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Wang H.,University of Heidelberg | Wang H.,Key Laboratory of Organ Transplantation | Daniel V.,University of Heidelberg | Sadeghi M.,University of Heidelberg | Opelz G.,University of Heidelberg
Transplantation Proceedings | Year: 2013

CD4+ CD25+ FoxP3+ T-regulatory cells (Treg) and CD3+ CD8+ CD28- T-suppressor cells (Ts) were shown to have immunosuppressive function in vivo and in vitro. However, the in vitro inducibility of Ts subsets is rather unclear. We investigated the induction of Treg and Ts subsets in peripheral blood mononuclear cells of 5 healthy control individuals during stimulation with phorbol 12-myristate 13-acetate (PMA)/ionomycin or phytohemagglutinin (PHA). Phenotypes were analyzed 0, 4, 8, 16, and 24 hours after initiation of cell culture using 4-color fluorescence flow-cytometry. Number of CD4+ CD25+ FoxP3+ CD127- Treg increased during PMA/ionomycin or PHA stimulation (P <.01). CD4+ CD25+ FoxP3+ Treg coexpressed the phenotypes interleukin (IL)-2 -, IL-10+, and/or transforming growth factor (TGF)-β+ after stimulation (all P <.01). Interferon (IFN)-γ production was induced only by PMA/ionomycin (P <.01) but not by PHA (P = NS). IFN-γ-secreting Treg were detectable at 4 hours whereas IL-2-, IL-10+ and/or TGF-β+ Treg required 16 hours of stimulation. In contrast, CD3+ CD8+ CD28 - Ts phenotypes were not inducible during 24-hour PMA/ionomycin or PHA stimulation (all P = NS). However, Ts coexpressed IL-10 and/or TGF-β during polyclonal stimulation (all P <.01), whereas the proportion of IL-2- Ts remained stable during the cell culture period (P = NS). Similar to Treg, IFN-γ-secreting Ts were detected only during PMA/ionomycin stimulation (P <.01), but not during PHA stimulation (P = NS). We conclude that the proportion of CD3+ CD8+ CD28 - Ts remains stable during polyclonal stimulation. They modify only the cytokine pattern indicating activation of the Ts. In contrast, CD4 + CD25+ FoxP3+ CD127- Treg are inducible by PMA/ionomycin and PHA stimulation. IFN-γ- secreting Treg form the first line of immunoregulatory T cells during an initiated immune response followed by IL-2-, IL-10+, and/or TGF-β+ Treg. © 2013 Elsevier Inc. All rights reserved. Source

Wang H.,University of Heidelberg | Wang H.,Key Laboratory of Organ Transplantation | Daniel V.,University of Heidelberg | Sadeghi M.,University of Heidelberg | Opelz G.,University of Heidelberg
Transplantation Proceedings | Year: 2013

Induced regulatory T cells (iTreg) are a heterogeneous T-cell subset that is induced during an allo-response and down-regulates the immune response. iTreg are commonly characterized as CD4+CD25high, CD4 +CD25highFoxP3+, CD4+CD25 highCD127-, or CD4+CD25 highFoxP3+CD127- peripheral blood lymphocytes (PBL). In the present study, we investigated the overlap of these 4 phenotypically determined iTreg subsets in normal human individuals. PBL of 8 healthy individuals were incubated for 0 hours (Group 1) or for 16 hours in medium without (Group 2) or with phorbol 12-myristate 13-acetate (PMA)/Ionomycin (Group 3). Thereafter, proportions of PBL with Treg phenotypes were determined using 4-color flow-cytometry. All 4 Treg subsets increased strongly during polyclonal stimulation (P <.001). After stimulation, combining 2 iTreg markers, 24% of stimulated CD4+ PBL were CD25 highFoxP3+, 18% CD25highCD127-, and 61% FoxP3+CD127-. Combining 3 iTreg markers, only 18% of the polyclonally stimulated CD4+ PBL were CD25 highFoxP3+CD127-. Importantly, the proportion of FoxP3+CD127- PBL increased with the quantity of CD25 on stimulated CD4+ PBL and was highest in CD25high PBL (P =.002), emphasizing the relevance of CD25high as iTreg marker. Different iTreg phenotypes should not be used interchangeably because they define different iTreg subsets that overlap only in part. CD25high is the most relevant iTreg marker. These conclusions should be considered when studies and experiments involving iTreg phenotypes are compared. © 2013 Elsevier Inc. All rights reserved. Source

Feng Z.,Zhejiang University | Zeng S.,Southern Medical University | Wang Y.,Zhejiang University | Zheng Z.,Key Laboratory of Organ Transplantation | Chen Z.,Zhejiang University
PLoS ONE | Year: 2013

