Inducing long-term transplant survival or tolerance without continuous global immunosuppression is a highly desired goal in transplantation given that conventional immunosuppressive drugs may cause side effects. It's known that memory T cells pose a threat to long-term allograft survival since they are resistant to moderate immunosuppression. The objective of this study is to suppress generation of donor-specific memory T cells via short-term treatments with a natural herb. Previous studies have demonstrated that Chinese herb Salvia miltiorrhiza or Danshen improves microcirculation and regulates immune responses. In this study, C57BL/6 mice were transplanted with BALB/c islets and treated with Danshen and/or low doses of rapamycin (0.25 mg/kg daily). To observe allospecific memory T cell generation, Thy1.1+ CD8+CD44low T cells were sorted by FACSAria and injected into B6 recipients one day before transplantation. Graft-infiltrating T cell proliferation was determined by BrdU staining and FACS analysis.

We found that Danshen alone significantly extended islet allograft survival (MST = 28 vs. 13 days, n=9, P<0.05). Interestingly, administration of both Danshen and low doses of rapamycin further prolonged islet allograft survival (MST = 85 versus 28 days), with 44% of recipients achieving long-term islet allograft survival (>100 days). Moreover, Danshen suppressed the generation of memory CD8+ T cells compared to control groups two months after transplantation (Thy1.1+CD8+CD44high cell numbers: 1.3±0.2 vs. 2.5±0.3, x10000 /LN, P<0.05 and 4.3±0.6 vs. 8.5±0.9, x100000/spleen, P<0.05) while Danshen plus low doses of rapamycin further reduced CD8+ memory T cell numbers compared to Danshen alone (0.7±0.1 vs. 1.3±0.2 /LN, P<0.05 and 2.6±0.4 vs. 4.3±0.6, /spleen, P<0.05). Finally, Danshen alone inhibited graft-infiltrating T cell proliferation as determined by BrdU staining one week after transplantation (52±4 vs. 35±3 %, P<0.05). Our studies, for the first time, demonstrated that Danshen inhibited donor-specific memory T cell generation and promoted induction of long-term allograft survival by rapamycin. Thus, Danshen could be utilized to induce long-term allograft survival in clinic.

CITATION INFORMATION: Dai Z., Liu H., Chen Y., Liang C-.L., Qiu F. A Natural Herb Danshen Suppresses Allospecific Memory CD8+ T Cell Generation and Murine Allograft Rejection Am J Transplant. 2017;17 (suppl 3).

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