Effects of Adenosine A2a Receptor Agonist on Composite Tissue Allotransplant Survival – An In Vivo Preliminary Study

In vitro experimental studies have shown that A2a receptor agonists reduce the allostimulatory functions of dendritic cells (DCs) through modulation of the surface expression of the co-stimulatory molecules. Similar suppressive effects on DCs were also observed with CsA. Therefore, the authors hypothesized that composite tissue allograft (CTA) survival might be prolonged through a synergistic effect by the combined use of A2a agonist and CsA.

A total of 24 hindlimb transplantations were performed across a major histocompability barrier from Brown Norway rats (BN, RT1n) to Lewis rats (LEW, RT1l). In the control groups, either isografts (Group 1, n = 2) or allografts (Group 2, n = 3) were performed, and no treatment was given. In the experimental groups, three kinds of treatment protocols were employed: Group 3, selective A2a agonist alone (n = 6); Group 4, CsA alone (n = 7); Group 5, A2a + CsA combined treatment (n = 6). CsA (16 mg/kg) was initiated on the day of transplantation, continued for 7 days, then totally ceased. The selective A2a agonist (CGS 21680) was introduced in an osmotic minipump on the back of the rat 1 day before transplantation. Mean survival times of each group, as well as cytokine levels including IL-4, IL-10, INF-ãã, TNF-áá, were compared by ELISA.

The mean survival times (MST) for those groups were 9.8 ± 1.3 days, 10.5 ± 1.0 days, 29.8 ± 1.7 days, respectively. Statistically, there was no difference between Groups 1, 2, and 3 (p = 0.35) in terms of allograft survival. However, survival of the allografts in Group 4 was significantly higher than Group 5 (p < 0.0001) and A2a treatment (p < 0.0001) groups. In vivo, A2a treatment alone increases the levels of INF-ãã and TNF-áá which are important cytokines for induction of allotransplant rejection. Its combination with CsA significantly reduces the levels of suppressor cytokines IL-4 and Il-10.

Although reports on CsA and A2a have shown similar effects on cytokine profiles from the antigen-presenting cells, the results from this in vivo study did not validate a synergistic effect of combined use of A2a agonist and CsA in CTA allotransplantation. The allotransplant survival was even shorter compared to CsA treatment alone. A possible mechanism is through the effect of decreased Th2 and Th1 responses.