Wang M

The regulation of CD4+ T cell immune responses toward Th2 cell development by prostaglandin E2.

As an important immune mediator, PGE2 plays an important role in the immune tolerance, autoimmune diseases, immune regulation and tumor immunotolerance. PGE2 is considered to be a promising candidate for the control of the immune diseases. To further understand the immuno-modulating effects of PGE2 on CD4+ T cells, in vitro investigation was conducted in the present study. The results showed that PGE2 inhibited the proliferation of T cells in vitro in a dose-dependent manner. Gene expression profiling showed that 1716 genes were down regulated and 73 genes were up regulated with a change of 1.5 fold. Several signal transduction pathways were involved, such as TNF-α and NF-kB signaling pathway, T cell receptor signaling pathway, IL-2 signaling pathway, and MAPK pathway. The results showed that PGE2 inhibited IFN-γ, TNF-α and IL-4 production by CD4+ T cells 24h after cell culture. A comparison between IFN-γ and IL-4 production showed that PGE2 enhanced the relative ratio of IL-4 to IFN-γ in CD4+ T cells culture, and regulated CD4+ T cells toward Th2 cell development. The results of the present study indicated that PGE2 has the potential to treat Th1-mediated inflammatory diseases by regulating CD4+ T cells toward Th2 cell immune response.

Risk factors and prognosis of invasive fungal infections in allogeneic stem cell transplantation recipients: a single-institution experience

P. Zhang, E.‐L. Jiang, D.‐L. Yang, Z.‐S. Yan, Y. Huang, J.‐L. Wei, M. Wang, Q.‐L. Ma, Q.‐G. Liu, D.‐H. Zou, Y. He, L.‐G. Qiu, S.‐Z. Feng, M.‐Z. Han. Risk factors and prognosis of invasive fungal infections in allogeneic stem cell transplantation recipients: a single‐institution experience. Transpl Infect Dis 2010: 12: 316–321. All rights reserved

Interferon-γ mediates the immunosuppression of bone marrow mesenchymal stem cells on T-lymphocytes in vitro.

ABSTRACT Objectives: In the present study, we first confirmed the suppressive function of MSCs in allogeneic T cell proliferation and then examined the underlying mechanisms for MSCs’ immunomodulation and the role of the pro-inflammatory cytokine interferon (IFN)-γ. Methods: Human MSCs were cultured in the presence or absence of IFN-γ. The expression level of prostaglandin E2 (PGE2), hepatocyte growth factor (HGF), transforming growth factor (TGF)-β1 and indoleamine 2,3-dioxygenase (IDO) by MSCs were measured. T lymphocytes were isolated from peripheral blood of healthy donors and then induced to proliferate under the stimulation of anti-human CD3 mAb and anti-human CD28 mAb. In the presence of MSCs, T cell proliferation was examined by BrdU incorporation. In addition, PGE2, HGF, TGF-β1, Kynurenine, recombinant human IFN-γ and anti-IFN-γ mAb were added and cell proliferation was examined. Results: Compared to the controls (MSCs alone), MSCs cocultured with IFN-γ expressed significantly higher concentrations of PGE2, HGF and TGF-β1. The mRNA level of IDO was remarkably increased. Human bone marrow-derived MSCs alone notably suppressed T lymphocytes proliferation in vitro. Addition of exogenous IFN-γ did not ablate the immunosuppressive effects of MSCs. Addition of anti-IFN-γ mAb partially restored suppression of T cell proliferation by MSCs. Conclusions: Human MSCs constitutively expressed immunosuppressive levels of PGE2, HGF and TGF-β1. The proinflammatory cytokine IFN-γ exhibited synergistic effects with MSCs on immunosuppression, possibly by up-regulating PGE2, HGF and TGF-β1 in MSCs and inducting MSCs expression of IDO, involved in tryptophan catabolism.

The impact of recipient HLA-Cw and donor killer immunoglobulin-like receptor genotyping on the outcome of patients receiving HLA-matched sibling donor hematopoietic stem cell transplantation for myeloid malignancies.

BACKGROUND The alloreactivity of natural killer cell and certain subsets of T lymphocyte are regulated by the interaction between killer immunoglobulin-like receptors (KIRs) of donor cells and human leukocyte antigen (HLA)-class I molecules on target cells. The interaction has been shown to influence the outcome of allogeneic haematopoietic stem cell transplantation (HSCT). Homozygous C1 or C2 and heterozygous C1/C2 were divided by HLA-Cw typing and they influenced the outcome of HSCT. OBJECTIVE The purpose of the study was to analyse the impact of interaction between recipient HLA-Cw and donor KIR on outcome. METHODS The genotypes of recipient HLA-Cw ligands and donor KIRs were correlated with the clinical outcomes of 52 patients who received HLA-matched, sibling donor HSCT for myeloid malignancies. RESULTS The incidence of chronic graft versus host disease (GVHD) was significantly lower in C1 or C2 homozygotes than in C1/C2 heterozygotes (p = 0.000). Higher overall survival (OS) and disease-free survival (DFS) rates were observed in C1 or C2 homozygotes than in C1/C2 heterozygotes (OS, 81% ± 8% vs 54% ± 10%, p = 0.034; DFS, 81% ± 8% vs 54% ± 10%, p = 0.024). A lower incidence of chronic GVHD and higher OS and DFS were observed in the HLA-KIR mismatched group (chronic GVHD, p = 0.007; OS, 84% ± 7% vs 47% ± 13%, p = 0.003; DFS, 84% ± 7% vs 47% ± 13%, p = 0.002). CONCLUSION The interaction between recipient HLA ligand and donor KIR had a significant impact on the outcome of patients receiving matched sibling HSCT. C1/C2 heterozygotes or HLA-KIR matched patients may benefit from additional intensified therapy with better outcome.

