No abstract

Buffalo/Mna rats spontaneously develop FSGS and nephrotic syndrome as a result of an immune disorder. Similar to some humans with FSGS, the disease recurs after renal transplantation, suggesting the involvement of a circulating factor. Here, we tested the effect of several immunosuppressive treatments on these rats. Although corticosteroids, cyclosporin A, and anti-T cell receptor treatment reduced proteinuria, only the deoxyspergualin derivative LF15-0195 led to a rapid and complete normalization of proteinuria. Furthermore, this compound led to the regression of renal lesions during both the initial disease and posttransplantation recurrence. The frequency of splenic and peripheral CD4 ϩ CD25 ϩ FoxP3 ϩ T lymphocytes significantly increased with remission. Moreover, the transfer of purified LF15-0195-induced CD4 ϩ CD25 ϩ T cells to irradiated Buff/Mna rats significantly reduced their proteinuria compared with the transfer of untreated control cells, suggesting that LF15-0195 induces regulatory T cells that are able to induce regression of rat nephropathy. These data suggest that idiopathic nephrotic syndrome/FSGS disease can be regulated by cellular transfer, but how this regulation leads to the reorganization of the podocyte cytoskeleton remains to be determined.

Our data suggest that the Buffalo/Mna rat disease may be the result of an immunologic disorder, involving macrophages and Th2 lymphocytes. We hypothesize that this modified environment could result in the production of a factor deleterious to the glomeruli. Thus, this rat strain could provide a new model for the study of human nephrotic syndrome.

T-cells and their cytokines are thought to play a major role in the genesis of cellular infiltration and rejection in human kidney allografts. Production of Th1 (IFN-gamma) and Th2-type (IL-4 and IL-5) cytokines was assessed in a large series of T-cell clones, derived from core biopsies of kidney grafts in 10 patients with acute interstitial grade I/II rejection (AIR), 6 patients with a histology of "borderline rejection" (BLR) and 3 with cyclosporine A (CsA) toxicity, all receiving standard maintenance immunosuppression. Biopsies were pre-cultured in IL-2 in order to preferentially expand T-cells activated in vivo, and T-cell blasts were cloned with phytohemagglutinin (PHA) and IL-2 using a highly efficient (23 to 98%) cloning technique. A total of 483 T-cell clones obtained from AIR episodes were compared with 346 and 132 clones derived from patients with BLR episodes and CsA toxicity, respectively. In two series of 22 AIR and 77 BLR T-cell clones, alloreactivity against donor cells was shown by 25 and 14% of CD8+ and 21 and 4% of CD4+ clones, respectively. When stimulated by donor-derived EBV B-cells, all these alloreactive clones produced IFN-gamma, but not IL-4 or IL-5 (Th1 clones). Upon stimulation with PHA, the principal qualitative and quantitative differences between AIR- and BLR-derived T-cell clones were that cells derived from AIR patients: (i) showed significantly higher proportions (80 +/- 15 vs. 55 +/- 13%) of Th1 clones in their progeny; (ii) included smaller proportions (3 +/- 4 vs. 20 +/- 17%) of clones incapable of producing IFN-gamma, IL-4 or IL-5 ('null' clones); and (iii) produced significantly higher quantities of IFN-gamma (100 +/- 50 vs. 36 +/- 7 U/10(6) cells/ml), these quantities also being significantly correlated (r = 0.83) with the degree of interstitial graft infiltration (item 'i' in the Banff histological grading). The clones derived from CsA toxicity biopsies exhibited a pattern very similar to that found in BIR cases. These data lead us to conclude that the powerful inflammatory response elicited in acute rejection of a kidney graft recruits and activates both allospecific and non-specific Th1 effector cells, which are primed to high IFN-gamma production. Our results also suggest that IFN-gamma could contribute, at least in part, to the degree of graft infiltration and to the severity of the rejection episode.