Background: While bisphosphonates (BPs) are commonly used in clinical treatment for osteoporosis, their roles on osteoporosis treatment for rheumatic patients remain unclear. We performed a meta-analysis to evaluate the efficacy of BPs on fractures prevention and bone mass preserving in rheumatic patients. Methodology/Principal Findings: We searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials for relevant literatures with a time limit of Jan. 6, 2012. All randomized clinical trials of BPs for adult rheumatic patients with a follow-up of 6 months or more were included. We calculated relative risks (RRs) for fractures and weighted mean difference (WMD) for percent change of bone mineral density (BMD). Twenty trials were included for analysis. The RR in rheumatic patients treated with BPs was 0.61 (95%CI [0.44, 0.83], P = 0.002) for vertebral fractures, and 0.49 (95%CI [0.23, 1.02], P = 0.06) for non-vertebral fractures. The WMD of BMD change in the lumbar spine was 3.72% (95%CI [2.72, 4.72], P<0.001) at 6 months, 3.67% (95%CI [2.84, 4.50], P<0.001) at 12 months, 3.64% (95%CI [2.59, 4.69], P<0.001) at 24 months, and 5.87% (95%CI [4.59, 7.15], P<0.001) at 36 months in patients using BPs, as compared with those treated with calcium, vitamin D or calcitonin. In subgroup analyses, rheumatic patients using BPs for osteoporosis prevention had greater WMD than those using BPs for treating osteoporosis at 6 months (4.53% vs. 2.73%, P = 0.05) and 12 months (4.93% vs. 2.91%, P = 0.01). Conclusions/Significance: In both short-term and middle-term, BPs can preserve bone mass and reduce the incidence of vertebral fractures in rheumatic patients, mainly for those who have GC consumption. The efficacy of BPs is better when using BPs to prevent rather than to treat osteoporosis in rheumatic patients. Copyright: © 2013 Feng et al. Source

Li Y.,Ohio State University | Cai M.,Ohio State University | Cai M.,Key Laboratory of Organ Transplantation | Xu Y.,Ohio State University | And 4 more authors.
Life Sciences | Year: 2011

Aims: Late phase ischemic preconditioning (LPC) protects the heart against ischemia-reperfusion (I/R) injury. However, its effect on myocardial tissue oxygenation and related mechanism(s) is unknown. The aim of the current study is to determine whether LPC attenuates post-ischemic myocardial tissue hyperoxygenation through preserving mitochondrial oxygen metabolism. Main methods: C57BL/6 mice were subjected to 30 min coronary ligation followed by 60 min or 24 h reperfusion with or without LPC (3 cycles of 5 min I/5 min R): Sham, LPC, I/R, and LPC + I/R group. Myocardial tissue Po2 and redox status were measured with electron paramagnetic resonance (EPR) spectroscopy. Key findings: Upon reperfusion, tissue Po2 rose significantly above the pre-ischemic level in the I/R mice (23.1 ± 2.2 vs. 12.6 ± 1.3 mm Hg, p < 0.01). This hyperoxygenation was attenuated by LPC in the LPC + I/R mice (11.9 ± 2.0 mm Hg, p < 0.01). Activities of NADH dehydrogenase (NADH-DH), succinate-cytochrome c reductase (SCR) and cytochrome c oxidase (CcO) were preserved or increased in the LPC group, significantly reduced in the I/R group, and conserved in the LPC + I/R group. Manganese superoxide dismutase (Mn-SOD) protein expression was increased by LPC in the LPC and LPC + I/R mice compared to that in the Sham control (1.24 ± 0.01 and 1.23 ± 0.01, p < 0.05). Tissue redox status was shifted to the oxidizing state with I/R (0.0268 ± 0.0016/min) and was corrected by LPC in the LPC + I/R mice (0.0379 ± 0.0023/min). Finally, LPC reduced the infarct size in the LPC + I/R mice (10.5 ± 0.4% vs. 33.3 ± 0.6%, p < 0.05). Significance: Thus, LPC preserved mitochondrial oxygen metabolism, attenuated post-ischemic myocardial tissue hyperoxygenation, and reduced I/R injury. © 2010 Elsevier Inc. All rights reserved. Source

Chen S.,Huazhong University of Science and Technology | Zhong S.,Huazhong University of Science and Technology | Xiang Y.,Huazhong University of Science and Technology | Li J.-H.,Huazhong University of Science and Technology | And 9 more authors.
American Journal of Transplantation | Year: 2011

Protection against humoral injury mediated by donor-specific antibodies (DSA), also known as accommodation, may allow for long-term allograft survival in presensitized recipients. In the present study, we determined the role of complement in renal allograft accommodation in donor skin-presensitized nonhuman primates under conventional immunosuppression. Donor skin allografts were transplanted to presensitized recipients 14 days prior to renal transplantation. Renal allografts not receiving any immunosuppressive treatment developed accelerated rejection with predominantly humoral injury, which was not prevented using conventional cyclosporine (CsA) triple therapy. Inhibition of complement activation with the Yunnan-cobra venom factor (Y-CVF) successfully prevented accelerated antibody-mediated rejection and resulted in successful accommodation and long-term renal allograft survival in most presensitized recipients. Accommodation in this model was associated with the prevention of the early antibody responses induced against donor antigens by complement inhibition. Some antiapoptotic proteins and complement regulatory proteins, including Bcl-2, CD59, CD46 and clusterin, were upregulated in the surviving renal allografts. These results suggest that the complement inhibition-based strategy may be valuable alternative in future clinical cross-match positive or ABO-incompatible transplantation. © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons. Source

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