Sachs - FOCIS 2009

Following an in vivo T cell depleting non-myeloablative conditioning regimen, 5 patients received combined kidney and bone marrow transplantation from haploidentical related donors in a clinical trial sponsored by the Immune Tolerance Network. All developed transient mixed chimerism (≤ Day 21). We recently reported that four patients discontinued post-transplant immunosuppression and remained off for 3 to 6 years without evidence of allograft rejection and with donor-specific unresponsiveness in vitro. A very high proportion of initially recovering CD3+CD4+ T cells expressed CD25 (for >1 year in 2 patients). At Day +120, all patients showed increased frequencies (10.7±4.6%) of CD4+CD25+CD127-FOXP3+ Treg compared to healthy subjects (3.8±0.4%). A significantly increased proportion of CD4+CD25-CD127- cells compared to normal was also detected at Day +120 (p<0.05). In Patient 1, depletion of CD4+CD25+ cells revealed residual anti-donor CML and MLR responses at 1 year but not at 18 months. In 2 other patients, depletion of CD4+CD25+ cells did not reveal anti-donor responses. Post-transplant limiting dilution assays showed specific absence of measurable donor-specific CTL precursors. However, in patient 5 at Day +275, there was evidence of a suppressive pattern in the Th assays, but depletion of CD25+ cells did not enhance the anti-donor response. The high percentage of Treg suggests that they may play a role in initial tolerance induction; post-transplant enrichment of CD4+CD25-CD127- cells, which have been reported to have suppressive activity, might also contribute to initial tolerance. This regulatory mechanism may be followed by later deletion, as shown by the absence of donor-reactive CTLp.