An evaluation of the RIFLE criteria for acute kidney injury after myeloablative allogeneic haematopoietic stem cell transplantation.

BACKGROUND Patients undergoing myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) have a higher incidence of acute kidney injury (AKI). RIFLE is a newly developed classification for AKI that includes three grades of severity - AKI-R, AKI-I, AKI-F. OBJECTIVE The purpose of this study was to analyse retrospectively major risk factors for AKI at the time of myeloablative allo-HSCT and to use the RIFLE criteria to predict mortality in myeloablative allo-HSCT. METHODS Renal function was evaluated in 143 patients with allo-HSCT by RIFLE criteria in order to assess the incidence, risk factors and mortality rate of various degrees of AKI. RESULTS The results of this study showed that patients with hepatic veno-occlusive disease (HVOD) have a higher incidence of AKI-F than those without HVOD (P = 0.002). The incidence of AKI-I and AKI-F in patients with grade III-IV acute graft-versus-host disease (aGVHD) and increased total bilirubin was significantly higher than in those without (P = 0.001, P <0.001). HVOD was an independent risk factor of AKI-F (OR 5.058, 95% CI 1.317-19.424, P = 0.018), and increased total bilirubin was an independent risk factor for AKI-F (OR 5.126, 95% CI 1.403-18.998, P = 0.014). Worsening RIFLE category was associated with increased mortality of the patients in the 100 days post-transplant (P = 0.003). In addition, 180-day survival of patients in different AKI classes was significantly different (P = 0.0095). CONCLUSION AKI is common in patients with myeloablative allo-HSCT and is associated with increased risk of death. The RIFLE criteria appear to be an important tool for stratification of these patients on the basis of death risk.

Treatment of hematologic malignancies with alternate hemibody irradiation combined with high-dose chemotherapy: A single-center experience

The objective of this study was to evaluate the clinical outcome of the treatment of hematologic malignancies with alternate hemibody irradiation (AHBI) combined with high-dose chemotherapy. Seventeen patients with hematologic malignancies were treated with AHBI combined with high-dose chemotherapy. Following high-dose chemotherapy, upper hemibody irradiation (UHBI) and lower hemibody irradiation (LHBI) were given sequentially in a dose of 6 to 9 Gy. UHBI was given 14 days (range, 12-22 days) after high-dose chemotherapy, and LHBI was performed 23 days (range, 7-34 days) after UHBI. Meanwhile, we treated a control group of 14 patients with acute lymphoblastic leukemia (ALL) with autologous hematopoietic stem cell transplantation (AHSCT). Hematopoietic reconstitution was observed in all of the patients. The median follow-up period was 927 days (range, 428-1446 days). The 3-year probabilities of disease-free survival (DFS) were 52.38% ± 13.47% for the patients in complete remission who underwent AHBI. No patient died of AHBI-related toxicity. The 3-year DFS rates for the 2 groups of patients with ALL were not significantly different (47.73% ± 17.55% in the AHBI group and 53.88% ± 14.08% in the AHSCT group; P >.05). AHBI combined with high-dose chemotherapy is a feasible approach for patients with hematologic malignancies and has the advantages of a desirable effectiveness, low costs, simple operation, and acceptable side effects.

Impact of Human Leukocyte Antigen Loci and Haplotypes on Intestinal Acute Graft-versus-host Disease after Human Leukocyte Antigen-matched Sibling Peripheral Blood Stem Cell Transplantation

Background: Acute graft-versus-host disease (aGVHD) is a common and severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Some studies have found that the presence of certain specific human leukocyte antigen (HLA) loci could affect the occurrence of aGVHD. Meanwhile, the impact of HLA haplotypes on aGVHD has been rarely studied. This study aimed to investigate the effects of HLA loci and haplotypes on intestinal aGVHD. Methods: Totally, 345 consecutive patients undergoing first HLA-matched sibling peripheral blood stem cell transplantation (PBSCT) from February 2004 to June 2013 at Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, were enrolled in this study. HLA loci and haplotypes of recipients with frequency over 5% were searched and their effects on intestinal aGVHD were investigated. Other important factors including donor age, recipient age, donor-recipient sex combinations, and conditioning regimens were also evaluated using logistic regression. Pure upper gastrointestinal tract aGVHD without diarrhea was excluded because the histological proof was unavailable. The follow-up end-point was 6 months after HSCT. Results: The cumulative incidence of intestinal aGVHD was 19.4%, with 18.0% of the patients classified as classic aGVHD and 1.4% as persistent, recurrent, or late aGVHD. Multivariate analysis showed that HLA-A31 locus (odds ratio [OR] 2.893, 95% confidence interval [CI] [1.054, 7.935], P = 0.039), HLA B40-DR15 (OR 3.133, 95% CI [1.250, 7.857], P = 0.015), and HLA B46-DR9 haplotypes (OR 2.580, 95% CI [1.070, 6.220], P = 0.035), female donor for male recipient (OR 2.434, 95% CI [1.319, 4.493], P = 0.004) were risk factors for intestinal aGVHD. Conclusion: The presence of certain HLA loci and haplotypes may influence the occurrence of intestinal aGVHD in PBSCT with HLA-identical sibling donors.