RESUMEN
The induction of transplantation tolerance involves a T-cell-mediated process of immune regulation. In clinical transplantation, the use of immunosuppressive drugs that promote or facilitate this process would be highly desirable. Here, we investigated the tolerance-promoting potential of the immunosuppressive drug FK778, currently under development for clinical therapy. Using a human allogeneic in vitro model we showed that, upon T-cell receptor (TCR) triggering, FK778 induced a regulatory phenotype in CD4+ CD25- T cells. Purified CD4+ CD25- T cells primed in the presence of FK778 showed hyporesponsiveness upon restimulation with alloantigen in the absence of the drug. This anergic state was reversible by exogenous interleukin-2 (IL-2) and was induced independent of naturally occurring CD4+ CD25+ regulatory T cells. Pyrimidine restriction was a crucial requirement for the de novo induction of regulatory activity by FK778. The FK778-induced anergic cells showed suppressor activity in a cell-cell contact-dependent manner; were CD25(high), CD45RO+, CD27-, and CD62L-; and expressed cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and FoxP3. The cells revealed delayed p27(kip1) degradation and enhanced phosphorylation of STAT3. In conclusion, the new drug FK778 shows tolerizing potential through the induction of a regulatory T-cell subset in CD4+ CD25- T cells.
Asunto(s)
Alquinos/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Inmunosupresores/farmacología , Isoxazoles/farmacología , Nitrilos/farmacología , Subgrupos de Linfocitos T/efectos de los fármacos , Adulto , Antígenos CD/análisis , Antígenos de Diferenciación/análisis , Linfocitos T CD4-Positivos/inmunología , Antígeno CTLA-4 , Comunicación Celular , División Celular/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Evaluación Preclínica de Medicamentos , Factores de Transcripción Forkhead/análisis , Proteína Relacionada con TNFR Inducida por Glucocorticoide , Humanos , Interferón gamma/biosíntesis , Interleucina-2/farmacología , Subunidad alfa del Receptor de Interleucina-2/análisis , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isoantígenos/inmunología , Selectina L/análisis , Antígenos Comunes de Leucocito/análisis , Activación de Linfocitos/efectos de los fármacos , Prueba de Cultivo Mixto de Linfocitos , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Pirimidinas/biosíntesis , Receptores de Factor de Crecimiento Nervioso/análisis , Receptores del Factor de Necrosis Tumoral/análisis , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Uridina/farmacologíaRESUMEN
BACKGROUND: Steroid-related bone loss is a recognized complication after renal transplantation. In a prospective, randomized, multicenter study we compared the influence of a steroid-free immunosuppressive regimen with a regimen with limited steroid exposure on the changes in bone mass after renal transplantation. METHODS: A total of 364 recipients of a renal transplant were randomized to receive either daclizumab (1 mg/kg on days 0 and 10 after transplantation; steroid-free group n=186) or prednisone (0.3 mg/kg per day tapered to 0 mg at week 16 after transplantation; steroids group n=178). All patients received tacrolimus, mycophenolate mofetil, and, during the first 3 days, 100 mg prednisolone intravenously. Changes in bone mineral density (BMD) were evaluated in 135 and 126 patients in the steroid-free and steroids group, respectively. RESULTS: The mean (+/- SD) BMD of the lumbar spine decreased slightly in both groups during the first 3 months after transplantation (steroid-free -1.3 +/- 4.0% [P<0.01]; steroids -2.3 +/-4.2% [P<0.01]). In the following months, lumbar BMD recovered in both groups (P<0.01), resulting in a lumbar BMD at 12 months after transplantation comparable with the baseline value. No difference between the groups was found at 3 months (steroid-free versus steroids +1.0%; 95% confidence interval -0.0%-+2.0%, P=0.060) and at 12 months after transplantation (steroid-free versus steroids +0.9%; 95% confidence interval -0.8%-+2.6%, NS). CONCLUSION: The use of a moderate dose of steroids during 4 months after transplantation has no important influence on bone mass during the first year after renal transplantation. On average, both regimens prevented accelerated bone loss.