IntroductionDonor T cells are responsible for both GVHD and GVL reactions after allogeneic HSCT. The activation status of T cells is modulated by dendritic cells (DCs), the most potent and professional antigenpresenting cells (APCs). 1,2 Both host and donor DCs have been shown to play critical roles in regulating GVHD and GVL effects after MHC-mismatched HSCT. 3-7 GVHD can be initiated by residual APCs that directly present host antigen (Ag) to donor T cells, 5 whereas GVHD intensity can be modulated by donor APCs that present host Ag to donor T cells via indirect antigen presentation. 1,3,8 However, despite extensive investigations of the role of host DCs on GVHD pathophysiology, much less is known about the mechanisms by which donor APCs activate and regulate donor T cells. A previous study by MacDonald et al 9 demonstrated that depleting CD11c ϩ donor conventional DCs (CDCs) reduced the severity of GVHD in mice. The same group then demonstrated that conventional donor cDCs isolated from the spleen are the most effective population in presenting alloantigen and stimulating naive donor T-cell responses early post-bone marrow transplantation (BMT). 3 Recently, using 2 allogeneic murine BMT models (C57BL/ 63B10.BR and C3H3C57BL/6), we showed that addition of donor bone marrow cells enriched for pre-pDCs to a graft composed of purified HSC and T cells significantly improved long-term leukemia-free survival without increasing GVHD compared with recipients of donor HSC and T cells. 10 Of note, higher numbers of IFN-␥-producing donor T cells were seen among recipients of pDCs. 10 The aim of the present work was to further define the mechanism by which donor pre-pDCs modulate the alloreactivity of donor T cells. Based on the marked up-regulation of IFN-␥ in donor T cells cotransplanted with bone marrow enriched for pre-pDCs, 10,11 we hypothesized that IFN-␥-responsive genes in donor pre-pDCs might be involved in their immunomodulatory activity.Using highly purified populations of donor pre-pDCs, we observed that IFN-␥ signaling by donor T cells to donor pre-pDCs led to increased indoleamine-2,3-dioxygenase (IDO) expression in donor pDCs and that IDO production by donor pDCs suppressed the GVHD activity of donor T cells and changed the balance between regulatory and inflammatory donor T cells. These data support a new paradigm for immune regulation in allogeneic HSCT in which donor DCs first activate donor T cells and then subsequently limit GVHD through IDO-dependent modulation of inflammation. Methods Mice B10.BR (H-2K k ), C57BL/6 (B6, H-2K b ), and FVB (H-2K q ) mice, as well as congenic strains of B6 expressing CD45.1 or CD90.1, and IFN-␥, IFN-␥ receptor, and IDO1 knockout strains on the B6 background (IFN-␥ Ϫ/Ϫ , IFNGR1 Ϫ/Ϫ , and IDO1 Ϫ/Ϫ ), were purchased from The Jackson Laboratory. A congenic strain of B10.BR (H-2K k ) expressing CD90.1, named BA.B10, For personal use only. on May 10, 2018. by guest www.bloodjournal.org From was generated by crossing B6 CD90.1 and B10.BR mice and then backcrossing 10 generatio...

Human mesenchymal stem cells (hMSCs) are currently investigated for a variety of therapeutic applications. However, MSCs isolated from primary tissue cannot meet clinical grade needs and should be expanded in vitro for several passages. Although hMSCs show low possibility for undergoing oncogenic transformation, they do, similar to other somatic cells, undergo cellular senescence and their therapeutic potential is diminished when cultured in vitro. However, the role of senescent MSCs in tumor progression remains largely elusive. In the current study, by establishing senescent human umbilical cord mesenchymal stem cells (s-UCMSCs) through the replicative senescence model and genotoxic stress induced premature senescence model, we show that s-UCMSCs significantly stimulate proliferation and migration of breast cancer cells in vitro and tumor progression in a co-transplant xenograft mouse model compared with ‘young’ counterparts (defined as MSCs at passage 5, in contrast to senescent MSCs at passage 45). In addition, we identified IL-6, a known pleiotropic cytokine, as a principal mediator for the tumor-promoting activity of s-UCMSCs by induction of STAT3 phosphorylation. Depletion of IL-6 from s-UCMSCs conditioned medium partially abrogated the stimulatory effect of s-UCMSCs on the proliferation and migration of breast tumor cells.

