Achieving long-term allograft survival or tolerance without continuously global immunosuppression is highly desirable in transplantation. This study was set to induce long-term allograft survival using a traditional Chinese herb without long-term administration of conventional immunosuppressive agents. Chinese herb Cordyceps sinensis (CS) has been shown to be immunosuppressive and anti-inflammatory in experimental animals. Here we speculated that CS would also modulate alloimmunity. In this study, C57BL/6 mice were transplanted with Balb/C skin and treated with CS (5mg/Kg/Day orally) and/or cyclosporine (15mg/Kg) for 4 weeks. CD4+FoxP3+ Tregs and CD8+CD44highCD62Lhigh central memory T cells were determined by FACS at 4 weeks while draining LN T cell proliferation was measured by BrdU labeling at 2 weeks. CS treatments did not result in any toxic injury to kidneys and livers of recipients as evidenced by histology, and UFLC fingerprinting indicated that CS did not contain cyclosporine and rapamycin.

We found that CS significantly prolonged skin allograft survival compared with control group (MST = 25 vs. 13 days, n=8-9, P<0.05) while cyclosporine also delayed the rejection with a statistical significance (MST = 27 vs. 13 days, n=7-8, P<0.05). Importantly, treatments with both CS and cyclosporine further prolonged skin allograft survival (MST = 61 versus 13 days, n=7-9, P<0.05), with 33% of recipient mice achieving long-term allograft survival (>100 days). Either CS or cyclosporine suppressed draining LN T cell proliferation (CS: BrdU+: 29±3 vs. 45±4 %, P<0.05; and cyclosporine: BrdU+: 27±3 vs. 45±4 %, P<0.05) while CS plus cyclosporine further suppressed T cell proliferation (BrdU+: 18±2 vs. 45±4 %, P<0.05). However, CS increased CD4+FoxP3+ Treg numbers in draining LNs (4.3±0.5 vs 2.6±0.4, x10000, P<0.05) while cyclosporine did the opposite (1.6±0.3 vs 2.6±0.4, P<0.05). CS plus cyclosporine reversed the cyclosporine-induced reduction in Treg numbers (2.7±0.4 vs. 1.6±0.3, P<0.05). Moreover, CS reduced CD8+CD44highCD62Lhigh Tcm numbers in LNs (1.5±0.2 vs. 2.5±0.3, P<0.05). Thus, for the first time, our studies demonstrated that Chinese herb CS induces FoxP3+ Tregs but reduces CD8+ central memory T-cells and hence synergizes with cyclosporine to promote long-term allograft survival.

CITATION INFORMATION: Dai Z, Dai H. Medicinal Herb Cordyceps Sinensis Promotes Long-Term Allograft Survival by Tipping the Balance Between CD4+FoxP3+ Tregs and CD8+ Tcm Cells. Am J Transplant. 2017;17 (suppl 3).

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