ABSTRACT
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.
Subject(s)
B-Lymphocytes/immunology , Kidney Transplantation/immunology , Transplantation Tolerance/immunology , Adult , Aged , B-Lymphocytes/metabolism , B-Lymphocytes, Regulatory/immunology , B-Lymphocytes, Regulatory/metabolism , CD40 Antigens/metabolism , Female , Humans , Male , Middle Aged , Receptors, Antigen, B-Cell/genetics , Receptors, Antigen, B-Cell/immunology , STAT3 Transcription Factor/metabolism , Signal TransductionABSTRACT
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.
Subject(s)
GATA3 Transcription Factor , Immunosuppressive Agents/metabolism , Kidney Transplantation/immunology , Leukocytes, Mononuclear/physiology , Transplantation Tolerance , Adult , Aged , Female , Forkhead Transcription Factors/blood , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , GATA3 Transcription Factor/blood , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/metabolism , Gene Expression Profiling , Graft Survival/immunology , Humans , Immunosuppressive Agents/blood , Male , Middle Aged , Receptors, Transforming Growth Factor beta/blood , Receptors, Transforming Growth Factor beta/genetics , Receptors, Transforming Growth Factor beta/metabolism , Retrospective Studies , Th2 Cells/metabolism , Transforming Growth Factor beta1/blood , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Transplantation Tolerance/genetics , Transplantation Tolerance/immunologyABSTRACT
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.
