promotes corneal allograft survival without expanding regulatory T cells. Invest. Ophthalmol. Vis. Sci. 2019;60(9):884.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Adenosine triphosphate (ATP) is released into the extracellular environment during transplantation, and acts via purinergic receptors to amplify the alloimmune response. The purpose of our study was to investigate the immunomodulatory mechanisms of the purinergic receptor antagonist oxidized ATP (oATP) in a murine model of corneal allotransplantation.

Methods : Allogeneic corneal transplantation was performed using 6-8 week-old C57BL/6 donors and BALB/c hosts. oATP was administered via intraperitoneal injection (250 μg) once daily for 14 days post-operatively. The control group received intraperitoneal injections of sterile saline. Single cell suspensions of corneal tissue and draining lymph nodes were prepared at 14 days post-transplantation, and frequencies of CD45+ leukocytes, CD11b+MHCII+ antigen presenting cells (APCs), CD4+IFN-γ+ effector Th1 cells and CD4+Foxp3+ regulatory T cells (Tregs) were evaluated by flow cytometry. Slit lamp microscopy was performed weekly for 8 weeks to evaluate graft opacity and determine transplant rejection.

Results : Treatment with oATP significantly reduced graft infiltration of CD45+ leukocytes compared to PBS-treated controls (4.4% and 11.4% of total corneal cells, respectively; p=0.040). oATP administration also resulted in decreased frequencies of CD11b+MHCII+ APCs in both the cornea (6.2% compared to 16.9% of CD45+ cells in PBS-treated controls; p=0.009) and the draining lymph nodes (1.5% compared to 4.5% of total cells in PBS-treated controls; p=0.016). Reduced frequencies of CD4+IFN-γ+ effector Th1 frequencies were demonstrated in the draining lymph nodes following treatment with oATP (0.54% compared to 0.86% of total cells in PBS-treated controls; p=0.045), which corresponded to decreased infiltration of CD4+ cells in the cornea (0.09% compared with 0.24% of total cells in PBS-treated controls; p=0.009). No difference in Treg frequencies or Foxp3 expression (mean fluorescence intensity) was observed between oATP-treated and PBS-treated groups in either corneal or draining lymph node single cell suspensions. oATP treatment significantly reduced graft opacity from week 4 to week 8 (p<0.05) and resulted in significantly improved transplant survival (p=0.027).

Conclusions : oATP limits the alloimmune response by regulating APC maturation and suppressing the generation of alloreactive Th1 immunity.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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