Final Report Summary - HASKODIABETES (Adenosine receptors in diabetes)
Several autoimmune diseases are characterised by common alterations in the Th1 versus Th2 and IL-12/TNF-a versus IL-10 balance. In rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes mellitus, autoimmune thyroid disease (ATD) and Crohn's disease, the balance is skewed toward Th1 activity and an excess of IL-12 and TNF-a production, whereas Th2 activity and the production of IL-10 are deficient. Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) result from an organ-specific immune-mediated attack on pancreatic ß-cells.
Dr. Haskó and his colleagues have shown (Haskó et al. J. Immunol. 164: 1013-1019, 2000) that adenosine receptor occupancy with inosine significantly increased IL-4 production and decreased IFN-gamma production in the pancreas; this finding indicates a shift of cytokines towards a Th2 bias. Since adenosine is a potent endogenous autocrine anti-inflammatory and immunosuppressive molecule that is released from cells into the extracellular space at sites of inflammation and tissue injury, and protective effects of adenosine receptor stimulation have been observed in various models of autoimmune disease, such as rheumatoid arthritis, multiple sclerosis, colitis, and hepatitis (see Haskó and Cronstein, Trends in Immunol. 25: 33-39, 2004), investigations of whether the subtypes of adenosine receptors that are involved in mediating the Th1/Th2 balance also regulate autoimmune diabetes are promising.
Dr. Haskó and his group have shown the following:
- Activation of the adenosine A2A receptor protects peripherial CD4+ T-lymphocytes from activation-induced cell death.
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Dr. Haskó and his colleagues have shown (Haskó et al. J. Immunol. 164: 1013-1019, 2000) that adenosine receptor occupancy with inosine significantly increased IL-4 production and decreased IFN-gamma production in the pancreas; this finding indicates a shift of cytokines towards a Th2 bias. Since adenosine is a potent endogenous autocrine anti-inflammatory and immunosuppressive molecule that is released from cells into the extracellular space at sites of inflammation and tissue injury, and protective effects of adenosine receptor stimulation have been observed in various models of autoimmune disease, such as rheumatoid arthritis, multiple sclerosis, colitis, and hepatitis (see Haskó and Cronstein, Trends in Immunol. 25: 33-39, 2004), investigations of whether the subtypes of adenosine receptors that are involved in mediating the Th1/Th2 balance also regulate autoimmune diabetes are promising.
Dr. Haskó and his group have shown the following:
- Activation of the adenosine A2A receptor protects peripherial CD4+ T-lymphocytes from activation-induced cell death.
-