The aim of this meta-analysis was to estimate the diagnostic performance of shear wave elastography (SWE) in differentiating malignant from benign breast lesions. A literature search of PubMed, Web of Science and Scopus up to November 2014 was conducted. A summary receiver operating characteristic curve was constructed, and pooled weighted estimates of sensitivity and specificity were calculated using a bivariate mixed-effects regression model. Thirty-three studies, which included a total of 5838 lesions (2093 malignant, 3745 benign) from 5397 patients, were finally analyzed. Summary sensitivity and specificity were 0.886 (95% confidence interval [CI], 0.858-0.909) and 0.866 (95% CI, 0.833-0.894), respectively. The pooled diagnostic odds ratio was 50.410 (95% CI, 34.972-72.664). And the area under the receiver operating characteristic curve of SWE was 0.94 (95% CI, 0.91-0.96). No publication bias existed among these studies (p = 0.245). In the subgroup analysis, sensitivity and specificity were 0.862 (95% CI, 0.811-0.901) and 0.875 (95% CI, 0.793-0.928) among 1552 lesions from 1429 patients in the 12 studies using acoustic radiation force impulse imaging and 0.897 (95% CI, 0.863-0.923) and 0.863 (95% CI, 0.831-0.889) among another 4436 lesions from 4097 patients in the 21 studies using supersonic shear imaging. When analysis confined to 9 studies evaluated the diagnostic performance of combination SWE and conventional ultrasound, the area under the curve was 0.96 (95% CI, 0.94-0.97), yielding a sensitivity of 0.971 (95% CI, 0.941-0.986) and specificity of 0.801 (95% CI, 0.733-0.856). SWE seems to be a good quantitative method for differentiating breast lesions, with promise for integration into routine imaging protocols.

Interferon (IFN)-γ is a pleiotropic cytokine with a central role in innate and adaptive immunity. As a potent pro-inflammatory and anti-tumor cytokine, IFN-γ is conventionally thought to be responsible for driving cellular immune response. On the other hand, accumulating evidence suggests that IFN-γ also has immuno-suppressive activity. An important role for IFN-γ in inhibiting graft-versus-host disease (GVHD) has been demonstrated in murine models, in spite of IFN-γ being one of the key factors amplifying T cell activation during the process of acute GVHD, the major complication and cause of post-transplant mortality in allogeneic bone marrow transplantation (BMT). At the same time, IFN-γ facilitates graft-versus-leukemia (GVL) activity. Dissociation of GVL effects from GVHD has been the ultimate goal of allogeneic BMT in the treatment of hematological malignancies. This paradoxical role of IFN-γ makes modulating its activity a promising strategy to maximize GVL while minimizing GVHD and improve clinical outcomes in BMT. In this review, the effects of IFN-γ on GVHD and GVL are discussed with consideration of the mechanism of IFN-γ action.

Recurrent pregnancy loss (RPL) is a common fertility problem that affects 1%-2% of couples all over the world. Despite exciting discoveries regarding the important roles of the decidual natural killer cell (dNK) and regulatory T cell in pregnancy, the immune heterogeneity in patients with unexplained recurrent pregnancy loss (URPL) remains elusive. Here, we profiled the transcriptomes of 13,953 CD45+ cells from three normal and three URPL deciduas. Based on our data, the cellular composition revealed three major populations of immune cells including dNK cell, T cell, and macrophage, and four minor populations including monocytes, dendritic cell (DC), mast cell, and B cell. Especially, we identified a subpopulation of CSF1+ CD59+ KIRs-expressing dNK cells in normal deciduas, while the proportion of this subpopulation was decreased in URPL deciduas. We also identified a small subpopulation of activated dDCs that were accumulated mainly in URPL deciduas. Furthermore, our data revealed that in decidua at early pregnancy, CD8+ T cells exhibited cytotoxic properties. The decidual macrophages expressed high levels of both M1 and M2 feature genes, which made them unique to the conventional M1/M2 classification. Our single-cell data revealed the immune heterogeneity in decidua and the potentially pathogenic immune variations in URPL.

