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Presenter: Takurin, Akiyoshi, Boston, United States
Authors: Akiyoshi T., Azzi J., Yang S., Moore R., Abdi R.
EXPERIMENTAL ISCHEMIA AND REPERFUSION INJURY
T. Akiyoshi1, J. Azzi2, S. Yang2, R. Moore2, R. Abdi2
1Medicine, Brigham and Women's Hospital, Boston/MA/UNITED STATES OF AMERICA, 2Medicine, Brigham and Women's Hospital, Boston/UNITED STATES OF AMERICA
Body: Phosphoinositide-3 kinase (PI3Kγ) has recently gained attention as a promising drug target for the treatment of inflammatory diseases such as rheumatoid arthritis. The role ofPI3Kγ in the process of allograft rejection remains to be elucidated. We hypothesize that since PI3Kγ is involved in the downstream signaling of chemokines and T cell activation, theinhibition of PI3Kγ will suppress the generation and trafficking of alloreactive T cells while sparing Tregs, thus prolonging heart allograft survival. We probed the effect of PI3Kγ inhibition on T cell activation by studying the proliferation of CD4+T cells after CD3/CD28 stimulation with different doses of the PI3Kγ inhibitor. The proliferation of responder splenocytes was suppressed in adose-dependent manner. To explore the effect of PI3Kγ inhibition on acute rejection, naive Balb/c allografts (H-2d) were transplanted into fully allogeneic C57BL/6 recipients (H-2b). The recipients were treated with 30 mg/kg of PI3Kγ inhibitor twice daily for 14 days. In the treated recipients, mediansurvival time (MST) of the allograft was significantly prolonged compared to that of the control group (MST of 21 vs. 8 days, respectively; n=4, p=0.0134). Histological analysis of control groupallografts on day 7 showed cellular rejection with many lymphocyte infiltrates and significant myocyte death. Histology of allografts recovered from treated recipients showed sparse lymphocyteinfiltrates and few regions of focal myocyte necrosis. Effector/memory CD8+ T cells as defined by CD44highCD62Llow expression was measured using splenocytes from recipients on day 7 to assay the immune response.The percentage of effector/memory CD8+ T cells in the treated group was considerablyreduced compared to control groups (mean percentage of 10 vs. 22% for treated and control animals, respectively, p=0.04). Using a class-II mismatch combination ofB6(C)-H2-Ab1bm12/KhEgJ (BM12) and C57BL/6 to investigate the effect of PI3Kγ inhibition on chronic rejection, we find that our therapy significantly reduces myocytenecrosis, scarring, and graft vasculopathy. Our pre-clinical data based on PI3Kγ inhibiton introduces a novel class ofimmunomodulatory treatment for organ transplantation.
Disclosure: All authors have declared no conflicts of interest.
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