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1.
Controversy exists on the role of leucocytospermia on fertilisation rates and IVF outcomes. The aim of our study was to identify the effect of leucocytes and leucocyte subpopulations on fertilisation rates in an IVF cycle. A prospective comparative study of the leucocyte subpopulations of seminal fluid of partners of women attending an IVF cycle was conducted. The samples underwent immunocytochemical staining. The monoclonal antibodies used in this study include CD3, CD4, CD8 (T Cells), CD14 (monocytes/macrophages), CD16 (granulocytes), CD20 (B Cells), CD45 (Pan Leucocytes), CD56 (natural killer cells) and CD69 (activated T and B Cells). Of 21 patients who were recruited into the study, seven were identified as poor fertilisers (<35%) and 14 were identified as good fertilisers (>60%). Data were analysed with SPSS version 14. The total leucocyte counts (CD45) between the poor and good fertilisers were not statistically significant. The macrophages and the monocytes (CD14) were significantly elevated in the good fertilisers group in comparison with the poor fertilisers (P < 0.05). We also found that T cells (CD2, CD4, CD8) and CD14 (macrophages) correlated significantly (r = 0.47, P value < 0.01) with the fertilisation rate. Our study confirms that the presence of leucocytes does not adversely affect the fertilisation rates and the outcome of an IVF cycle. However, macrophages and the monocytes (CD14) were significantly elevated in the good fertilisers group. The increased phagocytic activity in these individuals might increase their fertilising potential by removing spermatozoa with abnormal morphology.  相似文献   

2.
3.
Activated T cell has a key role in the interaction between bone and immune system. T cells produce proinflammatory cytokines, including receptor activator of NF‐κB ligand (RANKL), tumor necrosis factor α (TNF‐α), and interleukin 17 (IL‐17), all of which augment osteoclastogenesis. RANKL and TNF‐α are targeted by inhibitors such as denosumab, a human monoclonal RANKL antibody, and infliximab, which neutralizes TNF‐α. IL‐17 is also an important mediator of bone loss, and an antibody against IL‐17 is undergoing phase II clinical trial for rheumatoid arthritis. Although there are a few studies showing suppression of Th17 cell differentiation and induction of regulatory T cells (Tregs) by infliximab, the effect of denosumab remains poorly understood. In this study, we investigated the effects of anti‐TNF‐α, anti‐RANKL, or anti‐IL‐17 antibody administration to estrogen‐deficient mice on CD4+ T‐cell proliferation, CD28 loss, Th17/Treg balance and B lymphopoesis, and finally, the translation of these immunomodulatory effects on skeletal parameters. Adult Balb/c mice were treated with anti‐RANKL/‐TNF‐α/‐IL‐17 subcutaneously, twice a week, postovariectomy (Ovx) for 4 weeks. Animals were then autopsied; bone marrow cells were collected for FACS and RNA analysis and serum collected for ELISA. Bones were dissected for static and dynamic histomorphometry studies. We observed that although anti‐RANKL and anti‐TNF‐α therapies had no effect on Ovx‐induced CD4+ T‐cell proliferation and B lymphopoesis, anti‐IL‐17 effectively suppressed both events with concomitant reversal of CD28 loss. Anti‐IL‐17 antibody reduced proinflammatory cytokine production and induced Tregs. All three antibodies restored trabecular microarchitecture with comparable efficacy; however, cortical bone parameters, bone biomechanical properties, and histomorphometry were best preserved by anti‐IL‐17 antibody, likely attributable to its inhibitory effect on osteoblast apoptosis and increased number of bone lining cells and Wnt10b expression. Based on the superior immunoprotective effects of anti‐IL‐17, which appears to translate to a better skeletal preservation, we propose beginning clinical trials using a humanized antibody against IL‐17 for treatment of postmenopausal osteoporosis. © 2014 American Society for Bone and Mineral Research.  相似文献   

4.
The role of leucocytospermia in male subfertility is a much debated topic despite being a frequent finding. This study aimed to identify the role of leucocytes, leucocyte subpopulations and natural killer cells in male subfertility. Seventy-sex subfertile men attending a regional andrology unit were recruited into this prospective study and subdivided into groups based on their semen analysis. The different leucocyte subpopulations were identified using immunocytochemical staining. Significant levels of CD3 helper T lymphocytes (P < 0.001) were present in the oligospermic, asthenospermic, oligoasthenospermic and obstructive azoospermic group compared to the normospermic group. Significant levels of B cells (P < 0.05) were present in the asthenospermic, oligoasthenospermic and obstructive azoospermic group. The natural killer cells (CD56) were significantly raised in the oligoasthenospermic and obstructive azoospermic group (P < 0.05). Our study suggests that leucocytospermia impairs sperm function through enhanced T helper cell modulation, increased B cell population which leads to increased levels of antisperm antibody and natural killer cells mediated sperm damage. The site of seminal leucocyte production is not necessarily confined to the vas or the epididymis.  相似文献   

