Tuesday May 19, 2009 from 12.00 to 13.00
'Homeostatic proliferation of memory type CD8+ T cells as a barrier to tolerance induction in a clinical protocol of liver transplantation'
Background : Peritransplant T cell depletion was suggested to favour tolerance induction in solid organ transplantation. In a pilot trial in liver transplantation (LT), we performed a set of assays for the monitoring of patients included in protocols aiming the minimisation of immunosuppression to induce graft tolerance.
Methods : Peripheral blood was obtained from 16 patients received immunodepleting regimen followed by IS withdrawal at preTx, 2, 4, 6 and 12 months postTx. In these patients, we characterized the phenotype of circulating lymphocytes, we monitored interleukin (IL)-7 serum levels, interferon (IFN)- g and IL-17 mRNA accumulation in mixed leucocyte reaction (MLR) and intra-graft IFN-g mRNA and IL-17 expression by qPCR and immunohistochemistry respectively.
Results : Ten patients were included. In all cases, ATG therapy induced a profound early CD4+ and CD8+ T cells depletion. CD4+ T cells remained low for more than 12 months, but, in contrast, CD8+ T cells, mostly of memory phenotype (TEMRA, CCR7-CD45RA+), recovered from month 2, reaching levels above pretransplant counts at month 6. After ATG administration, increased IL-7 serum levels were measured, peaking at day 25 and remaining elevated until day 300. In the first 3 patients, attempts of IS discontinuation at days 140, 206 and 124 was followed by reversible acute rejection (AR), 140, 40 and 39 after IS withdrawal. At the time of AR, significant levels of IFN- g and IL-17 mRNA were measured in MLR between recipient T-cells and donor spleen cells. Consistently, high levels of IFN- g mRNA and IL-17 were measured within rejecting liver grafts.
Conclusions : Lymphopenia-induced IL-7 production following ATG induction might lead to homeostatic proliferation of memory-type CD8+ T-cells, potentially responsible for AR after IS withdrawal through IFN- g and IL-17 secretion.