Pre-transplant administration of antithymocyte globulin increases its efficacy in inhibiting anti-donor memory T cell responses (126.9)

Abstract

Abstract Antithymocyte globulin (ATG) is a lymphoablative agent used in transplant patients. In this study, we tested how murine analog of ATG (mATG)affects pre-existent donor-reactive memory T cells. mATG treatment of heart allograft recipients on d.-7 and -4 (pre-TP)led to better outcome than treatment on d.0 and d.4 (peri-TP). Pre-TP mATG resulted in lower frequencies of donor-specific IFNγ-secreting T cells than peri-TP mATG(72000 vs 12500spots/million CD44hi cells). Studies in recipients injected with tracer subsets of donor-reactive T cells showed that while both mATG regimens depleted naïve T cells equally well, pre-TP mATG was four times more efficient in depleting pre-existing memory T cells. IFNγ production by donor-specific memory T cell was diminished by 99% with pre-TP mATG and only by 70% with peri-TP mATG. Transfer of TCR transgenic Ld-reactive 2C memory CD8 cells into recipients of Ld+ or Ld- heart allografts showed that memory T cells resistance to peri-TP mATG depletion depended on the systemic inflammation after transplantation but not on their antigen specificity. In summary,pre-TP ATG is more efficient in targeting pre-existing alloreactive memory T cells and anti-donor T cell responses. Our findings may guide the future use of ATG in sensitized transplant patients.