Inducing long-term transplant survival or tolerance without continuous global immunosuppression is a highly desired goal in organ transplantation because conventional immunosuppressive drugs usually cause severe side effects. Memory T cells pose a threat to long-term allograft survival since they are somewhat resistant to tolerance-inducing regimen. The objective of this study is to suppress generation of donor-specific memory T cells via short-term treatments with a novel protein ESAT-6, which is originally identified as a T cell Ag in the culture filtrate of M. tuberculosis. Previous studies have demonstrated that ESAT-6 is a virulence factor that promotes the growth and pathogenesis of M. tuberculosis while weakening immunity. In this study, C57BL/6 mice were transplanted with Balb/C islets and treated with ESTA-6 (0.05mg i.p. on days 0, 2, 4 and 6) and/or low doses of CTLA4-Ig (0.2 mg on days 2, 4, and 6). To observe allospecific memory T cell generation, Thy1.1+ CD8+CD44- T cells were sorted by FACS and injected into B6 recipients 1 day before transplantation.

We found that ESAT-6 significantly extended islet allograft survival (MST = 30 vs. 14 days, P<0.05). Importantly, treatments with both CTLA4-Ig and ESAT-6 further prolonged islet allograft survival (MST = 88 versus 30 days), with 50% of recipients achieving long-term allograft survival (>100 days). ESAT-6 also suppressed the generation of memory CD8+ T cells compared to control groups two months after transplantation (Thy1.1+CD8+CD44high cell numbers: 1.1±0.2 vs. 2.3±0.3, x10000 /LN, P<0.05 and 4.3±0.5 vs. 8.2±1.1, x100000/spleen, P<0.05) while ESAT-6 further reduced CD8+ memory T cell numbers in the presence of CTLA4-Ig (0.9±0.2 vs. 2.0±0.2 /LN, P<0.05 and 3.6±0.5 vs. 7.5±0.8, /spleen, P<0.05). Our studies, for the first time, demonstrated that ESAT-6 inhibits donor-specific memory T cell generation and promotes the induction of long-term allograft survival. Thus, ESAT-6 could be potentially used as an effective agent to induce long-term allograft survival in humans.

CITATION INFORMATION: Dai Z, Dai H. ESAT-6 Inhibits Donor-Specific Memory CD8+ T Cell Generation and Alloimmune Responses. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress