Han-Yun Ren

Clinical and laboratory characterization of 114 cases of Castleman disease patients from a single centre: paraneoplastic pemphigus is an unfavourable prognostic factor

This study retrospectively collected the clinical and laboratory data of 114 patients with Castleman disease (CD) from a single medical centre. Clinical classification identified 62 patients (54·4%) with unicentric Castleman disease and 52 (45·6%) with multi‐centric Castleman disease. Pathological classification revealed 68 cases (59·6%) of hyaline vascular variant, 16 (14·1%) mixed cellular variant (Mix) and 30 (26·3%) plasmacytic variant. Clinical complications occurred in 69 CD patients, including 37 cases of paraneoplastic pemphigus (PNP) and 25 cases with renal complications. Haematological involvement, pleural effusion and/or ascites and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) were also found. Univariate analysis showed that presence of clinical complications and PNP were both risk factors relating to CD patient survival. Prognostic factors showing P < 0·15 in univariate analysis and those with clinical significance were subjected to multivariate analysis using a Cox regression model. PNP presence and age over 40 years both significantly adversely affected survival. Thus, only presence of PNP was identified as an independent unfavourable survival risk factor in both univariate and multivariate analyses. Overall, the present data provide a panoramic description of CD cases and emphasize that the presence of PNP is an adverse prognostic factor.

Bortezomib regulates the chemotactic characteristics of T cells through downregulation of CXCR3/CXCL9 expression and induction of apoptosis

The chemotactic movement of T lymphocytes mediated by chemokines and their receptors plays an important role in the pathogenesis of graft-versus-host disease (GVHD) post-allogeneic hematopoietic stem cell transplantation (allo-HSCT). CCR7 and CXCR3 are two receptors associated with the development of GVHD. Bortezomib, a proteasome inhibitor, was recently found to prevent GVHD in a mouse model and to decrease the production of Th1 cytokines. Here, we report that bortezomib differentially regulates the expression of CXCR3 and CCR7 on T cells; it significantly decreases CXCR3 expression on T cells as well as its CD4+/CD8+ subsets in a dose-dependent manner, while it does not significantly affect CCR7 expression on T cells and subsets. Moreover, the secretion of CXCL9 by activated T cells is also increasingly downregulated with increasing concentrations of bortezomib. Meanwhile, bortezomib inhibits T-cell chemotactic movements toward CXCL9 in a dose-dependent manner, but has no effect on CCL19-induced T-cell chemotaxis. Additionally, it was found that bortezomib treatment also prompts T-lymphocyte apoptosis through activation of caspase-3 and its downstream PARP cleavage in a dose- and time-dependent manner. These results suggest that bortezomib may act as a suppressor of GVHD by downregulating T-cell chemotatic movement toward GVHD target organs, as well as by inducing apoptosis.

HLA Disparity is not crucial for the survival rate and severity of chronic health conditions in adult recipients following family donor hematopoietic stem cell transplantation

The shortage of HLA-identical siblings or unrelated donors has restricted the application of hematopoietic stem cell transplantation (HSCT). Few studies have systematically assessed survival and chronic health conditions (CHCs) in the same cohort of patients after HLA-mismatched/haploidentical (mismatched) family donor transplantation. In the present study, we retrospectively analyzed the survival of 127 adult patients receiving either HLA-matched (71 cases) or HLA-mismatched (56 cases) family donor transplantation. Of 127 patients, 81 patients survived at least 2xa0years after HSCT and were still alive until the present investigation. We evaluated the CHCs in 76 survivors (41 matched and 35 mismatched). CHC-related information was scored according to the Bone Marrow Transplant Survivor Study questionnaire. There was no significant difference in overall survival or disease-free survival between HLA-matched and -mismatched transplant recipients. The CHCs were less severe in HLA-mismatched recipients than in matched cohorts. Multivariate analysis identified that age over 40xa0years at transplantation and presence of chronic graft-versus-host disease were independent risk factors for CHCs, while anti-thymocyte globulin-containing conditioning regimens might be protective. However, HLA disparity was not crucial for either the survival rate or CHCs. In conclusion, HLA-mismatched family donor transplantation can achieve comparable therapeutic effects to HLA-identical sibling transplantation.

