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Methylprednisolone is widely used to improve immune suppression in transplanted patients threatened by acute rejection. Recently, we showed that the suppressive activity of a Treg cell population depends decisively on their percentage of highly suppressive HLA-DR(high+)-Treg cells, which are strongly reduced in rejecting transplant patients. In order to examine whether the composition of the total CD4(+)CD127(low+/-)FoxP3(+)-Treg cell pool with different Treg-subsets (DR(high+)CD45RA(-)-Tregs, DR(low+)CD45RA(-)-Tregs, DR(-)CD45RA(-)-Tregs, DR(-)CD45RA(+)-Tregs) is affected by methylprednisolone bolus therapy we compared the percentages of these four different Treg cell subsets in transplant patients with biopsy proven rejection before and after steroid bolus therapy (n=23). In patients treated with steroid bolus therapy, the percentage of the naïve DR(-)CD45RA(+)-Tregs was significantly decreased, whereas the percentage of the DR(+)CD45RA(-)-Tregs was significantly increased. By that, the strongest increase was detected for the most suppressive DR(high+)CD45RA(-)-Tregs. However, these effects were only temporarily and closely associated to the duration of the bolus therapy. Our results suggest that besides various anti-inflammatory effects on cells of the adaptive and innate immune system, methylprednisolone also has the capacity to enhance the suppressive activity of the total Treg cell pool by increasing its percentage of highly differentiated and highly suppressive DR(high+)CD45RA(-)-Tregs.

Shortening of telomeres: Evidence for replicative senescence of T cells derived from patients with Wegener's granulomatosis. Background Replicative senescence describes the fact that somatic cells undergo a finite and predictable number of cell divisions before entering an irreversible state of growth arrest. Progressive shortening of the telomeres, a consequence of cell division, is a reliable indicator of replicative senescence. Method We analyzed telomere length of DNA derived from T cells of patients suffering from Wegener's granulomatosis by Sourthern blotting. Moreover, expression of CD28, another marker for replicative senescence, was tested by cytofluorometry. Results In patients with disease for more than 5 years, short telomeres were detected in addition to telomeres of normal length, indicating replicative senescence of discrete T-cell clones. Reduced expression of CD28 was noted, particularly on CD8-positive T cells, derived from patients with disease for more than 5 years and short telomeres. Conclusion Our data provide evidence that a portion of T cells had undergone replicative senescence, which in turn indicates clonal expansion of T cells as consequence of activation.

Fibronectin synthesis by human tubular epithelial cells in culture: Effects of PDGF and TGF-β on synthesis and splicing. Background Enhanced synthesis of extracellular matrix proteins including fibronectin (FN) is associated with the development of sclerosis. In this context we studied FN synthesis by tubular epithelial cells in response to transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF). Methods FN protein synthesis by human tubular epithelial cells in culture (TEC) was measured by biosynthetic labeling and ELISA. Splicing of FN was assessed by RT-PCR and by Northern blotting. Results Cultivated TEC synthesized and released FN, the majority of which was deposited as an unsoluble protein and a minor portion (10 to 15%) was released into the supernatant. TGF-β and, to a lesser degree, PDGF, up-regulated FN synthesis. All three FN splice variants (EDA, EDB, and IIICS) were produced. PDGF did not influence the splicing. TGF-β preferentially up-regulated the EDA splice variant, but had no effect on the splicing of the other domains. Conclusions PDGF and TGF-β both up-regulate FN synthesis of TEC. TGF-β, but not PDGF, also changed the quality of the de novo synthesized FN, and thus has a different role in the development of sclerosis.