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Effect of the Purinergic Inhibitor Oxidized ATP in a Model of Islet Allograft Rejection
- Source :
- Diabetes
- Publication Year :
- 2013
- Publisher :
- American Diabetes Association, 2013.
-
Abstract
- The lymphocytic ionotropic purinergic P2X receptors (P2X1R-P2X7R, or P2XRs) sense ATP released during cell damage-activation, thus regulating T-cell activation. We aim to define the role of P2XRs during islet allograft rejection and to establish a novel anti-P2XRs strategy to achieve long-term islet allograft function. Our data demonstrate that P2X1R and P2X7R are induced in islet allograft-infiltrating cells, that only P2X7R is increasingly expressed during alloimmune response, and that P2X1R is augmented in both allogeneic and syngeneic transplantation. In vivo short-term P2X7R targeting (using periodate-oxidized ATP [oATP]) delays islet allograft rejection, reduces the frequency of Th1/Th17 cells, and induces hyporesponsiveness toward donor antigens. oATP-treated mice displayed preserved islet grafts with reduced Th1 transcripts. P2X7R targeting and rapamycin synergized in inducing long-term islet function in 80% of transplanted mice and resulted in reshaping of the recipient immune system. In vitro P2X7R targeting using oATP reduced T-cell activation and diminished Th1/Th17 cytokine production. Peripheral blood mononuclear cells obtained from long-term islet-transplanted patients showed an increased percentage of P2X7R+CD4+ T cells compared with controls. The beneficial effects of oATP treatment revealed a role for the purinergic system in islet allograft rejection, and the targeting of P2X7R is a novel strategy to induce long-term islet allograft function.
- Subjects :
- Graft Rejection
Male
Transplantation, Heterotopic
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Islets of Langerhans Transplantation
Mice
0302 clinical medicine
Adenosine Triphosphate
T-Lymphocyte Subsets
Receptor
Original Research
Mice, Knockout
Mice, Inbred BALB C
0303 health sciences
geography.geographical_feature_category
Purinergic receptor
Middle Aged
Islet
Cytokine
Female
Immunosuppressive Agents
medicine.drug
Adult
medicine.medical_specialty
endocrine system
Purinergic P2X Receptor Antagonists
Biology
03 medical and health sciences
Immune system
Internal medicine
Internal Medicine
medicine
Transplantation, Homologous
Animals
Humans
030304 developmental biology
Sirolimus
Immunosuppression Therapy
geography
Mice, Inbred C57BL
Transplantation
Transplantation, Isogeneic
Endocrinology
Commentary
Cancer research
Receptors, Purinergic P2X7
Immunology and Transplantation
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 1939327X and 00121797
- Volume :
- 62
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....a5e576e568193c7f58b5423e3bf68496