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Due to its extremely pleiotropic nature, the complex effects of IFN-γ exerted both on immune and non-immune cell types still remain only partially understood. The longstanding view of IFN-γ as being a predominantly inflammatory cytokine is constantly challenged by increasing demonstrations of its direct or indirect regulatory roles. Interferon-γ can exert tolerogenic effects on both innate and adaptive immune cell types, promoting tolerance of various antigen-presenting cells, and augmenting function and differentiation of regulatory T cells, respectively. Its capacity to induce IDO-competence is not limited to immune cells but extends to other cell types such as mesenchymal stem cells, epithelial cells, and tumors. The pro-inflammatory role of IFN-γ in tumor immune surveillance can backfire by directly inducing inhibitory molecule expression, such as PDL-1, on tumor cells. With increasing knowledge regarding the role of different helper T cell subsets in certain autoimmune diseases, the once contradictory observations of disease attenuation by IFN-γ can now be explained by its opposing interplay with other effector cytokines, particularly IL-17. The paradoxically immunosuppressive role of IFN-γ is also becoming evident in the transplantation setting, and graft-versus-host-disease. In the present review, we will discuss the latest findings that help to elucidate this dual role of IFN-γ at a cellular level, and in various pathophysiological states. [ABSTRACT FROM AUTHOR]

There have been some proposals that stem cells exist in the ovarian surface epithelium (OSE) of the adult human ovary; however, no direct evidence of such cells has been given until now. The aim of this study was to isolate the putative ovarian stem cells (OSCs) from the OSE layer in women with no naturally present oocytes and follicles—20 postmenopausal women and five women with premature ovarian failure. Small round cells with a bubble-like structure and diameters from 2 to 4 μm were isolated from the material obtained by OSE scraping. They expressed early embryonic developmental markers such as stage-specific embryonic antigen-4 and Oct-4, Nanog, Sox-2, and c-kit transcription markers, and they displayed prominent c-kit immunohistochemical staining. These cells were separated by density gradient centrifugation and grown in vitro, where they proliferated. Some of them grew intensively and reached a diameter of approximately 20 μm after 5–7 days. In the OSE cell culture, oocyte-like cells developed, which reached a diameter of up to 95 μm and expressed Oct-4A, Oct-4B, c-kit, VASA, and ZP2 transcription markers, corresponding to early oocytes. They did not express SCP3 meiotic marker. In conclusion, the discovered cells are proposed to represent the adult OSCs with the expression of embryonic stem cell markers. The expression of germ lineage marker c-kit points toward their primordial germ cell ancestry. A new term “embryonic-like stem cells of the adult” is proposed for embryonic-like stem cells that might persist in various tissues and organs of adults. These findings could be used for further studies aimed at the autologous treatment of ovarian infertility and degenerative diseases. [ABSTRACT FROM AUTHOR]

ABO histo-bloodgroups are strong transplantation antigens. In bone marrow transplantation, foreign ABO red cell antigens are not ignored by the immune system of the host, neither by the immunocompetent cells of the graft. Although ABO incompatibility is not considered a contraindication in bone marrow transplantation (BMT), its clinical consequences are still a matter of investigation. An overview of reports published by different groups is given and discussed. They present conflicting data regarding the role of the ABO match between patient and donor in the haematopoietic stem cell (HSC) transplantation. We report on the clinical outcome of bone marrow transplantation in 223 patients who received grafts from MHC identical siblings. Included are 139 ABO identical, 32 ABO minor mismatched, 34 major mismatched and 13 bi-directionally mismatched pairs. The statistical evaluation of standard parameters used to monitor the post-transplant period gave a proof that in neither group of patients with an ABO incompatible donor the recovery and success rate of transplantation, including the relapse incidence, risk of graft vs. host disease (GVHD) or overall survival, were significantly inferior. However, in all three cohorts of ABO mismatched patients, a delayed recovery of neutrophils was recorded as compared to the group receiving an ABO compatible graft. These finding leads us to the conclusion that the ABO compatibility is not a disadvantage in BMT, whereas the delayed recovery of neutrophils in patients having received an ABO mismatched graft is probably reflecting a transient humoral process leading to immune tolerance and graft accommodation. [ABSTRACT FROM AUTHOR]