In Vitro Immunological Effects of Blocking CCR5 on T Cells

Blockade of CC chemokine receptor 5 (CCR5) by maraviroc may induce immunological changes independent of its antiviral effects and may have immunoregulation properties. This study was designed to determine the effects of blocking CCR5 on human activated T cells in vitro and investigate the potential immunological mechanisms. Human CD3+ T cells were purified from peripheral blood mononuclear cells and then activated by cytokines. We tested the surface expressions and relative messenger RNA (mRNA) levels of CCR2, CCR5, CCR6, CCR7, and CXCR3, chemotaxis toward their cognate ligands, internalization of chemokine receptors, and production of cytokines. In conclusion, blocking CCR5 by maraviroc not only can block CCR5 and CCR2 internalization processes induced by CCL5 and CCL2, but also inhibit T cell chemotactic activities toward their cognate ligands, respectively. Moreover, blocking CCR5 with maraviroc at high doses tends to decrease the production of TNF-α and IFN-γ. In addition, there might be a form of cross talk between CCR5 and CCR2, and this may offer a novel immunological effect for blockade of CCR5.

Allogeneic Compact Bone-Derived Mesenchymal Stem Cell Transplantation Attenuates the Severity of Idiopathic Pneumonia Syndrome in a Murine Bone Marrow Transplantation Model

Background/Aims: Idiopathic pneumonia syndrome (IPS) is a serious and life-threatening lung complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and currently no effective therapies exist. This study was designed to determine whether transplantation of allogeneic murine compact bone derived- mesenchymal stem cells (CB-MSCs) could prevent the development of IPS. Methods: We tested the effects of CB-MSCs transplantation on IPS using an established murine model of C57BL/6 (H-2b)→BALB/c (H-2d). Survival rates, body weight change, clinical GVHD scores, lung histological changes were assessed after IPS induction. Mechanistically, concentrations of cytokines (TNF-α, IFN-γ and IL-4) and chemokines (CCL5, CXCL9 and CXCL10) in bronchoalveolar lavage fluid (BALF) from the recipient mice were measured at different time point post-transplantation. CD4+CD25+Foxp3+ regulatory T cell (Treg) percentage, CCR5, CXCR3 and CCR7 expression on CD3+ T cells, and lung CXCR3, CCR5, CCR7, T-bet and GATA-3 mRNA levels were also evaluated at different time point post-transplantation. Results: Co-transplantation of CB-MSCs significantly attenuated the severity of lung injuries and increased survival rate of mice compared to non-cotransplanted mice. A higher Treg percentage, reduction of TNF-α, IFN-γ, CCL5, CXCL9 and CXCL10 levels, down-regulation of CXCR3 and CCR5, as well as up-regulation of CCR7, were observed in MSCs co-transplantation mice. Also, the prophylactic effect of CB-MSCs was associated with a shift of Th1/Th2 balance toward anti-inflammatory Th2 polarization. Conclusions: Allogeneic CB-MSCs effectively controlled the occurrence of IPS due to its profound immunomodulatory capacity. This may offer a novel prophylactic approach for IPS after allo-HSCT.

Prophylaxis of acute graft-versus-host disease by CCR5 blockade combined with cyclosporine A in a murine model.

ObjectiveOne characteristic feature of graft-versus-host disease (GVHD) is lymphocytes’ trafficking and recruitment to target tissues, and CCR5 plays a key role in the process. Thus, blockade of lymphocytes’ chemotaxis may attenuate GVHD.MethodsWe tested the effects of CCR5 blockade using an established murine model. The mean survival time, body weight change, and clinical GVHD scores were assessed. Concentrations of cytokines and chemokines, the CCR5, CXCR3, and CCR7 expressions on T lymphocytes, and histological changes of visceral organs were also evaluated. Additionally, we assessed the immunophenotype of infiltration cells in liver and intestine.ResultsMice undergoing total body irradiation and allogenic hematopoietic stem cell transplantation (allo-HSCT) developed typical GVHD. MVC increased CCR5 expression whereas CCR7 and CXCR3 expression were unaffected. MVC also increased plasma levels of the ligands of CCR5. A combination of MVC with CsA significantly alleviated the degree of visceral injuries and prolonged survival time.ConclusionMVC has a synergistic effect with CsA. It can attenuate the severity of GVHD and increase survival rate of mice in our murine model. This may offer a novel therapeutic perspective for clinical GVHD after allo-HSCT.