Concern that misinformation from direct-to-consumer marketing of largely unproven “biologic” treatments such as platelet-rich plasma and cell-based therapies may erode the public trust and the responsible investment needed to bring legitimate biological therapies to patients have resulted in calls to action from professional organizations and governing bodies. In response to substantial patient demand for biologic treatment of orthopaedic conditions, the American Academy of Orthopaedic Surgeons convened a collaborative symposium and established a consensus framework for improving and accelerating the clinical evaluation, use, and optimization of biologic therapies for musculoskeletal diseases. The economic and disease burden of musculoskeletal conditions is high. Of the various conditions discussed, knee osteoarthritis was identified as a “serious condition” associated with substantial and progressive morbidity and emerged as the condition with the most urgent need for clinical trial development. It was also recognized that stem cells have unique characteristics that are not met by minimally manipulated mixed cell preparations. The work group recommended that minimally manipulated cell products be referred to as cell therapy and that the untested and uncharacterized nature of these treatments be clearly communicated within the profession, to patients, and to the public. Minimum standards for product characterization and clinical research should also be followed. A framework for developing clinical trials related to knee OA was agreed upon. In addition to recommendations for development of high-quality multicenter clinical trials, another important recommendation was that physicians and institutions offering biologic therapies commit to establishing high-quality patient registries and biorepository-linked registries that can be used for postmarket surveillance and quality assessments.

Mesenchymal stem cells (MSC) are a kind of stromal cell within the tumor microenvironment. In our research, MSC derived from acute myeloid leukemia patients' bone marrow (AML-MSC) and lung cancer tissues (LC-MSC) as well as normal bone marrow-derived MSC (BM-MSC) cultured in conditioned medium of HeLa cells were found to have higher expressions of Toll-like receptor (TLR4) mRNA compared with BM-MSC. The sorted TLR4-positive MSC (TLR4+ MSC) differed in cytokine (interleukin-6, interleukin-8, and monocyte chemoattractant protein-1) secretion from those of unsorted MSC. MSC was reported to inhibit natural killer (NK) cell proliferation and function. In this research, we confirmed that TLR4+ MSC aggravate this suppression. Furthermore, when TLR4 in the sorted cells were stimulated by LPS or following blocked by antibody, the suppression on NK cell proliferation and cytotoxicity were more intensive or recovered respectively. Compared to unsorted MSC, NKG2D receptor expression on NK cells were also inhibited by TLR4+ MSC. These findings suggest that activation of TLR4 pathway is important for TLR4+ MSC and MSC to obstruct anti-tumor immunity by inhibiting NK cell function, which may provide a potential stroma-targeted tumor therapy.

We investigated the roles of specific subsets of donor APCs purified from bone marrow in donor T cell activation and graft-vs-leukemia (GvL) activity in murine models of hemopoietic stem cell transplantation. Lineage−CD11c+ APC precursors were separated from donor bone marrow based on expression of CD11b. Transplanting lineage−CD11c+CD11b− APC (CD11b− APC) in combination with c-kit+Sca-1+lineage− hemopoietic stem cells (HSC) and congenic donor T cells led to increased donor CD4+ and CD8+ T cell proliferation and higher donor T cell chimerism than with transplanting grafts containing HSC, T cells, and lineage−CD11c+CD11b+ APCs (CD11b+ APC), or grafts containing only HSC and T cells. Transplanting CD11b− APCs induced Th1/type 1 cytotoxic T lymphocyte donor T cell immune polarization and enhanced GvL activity of donor T cells without increased graft-vs-host disease in both MHC- and minor histocompatibility Ag-mismatched murine hemopoietic stem cell transplantation models, whereas CD11b+ APCs led to Th2/type 2 cytotoxic T lymphocyte donor T cell immune polarization. Donor CD11b− APCs were plasmacytoid dendritic cell progenitors (>90% CD317; PDCA-1+) and up-regulated CD80, CD86, and IL-12 during alloantigen presentation, whereas CD11b+ APCs expressed Gr-1 and up-regulated expression of programmed death ligands-1 and 2 after activation. These results are the first to show that manipulation of the content of donor APCs in allogeneic HSC grafts can regulate donor T cell immunity and enhance GvL without increasing graft-vs-host disease activity.