5.
Changes in seminal fluid viscosity (SFV), reactive oxygen species (ROS) production, cytokines and seminal leucocyte concentration related to microbiological outcome in patients with chronic bacterial prostatitis (CBP) were studied. One hundred and ten infertile patients with CBP (positive sperm culture ≥105 colony‐forming units [CFU] ml?1, pathogens or Chlamydia in expressed prostatic secretions) were treated with levofloxacin 500 mg daily for 14 consecutive days per month for 3 months. In case of bacterial prostatitis, two conditions were examined: responders, eradication of 0 to <103 CFU ml?1 (n = 78) and poor responders, >103 to <105 CFU ml?1 (n = 32). Compared with poor responders, responders showed a significant increase of sperm progressive motility and a significant decrease in seminal leucocyte count, SFV, liquefaction time, ROS production (in all fractions and conditions), seminal tumour necrosis factor‐α and interleukin 6. None of these variables showed significant differences compared with a control group of 37 fertile men. On the other hand, the poor responders showed significant changes in these variables compared with matched pretreatment values. In patients with CBP, antibiotic therapy alone leads to eradication in ≈71%, with improvement of sperm progressive motility, SFV and the framework of prooxidative factors. However, in the remaining ≈29% with poor antibiotic responsiveness, a deterioration of all variables is observed.  相似文献   

6.
Leucocytospermia has been associated with loss of sperm function. Extracellular traps (ETs) of leucocytes are produced during innate immune response. ETs can be activated by spermatozoa in contact with polymorphonuclear (in vitro), inducing sperm entrapment and decrease motility. In this pilot study, we describe the results of ETosis ex vivo, in seminal fluid (SF) smear of infertile patients, associating ETs with leucocytospermia and bacteriospermia. In 21 infertile patients, semen parameters (WHO, 2010), microbiological study, leucocytospermia and presence of ETs in SF were determined. Leucocytes (CD45, CD15 and CD68) were evaluated by immunostaining in SF smears. Indirect immunofluorescence (global histone and H4‐citrullinated 3) and scanning electron microscopy (SEM) were used to determine ETs morphology. In 28.6% of patients presented leucocytospermia without bacteriospermia, all of them presented a large number of ETs in the SF smears examined. About 76.6% of the patients without leucocytospermia were positive for ETs. Samples with leucocytospermia have a higher number of ETs and would be related to the amount of leucocytes in the SF. The morphological predominant ETs were diffuse (diffETs) and spread (sprETs). The formation of ETs indicates leucocyte activation in semen, and it was observed that ETosis does not depend exclusively on the presence of bacterial contamination.  相似文献   

7.
H. Wang  Y. Lv  K. Hu  T. Feng  Y. Jin  Y. Wang  Y. Huang  B. Chen 《Andrologia》2015,47(6):655-661
Excessive apoptotic spermatozoon death is associated with male infertility. Leptin regulates apoptosis in several cell types. We prospectively investigated if seminal plasma leptin mediates spermatozoon apoptosis in 74 varicocele (VC) patients and 70 leucocytospermia patients. Spermatozoa from 40 normospermic men were used as controls. Routine semen analysis, spermatozoon apoptosis rate, seminal plasma leptin, reactive oxygen species (ROS) and tumour necrosis factor‐alpha (TNF‐α) levels were measured. In VC and leucocytospermia patients, seminal plasma leptin levels and spermatozoon apoptosis rates were significantly higher compared with controls. In the VC group, seminal plasma ROS levels were significantly higher compared with controls; there were no significant differences in TNF‐α levels. In the leucocytospermia group, both ROS and TNF‐α levels were significantly higher compared with controls. In both the VC and leucocytospermia groups, there was a significant positive correlation between the spermatozoon apoptosis rate and leptin levels and ROS and leptin levels. There was a significant correlation between leptin and TNF‐α levels in the leucocytospermia group. Seminal plasma leptin levels correlate significantly with spermatozoon apoptosis rate, and leptin may be a spermatozoon pro‐apoptotic factors. The generation of ROS is a possible mechanism. Leptin may induce apoptosis via TNF‐α in leucocytospermia patients.  相似文献   