Silencing HCCR2 expression inhibits the proliferation of leukemia cells by inducing apoptosis and promoting cell cycle arrest

The human cervical cancer oncogene (HCCR2) has been found to be overexpressed in a variety of human malignant tumors cells, and its function is related to cell cycle progression and survival. However, the molecular mechanisms of action of HCCR2 in leukemia remain unclear. In this study, we used the RNA interference strategy to investigate the effects of HCCR2 knockdown in the K562 leukemia cell line, and to explore the potential mechanisms involved. Following transfection with small interfering RNA (siRNA) targeting HCCR2 (HCCR2-siRNA), we examined the effects of HCCR2 knockdown on cell morphology, cell proliferation, cell cycle progression and apoptosis in K562 cells. Morphological changes were evaluated by Wright-Giemsa staining. Cell cycle progression and apoptosis were measured by flow cytometry. The expression levels of genes related to the cell cycle and apoptosis were detected by quantitative RT-PCR (qRT-PCR) and western blot analysis. HCCR2 expression at the mRNA and protein level was significantly decreased following transfection with plasmids expressing HCCR2-siRNA. Silencing HCCR2 expression significantly suppressed cell proliferation, induced G1 cell cycle arrest and promoted the apoptosis of K562 cells. Additionally, we found that the expression of Bax, p53 and p21 was significantly increased, while Bcl-2 expression was significantly decreased in the HCCR2-siRNA-transfected cells. However, the expression of p27 was not affected. These results suggest that the HCCR2 gene plays an important role in the tumorigenesis of leukemia, thus making it an attractive therapeutic target for acute leukemia.

TRBV kinetics and its association with HLA disparity and aGVHD following allogeneic hematopoietic stem cell transplantation

The relative expression of T cell receptor (TCR) beta variable (TRBV) and TCR diversity was compared between recipients receiving human leukocyte antigen (HLA)‐mismatched transplants and those receiving HLA‐matched transplants, using granulocyte colony‐stimulating factor (G‐CSF)‐mobilized peripheral blood stem cells and bone marrow as grafts.

CCR5 blockade combined with cyclosporine A attenuates liver GVHD by impairing T cells function

ObjectiveOur preview study found that CCR5 blockade combined with cyclosporine A could attenuate the severity of liver GVHD. But the potential immunological mechanisms have not yet been explored. So our present study was designed to clarify the potential immunological mechanisms in mouse models after allo-HSCT.MethodsFirstly, we detected donor T cells homing to target organs, and analyzed the specific effector subsets in liver. Additionally, we assessed antigen-presenting cells (APCs), especially DCs and CD4+ T cells differentiation in secondary lymphoid organs.ResultsData showed that MVC combined with CsA reduced donor T cells migration to target organs in vivo. MVC and CsA treatment reduced the amount of donor T cells in the absolute numbers, also in donor CD4+ and CD8+ T cells by targeting at CCR5. And MVC co-injected with CsA was capable of slightly suppressing DC maturation, and reduced the percentage of Th1 and Th17 mainly by noncompetitive combination of CCR5.ConclusionCombined use of MVC and CsA was effective in attenuating liver GVHD in murine model. It can suppress DC maturation, affect T cells differentiation, and reduce donor T cells homing to target organs. This may offer a novel therapeutic perspective approach for clinical liver GVHD after allo-HSCT.

Alterations of CCR5 and CCR7 expression on donor peripheral blood T cell subsets after mobilization with rhG-CSF correlate with acute graft-versus-host disease

To investigate the effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on chemokine receptors and explore the potential mechanism of rhG-CSF inducing immune tolerance, ninety-seven donor and recipient pairs undergoing family-donor allogeneic hematopoietic stem cell transplantation were studied. The results indicated that different donors showed great disparities in expression changes after mobilization. Multivariate analysis revealed that both HLA mismatching and CCR7 downregulation on donors CD4+ T cells after mobilization were independent risk factors for acute graft-versus-host disease (GVHD). In contrast, CCR5 downregulation on CD4+ T cells was associated with reduced incidence of acute GVHD. In conclusion, rhG-CSF mobilization could lead to differential regulation of chemokine receptors expression on T cell subsets in different donors. Downregulation of CCR5 and upregulation of CCR7 expression on donor CD4+ T cells might protect recipients from acute GVHD. This finding may provide a promising new strategy for the prevention and treatment of acute GVHD.