Functional compartmentalization following induction of long-term graft survival with pregraft donor-specific transfusion.

Long-term survival is achieved in rat recipients by pre-graft donor-specific blood transfusion. We characterized the immune compartments in long-term survivors and analyzed them for capacity to transfer tolerance and protect against chronic rejection. Splenocytes and spleen T cells from treated recipients transferred long-term graft survival to 100% of secondary recipients. In contrast, blood transferred graft survival to only 50% of recipients whereas blood T cells had no effect. An unaltered TCR repertoire, an increase in suppressive CD4+CD25+ T cells, a decrease in antidonor T-cell proliferative response and normal perforin-granzyme levels were the hallmarks of the spleen T cells. Blood T cells were characterized by a strongly altered CD8+ repertoire, normal CD4+CD25+ T cell number with unchanged antidonor T-cell proliferative response, an activated T-cell phenotype and an increase in perforin-granzyme levels. However, following the transfer of blood or spleen cells into secondary recipients, all grafts displayed chronic rejection. These findings provide evidence that distinct compartments play critical roles in DST recipients. Regulatory cells do not accumulate in blood, which appears to be a reservoir for cytotoxic T cells. Spleen T cells, which display a regulatory-like profile and transfer graft survival, are not able to prevent chronic rejection.

Humoral and cellular responses to influenza vaccination in human recipients naturally tolerant to a kidney allograft.

Rare kidney allograft recipients enjoy unaltered graft function years after interruption of their immunosuppressive treatment. To assess the extent to which this state of 'operational tolerance' (TOL) is specific to the graft and not the result of a global immunodeficiency, we analyzed the response of such patients following influenza vaccination. Hemagglutination inhibition titers and frequency of IFNgamma-secreting T cells were measured before 1 and 3 months after vaccination. The proportion of healthy volunteers (HV) responding to vaccine was significantly higher than that of immunosuppressed (IS) patients. Three 'TOL' patients presented a humoral response similar to that of HV, whereas the two others had a poor response, like the IS recipients. Although the small number of patients does not allow for definitive conclusions to be made, these data suggest that the status of tolerance may be heterogeneous, with some patients with a global immunodeficiency and others with an adapted response to vaccination.

Blood T-cell repertoire in idiopathic nephrotic syndrome recurrence following kidney transplantation.

Corticosteroid resistant idiopathic nephrotic syndrome (CR-INS) is a glomerulopathy that recurs after kidney transplantation in 30-50% of patients, suggesting the involvement of systemic albuminuric factors, probably produced by activated T cells. We investigated peripheral T-cell selection and expansion before and after transplantation to identify and characterize T-lymphocyte patterns potentially associated with INS recurrence. We used a combined qualitative and quantitative assessment of Vbeta mRNA alterations at the level of the complementary determining region 3-length distribution (CDR3-LD) of the T-cell receptor (TCR). Peripheral blood mononuclear cells (PBMC) were collected from 18 CR-INS patients (8 with recurrence and 10 without recurrence) on the day of transplantation as well as at 1 month, 1 year and 5 years after transplantation, and Vbeta transcriptomes were analyzed. Our data show that blood T cells from patients with INS recurrence display a TCR repertoire that is stable in time and has a similar level of CDR3-LD alterations as the T-cell repertoire of control patients, both before and after transplantation. These results suggest that the process of INS recurrence does not involve TCR activation or specific clonal expansion of T cells. However, these results do not exclude a role for T cells in the production of an albuminuric factor.