Influence of Chimerism on Tolerance After Combined Human Kidney and Hematopoietic Cell Transplantation

Abstract

Oral Abstracts2 2 8 WEDNESDAY Supplement to Transplantation July 27, 2008, Volume 86 Number 2S (d0) under the cover of costimulation blockade (anti-CD154 mAb, MR1 d0 and CTLA4Ig d+2) and short-course rapamycin (d-1/0/+2). A separate group of BMT recipients was treated in addition with 2-4x10 6 FoxP3-transduced CD4 cells (d0, d+6). Multi-lineage chimerism and deletion of donor-reactive T cells was followed by fl ow cytometry. Tolerance was assessed by grafting donor and 3rd party skin. Results: All mice receiving additional Treg treatment developed long-term multilineage chimerism, whereas BMT recipients without Tregs uniformly failed to do so (7/7 vs 0/7 at wk 19, p<0.01; e.g. 7.08% mean chimerism among myeloid lineage at wk 12). Notably donor chimerism among T cells, which is known to correlate with tolerance, was gradually rising in FoxP3-Treg recipients. Treg treated recipients showed profound and specifi c deletion of donor-reactive T cells in comparison to control group (1.87% vs 3.75% for V 11 + P < 0.05, 0.86 vs 2.46 for V 5 + P < 0.01; 13 weeks after BMT) and naïve B6 mice (1.87 vs 4.96 for V 11 + P < 0.05, 0.86 vs 1.72 for V 5 + P < 0.05). Notably, additional treatment with FoxP3-transduced Tregs led to tolerance induction with this otherwise unsuccessful regimen (long-term donor skin graft acceptance >100days in 7/7 mice in Treg-group vs 1/6 control group, p<0.005). Conclusions: These results demonstrate that polyclonal FoxP3-Tregs permit engraftment of achievable allogeneic BM doses without cytotoxic recipient treatment. FoxP3-Tregs lead to the induction of lasting mixed chimerism, deletion of donor-reactive T cells and donor-specifi c skin graft tolerance in an irradiation-free BMT protocol. Robust non-cytotoxic BMT regimens with clinically obtainable BM doses have been elusive so far. We think that these fi ndings are an important step towards the development of non-toxic BMT protocols.