Interestingly, the last group shows low levels of transitional B cells comparable to the ones of SI patients . Drawing on the correlation between kidney transplant tolerance and regulatory B cells, the prognostic value of pretransplantation transitional/regulatory B cells and transplantation outcome has been approached [48, 49]. holy grail of organ transplantation is to maintain long-term graft function without immunosuppressive treatment, namely, operational tolerance (OT). However, OT is a rare event in kidney transplanted patients , as only about 0.03% of cases are estimated to be in such state . Thus, despite the efforts made in the past, there is still a clear need to find new strategies to achieve long-term tolerance and to investigate the immunological mechanisms that may be implicated in the process of OT. Among the actors implicated in the mechanisms of the immune response, B and T lymphocytes are the main characters that lead to graft rejection. In this play, B lymphocytes have a dual key role since they present antigens of the donor to T cells in addition to secreting antibodies that can lead to acute rejection or, later in time, chronic rejection . Nevertheless, a sparse B cell subset has been attributed immune regulatory functions which conveys that Cladribine not all Cladribine B cells play on the rejection side. Rabbit Polyclonal to TUBGCP3 Although it was first described in 1974  it was not until 2000 that this population was named regulatory B cells (Breg) . In the last decade, the regulatory role played by Breg has been highlighted by many authors in autoimmune diseases such as systemic lupus erythematosus (SLE) , rheumatoid arthritis , and pathologies that promote antineutrophil cytoplasmic antibodies  and also in allograft tolerance in organ transplantation [12, 13]. The current general consensus is that Breg develop their function mainly Cladribine via the secretion of IL-10 [14, 15]. However, a complete phenotype signature, development pathway, or the immunoregulatory properties of Breg have not been fully discovered in mice nor in humans, thus granting future research on this cell type. In this review, our aim is to gather the current knowledge about regulatory B cells and their role in kidney transplantation tolerance in humans and to discuss their potential application as cellular therapeutic agent. 2. Regulatory B Cells: Phenotype and Function One of the darkest spots of Breg is their phenotype, since for years researchers in the field have tried through multiple approaches to find unique characteristic markers to define them. However, there is still no consensus on it. There is less discussion about their mechanism of action, which is principally accepted to be IL-10, but the lack of knowledge on what triggers its secretion and the fact that other regulatory mechanisms have also been proposed leave this issue, to date, unresolved. 2.1. Does a Unique Breg Phenotype Exist? As previously occurred in the studies on regulatory T cells, many researchers have prompted to identify a unique set of markers, transcription factors, or mechanism of action that exclusively identify Breg in all contexts. In this sense, genetic and surface expression studies have been conducted with partial success to unravel a unique Breg signature [16, 17]. Unfortunately, to date such unequivocal markers have not been found yet. Also, some hypothesis have been formulated on Breg development pathways from a common precursor [18, 19], but the results so far are not conclusive. Thus, most authors rely on the capacity to produce interleukin- (IL-) 10 and on the two main phenotypical signatures used to define Breg: (1) transitional B cell phenotype CD19+CD24hiCD38hi and (2) CD19+CD5+CD1dhi (used in both human and mice) [20, 21]. Nevertheless, we still face a lack of specific Breg markers, and different phenotypes for IL-10-producing B cells with regulatory capacity have been proposed through the years. In 2008, Yanaba and colleagues identified an IL-10-producing regulatory B cell Cladribine subset in mice expressing CD1dhiCD5+ which they referred to as B10 cells . A few years later, the same group characterized a similar IL-10-producing B cell subset in humans. Human B10 cells’ regulatory potential was shown by their capacity to inhibit tumor necrosis factor- (TNF-) production by CD4+ T helper cells and monocytes. In peripheral blood, B10 cells were found exclusively among CD24hiCD27+ cells, whereas in spleen no difference was observed between IL-10-producing and nonproducing B cells regarding their surface markers . When testing the immunomodulatory capacity of the same subset from patients with allergic asthmain vitroin vitrostimulation . Yet, the transitional B cell subset CD24hiCD38hi also.