8.
Infection and rejection are common complications faced by lung transplant recipients (LTRs) and have become major impediments to long‐term survival. Cytokines may play an important role in the development of these complications. In this study, we explored the correlation between TNF‐α (?308 A/G), TGF‐β1 (+869 T/C, +915 G/C), IL‐10 (?592 C/A, ?819 T/C, ?1082 G/A), IL‐6 (?174 G/C), and IFN‐γ (+874 T/A) gene polymorphisms and the incidence of acute rejection and infection. Transplant outcomes were reviewed in a retrospective cohort of 113 LTRs from a single center between December 2004 and November 2012. Cytokine polymorphisms were measured using sequence‐specific primer‐based PCR. HLA typing was performed for the donors and recipients. We found that the LTRs with the IL‐10 ?819 CC and ?592 CC genotypes had a significantly decreased risk of infection (p = 0.017, OR = 0.177, 95% CI = 0.04–0.85). However, we found no significant association between cytokine polymorphisms and acute rejection. Furthermore, the data revealed that the occurrence of acute rejection was strongly associated with infection episodes (χ2 = 8.5256, p < 0.01). These results suggest that LTRs possessing the IL‐10 ?819 CC and ?592 CC genotype may be protected from the occurrence of infection. Our results demonstrated that infection is an important cause of acute rejection for LTRs.  相似文献   

9.
Background—Tumor necrosis factor‐α (TNF‐α), a key factor in the inflammatory cascade, has been implicated in coronary artery disease. Two biallelic polymorphisms in the TNF gene locus (TNFA at position ?308 and TNFB at +252) may influence TNF‐α production. Individuals with the rare TNFA2 allele or TNFB2 homozygosity have augmented TNF‐α production. We investigated the genotypes associated with increased TNF‐α production in coronary artery bypass grafting (CABG) patients and if these genotypes influence the magnitude of the postoperative inflammatory response.

Methods—TNF gene polymorphisms were analyzed by multiplex fluorescent solid‐phase minisequencing in 86 CABG patients. Plasma concentrations of TNF‐α, IL‐6 and C3a and C‐reactive protein (CRP) were analyzed before and after surgery in 45 of the patients and compared with genetically high and low TNF‐α producers.

Results—Thirty percent of the patients carried the TNFA2 allele and 45% were TNFB2 homozygous. The allelic frequencies were TNFA1/TNFA2?=?0.84/0.16 and TNFB1/TNFB2?=?0.32/0.68. Pre‐ and postoperative levels of TNF‐α, IL‐6, C3a and CRP did not differ significantly between genetically high and low TNF‐α producers.

Conclusions—The frequency of high TNF‐α producing genotypes in a CABG population was comparable to that previously reported from normal populations. Furthermore, we found no evidence that the investigated TNF‐α gene polymorphisms influence postoperative inflammatory response after uncomplicated coronary surgery.  相似文献   

10.
Epithelial to mesenchymal transition (EMT) has been implicated in the pathogenesis of obliterative bronchiolitis (OB) after lung transplant. Although TNF‐α accentuates TGF‐β1 driven EMT in primary human bronchial epithelial cells (PBECs), we hypothesized that other acute pro‐inflammatory cytokines elevated in the airways of patients with OB may also accentuate EMT and contribute to dysregulated epithelial wound repair. PBECs from lung transplant recipients were stimulated with TGF‐β1 ± IL‐1β, IL‐8, TNF‐α or activated macrophages in co‐culture and EMT assessed. The quality and rate of wound closure in a standardized model of lung epithelial injury was assessed in response to above stimuli. Co‐treatment with TGF‐β1 + TNF‐α or IL‐1β significantly accentuates phenotypic and some functional features of EMT compared to TGF‐β1 alone. Co‐treatment with TGF‐β1 + TNF‐α or IL‐1β accelerates epithelial wound closure however the quality of repair is highly dysregulated. Co‐treatment with TGF‐β1 + IL‐8 has no significant effect on EMT or the speed or quality of wound healing. Activated macrophages dramatically accentuate TGF‐β1‐driven EMT and cause dysregulated wound repair. Crosstalk between macrophage‐derived acute inflammation in the airway and elevated TGF‐β1 may favor dysregulated airway epithelial repair and fibrosis in the lung allograft via EMT.  相似文献   

