RESUMEN
Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-cell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT.
Asunto(s)
Linfocitos B/inmunología , Trasplante de Riñón/inmunología , Tolerancia al Trasplante/inmunología , Adulto , Anciano , Linfocitos B/metabolismo , Linfocitos B Reguladores/inmunología , Linfocitos B Reguladores/metabolismo , Antígenos CD40/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
Some organ-transplanted patients achieve a state of "operational tolerance" (OT) in which graft function is maintained after the complete withdrawal of immunosuppressive drugs. We used a gene panel of regulatory/inflammatory molecules (FOXP3, GATA3, IL10, TGFB1, TGFBR1/ TBX21, TNF and IFNG) to investigate the gene expression profile in peripheral blood mononuclear cells of renal-transplanted individuals experiencing OT compared to transplanted individuals not displaying OT and healthy individuals (HI). OT subjects showed a predominant regulatory (REG) profile with higher gene expression of GATA3, FOXP3, TGFB1 and TGFB receptor 1 compared to the other groups. This predominant REG gene expression profile displayed stability over time. The significant GATA3 gene and protein expressions in OT individuals suggest that a Th2 deviation may be a relevant pathway to OT. Moreover, the capacity of the REG/INFLAMMA gene panel to discriminate OT by peripheral blood analysis indicates that this state has systemic repercussions.
Asunto(s)
Factor de Transcripción GATA3 , Inmunosupresores/metabolismo , Trasplante de Riñón/inmunología , Leucocitos Mononucleares/fisiología , Tolerancia al Trasplante , Adulto , Anciano , Femenino , Factores de Transcripción Forkhead/sangre , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Factor de Transcripción GATA3/sangre , Factor de Transcripción GATA3/genética , Factor de Transcripción GATA3/metabolismo , Perfilación de la Expresión Génica , Supervivencia de Injerto/inmunología , Humanos , Inmunosupresores/sangre , Masculino , Persona de Mediana Edad , Receptores de Factores de Crecimiento Transformadores beta/sangre , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Estudios Retrospectivos , Células Th2/metabolismo , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo , Tolerancia al Trasplante/genética , Tolerancia al Trasplante/inmunologíaRESUMEN
In organ transplantation, the immunosuppression withdrawal leads, in most cases, to rejection. Nonetheless, a special group of patients maintain stable graft function after complete withdrawal of immunosuppression, achieving a state called "operational tolerance." The study of such patients may be important to understand the mechanisms involved in human transplantation tolerance. We compared the profile of CD4(+)CD25(+)Foxp3(+) T cells and the signaling pathways IL-6/STAT3 (signal transducers and activators of transcription) and IL-4/STAT6 in peripheral blood mononuclear cells of four kidney transplant groups: (i) operational tolerance (OT), (ii) chronic allograft nephropathy (CR), (iii) stable graft function under standard immunosuppression (Sta), (iv) stable graft function under low immunosuppression, and (v) healthy individuals. Both CR and Sta displayed lower numbers and percentages of CD4(+)CD25(+)Foxp3(+) T cells compared with all other groups (p < 0.05). The OT patients displayed a reduced activation of the IL-4/STAT6 pathway in monocytes, compared with all other groups (p < 0.05). The lower numbers of CD4(+)CD25(+)Foxp3(+) T cells observed in CR individuals may be a feature of chronic allograft nephropathy. The differential OT signaling profile, with reduced phosphorylation of STAT6, in monocytes' region, suggests that some altered function of STAT6 signaling may be important for the operational tolerance state.