• Recent evidence points to increased diversity of Tol-DC characteristics. • Discovery of novel Tol-DC inducing agents will allow for advances in fine-tuning their immunosuppressive characteristics. • In the last 5 years, several pharmacological drugs have been found to be capable of inducing Tol-DCs. • Discovery of Tol-DC inducing protocols focusing on synergy between different agents can lead to enhancement of DC tolerogenic potential. Dendritic cells (DCs) represent one of the most important biological tools for cellular immunotherapy purposes. There are an increasing number of phase I and II studies, where regulatory or tolerogenic DCs (TolDCs) are utilized as negative vaccines, with the aim of inducing tolerogenic outcomes in patients with various autoimmune or chronic-inflammatory diseases, as well as in transplant settings. The induction of tolerogenic properties in DCs can be achieved by altering their activation state toward expression of immunosuppressive elements and/or by achieving resistance to maturation, which leads to insufficient co-stimulatory signal delivery and inability to efficiently present antigens. In the past, one of the most efficient ways to induce DC tolerance has been the application of selected pharmacological agents which actively induce a tolerogenic transcription program or inhibit major pro-inflammatory transcription factors such as Nf-κB. Important examples include immunosuppressants such as different corticosteroids, vitamin D 3 , rapamycin and others. The quality of TolDCs induced by different approaches is becoming a vital issue and recent evidence suggests substantial heterogeneity between variously-generated TolDCs as evidenced by their transcriptomic profile and function. The possibility of various "flavors" of TolDCs encourages future research in discovery of Tol-DC inducing agents to enrich various ways of DC manipulation. This would enable a broader range of tools to manipulate DC toward specific characteristics desirable in different disease settings. In recent years, several novel small molecules have been identified with the capacity to promote DC tolerogenic characteristics. In this review, we will present and discuss these novel findings and also highlight novel understandings of tolerogenic mechanisms by which DC tolerogenicity is induced by already established agents. [ABSTRACT FROM AUTHOR]

• IFN-γ possesses the capacity to induce tolerogenic DC characteristics. • Dendritic cells treated with IFN-γ induce CD4+CD25+CD127−FoxP3+ T cell populations. • The induction of PD-L1 by IFN-γ is required for DCs' tolerogenic effect. Interferon-γ (IFN-γ) is the sole representative of type II IFNs, with well recognized role in numerous inflammatory processes. Lately, its significant pleiotropic nature has been recognized in many scenarios, where IFN-γ contributes to maintenance or induction of tolerogenic responses in context of various immune cell types. In this manuscript we demonstrate, that IFN-γ-mediated induction of programmed death ligand 1 (PD-L1) on human monocyte-derived dendritic cells (DCs) represents an important tolerogenic aspect in immunological network of type II IFNs. When fully differentiated, immature DCs were treated with increasing concentrations of IFN-γ there was no sign of maturation, as revealed by CD80, CD83 and CD86 expression. In terms of co-stimulatory receptor response, we did observe a dose-dependent increase in CD40 expression. Phenotypic analysis of inhibitory molecules revealed that PD-L1 expression is particularly sensitive to IFN-γ, as its expression can be induced almost 10-fold in comparison to non-treated DCs. Functional analysis of such PD-L1high DCs revealed significant immunosuppressive properties in a mixed lymphocyte reaction with whole or memory CD4+ T cells. When IFN-γ treated DCs were co-cultured with naive CD4+CD45RA+ T cells, they induced an increased percentage of CD4+CD25+CD127−FoxP3+ Tregs. Inhibition of PD-1/PD-L1 axis using neutralizing anti-PD-L1 mAbs, reversed the immunosuppressive effect of IFN-γ-treated DCs to suppress CD4+ T cell proliferation and to induce Tregs. In summary, our findings demonstrate the importance of IFN-γ-mediated tolerogenic effects, exerted on DCs by inducing increased expression of PD-L1, which enhances their regulatory function. [ABSTRACT FROM AUTHOR]

Abstract: The plasma levels of matrix metalloproteinase-9 (MMP-9) were determined during 41 collections of peripheral blood stem cells (PBSC) by standard volume (two blood volumes) leukaphereses (SVL) in 29 donors (7 allogeneic and 22 autologous) mobilized with the granulocyte-colony stimulating factor (G-CSF). The association between MMP-9 levels and cell counts in donor’s blood was explored. During the processing of the first blood volume (BV), MMP-9 levels declined on average by 31% and persisted at the same level during the processing of the second BV. During the collection, a slight decline of white blood cells (WBC), polymorphonuclear neutrophils (PMN) and platelets (PLT) in donor’s blood was accompanied by a significant drop of CD34+ cells by 37% after 1 BV and by 44% after 2 BV had been processed (p =0.001). The drop of MMP-9 plasma levels showed a loose correlation with the decrease of WBC (r =0.68, p =0.002) and PMN counts (r =0.67, p =0.001). We conclude that the levels of MMP-9 that have been elevated by the mobilization of donors with G-CSF, decrease during the collection of PBSC by 4h SVL. The observed decrease was indirectly related to the drop of WBC and PMN counts, suggesting that certain other factors have an influence on MMP-9 kinetics during PBSC collection. [Copyright &y& Elsevier]