Abstract
Adenosine is widely known as a potent modulator of innate and acquired immunity. It is released during transplants, and acts on four subtype receptors. In previous studies, we demonstrated that pharmacological preconditioning (PPC), pre-administration of the selective A1 receptor (A1R) agonist led to A1R desensitization, is followed by upregulation of the adenosine A2A receptor. This immunosuppressive effect resulted in lymphopenia, and it reduced T-cell reactivity. The aim of the current study was to challenge the immunosuppressive effects of A1R-PPC in models of allogeneic grafts. PPC mice were treated by intraperitoneal injection using specific adenosine A1R agonist 24 h and 12 h before starting any procedure. We challenged our method in novel allogeneic muscle and skin grafts models. Mice and grafts were assessed by complete blood counts, MLR from PPC splenocytes, and pathological evaluation. We found a significant reduction in WBC and lymphocyte counts in PPC-treated mice. Two-way MLR with splenocytes from PPC grafted mice showed decreased proliferation and anergy. Histology of PPC allogeneic grafts revealed profoundly less infiltration and even less muscle necrosis compared to vehicle treated allografts. Similar results observed in PPC skin transplantation. To conclude, PPC moderated graft rejection in separate allogeneic challenges, and reduced lymphocytes infiltration and ischemic damage.
Highlights
Adenosine is widely known as a potent modulator of innate and acquired immunity
Our aim was to challenge the immunosuppressive effects of A1 receptor (A1R)-pharmacological preconditioning (PPC) in models of allogeneic grafts
Adenosine is a potent modulator of lymphocyte development, proliferation, and activity, and its effect depends both on its bioavailability and on cell surface receptor expression
Summary
Adenosine is widely known as a potent modulator of innate and acquired immunity. It is released during transplants, and acts on four subtype receptors. We demonstrated that pharmacological preconditioning (PPC), pre-administration of the selective A1 receptor (A1R) agonist led to A1R desensitization, is followed by upregulation of the adenosine A2A receptor. This immunosuppressive effect resulted in lymphopenia, and it reduced T-cell reactivity. We found that 24 h pre-activation of the A1R by a selective adenosine A1R agonist, 2-Chloro-n(6)-cyclopentyladenosine (CCPA), led to downregulation of A1R and upregulated A2AR, mitigated the inflammatory response against invading bacteria, decreasing the number of blood lymphocytes and their reactivity to mitogen and MLR13,14. Tregs induce suppression in effector T cells either by direct transfer of cAMP via gap junctions[18], or by PGE219 and adenosine secretion[5]
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