11.
Oxidative stress aggravates several long‐term complications in diabetes mellitus. We evaluated the effectiveness of the oral administration of antioxidants (vitamins E and C, 40 and 100 mg/kg b.w., respectively) on skin wound healing acceleration in alloxan‐induced diabetic mice. Mice were wounded 30 days after the induction of diabetes. Antioxidants were effective in preventing oxidative stress, as assessed by TBARS. The enzymes catalase, glutathione reductase, glutathione peroxidase, and superoxide dismutase were increased in diabetics on the 3rd day post‐wounding; catalase and glutathione peroxidase remained still augmented in diabetics after 14th day postwounding, and the treatment with vitamins restored their activities to control. After 3 days, diabetic mice showed lower infiltration of inflammatory cells (including CD11b+ and Ly6G+ cells) and reduced levels of KC, TNF‐α, IL‐1β, and IL‐12 p40 when compared with control mice. The treatment restored cytokine levels. After 14 days, diabetic mice showed late wound closure, persistent inflammation and delayed reepithelialization, accompanied by an increase in MIG+/CD206? macrophages whereas CD206+/MIG? macrophages were decreased. Cytokines IL‐12p40, TNF‐α, IL‐1β, and KC were increased and normal levels were restored after treatment with antioxidants. These results suggest that oxidative stress plays a major role in diabetic wound healing impairment and the oral administration of antioxidants improves healing by modulating inflammation and the antioxidant system with no effect on glycemia.  相似文献   

12.
Mice engrafted with human CD34+ hematopoietic stem and progenitor cells (CD34+‐HSPCs) have been used to study human infection, diabetes, sepsis, and burn, suggesting that they could be highly amenable to characterizing the human inflammatory response to injury. To this end, human leukocytes infiltrating subcutaneous implants of polyvinyl alcohol (PVA) sponges were analyzed in immunodeficient NSG mice reconstituted with CD34+‐HSPCs. It was reported that human CD45+ (hCD45+) leukocytes were present in PVA sponges 3 and 7 days postimplantation and could be localized within the sponges by immunohistochemistry. The different CD45+ subtypes were characterized by flow cytometry and the profile of human cytokines they secreted into PVA wound fluid was assessed using a human‐specific multiplex bead analyses of human IL‐12p70, TNFα, IL‐10, IL‐6, IL1β, and IL‐8. This enabled tracking the functional contributions of HLA‐DR+, CD33+, CD19+, CD62L+, CD11b+, or CX3CR1+ hCD45+ infiltrating inflammatory leukocytes. PCR of cDNA prepared from these cells enabled the assessment and differentiation of human, mouse, and uniquely human genes. These findings support the hypothesis that mice engrafted with CD34+‐HSPCs can be deployed as precision avatars to study the human inflammatory response to injury.  相似文献   

13.
Whether porcine cytokines are induced after pig‐to‐primate xenotransplantation and activate human cells remains unknown. First, we investigated the regulation of porcine IL‐6, IFN‐γ, IL‐1β, and TNF‐α in xenotransplantation using an in vitro model in which porcine aortic endothelial cells (PAECs) and porcine peripheral blood mononuclear cells (PBMCs) were stimulated with human serum. Downstream cytokines/chemokines were monitored. Pro‐inflammatory cytokines (IL‐6, IFN‐γ, and IL‐1β) and chemokines (IL‐8, MCP‐1, and CXCL2) were upregulated in the both cell types. TNF‐α was induced 10‐fold in PAECs, but not in PBMCs. Then, we assessed the role of porcine IL‐6, IFN‐γ, IL‐1β, and TNF‐α in xenotransplantation using western blotting and real‐time PCR. Human umbilical vein endothelial cells (HUVECs) were selected as the target cells. Signaling pathways and downstream genes, such as those related to adhesion, inflammation, and coagulation, and chemokines were investigated. Porcine IL‐1β and TNF‐α significantly activated NF‐κB and P38, and STAT3 was activated by porcine IL‐6 in HUVECs. The adhesion genes (E‐selectin, VCAM‐1, and ICAM‐1), inflammatory cytokines (IL‐6, IL‐1β, and TNF‐α), chemokines (MCP‐1 and IL‐8), and the pro‐coagulation gene (tissue factor) were upregulated by porcine IL‐1β and TNF‐α. Porcine IL‐6 increased the expression of ICAM‐1, IL‐6, MCP‐1, and tissue factor, but decreased IL‐8 expression slightly. Surprisingly, porcine IFN‐γ could not activate STAT1 or regulate the expression of any of the above genes in HUVECs. In conclusion, these findings suggest that porcine IL‐6, IL‐1β, and TNF‐α activate HUVECs and regulate downstream genes expression, which may promote inflammation and coagulation response after xenotransplantation.  相似文献   

14.
Background: The specific aim of this study was to examine the efficacy of a low dose of methylprednisolone in minimizing inflammatory response in juvenile piglets when given 45–60 min prior to onset of one‐lung ventilation. Methods: Twenty piglets aged 3 weeks were assigned to either the control group (n = 10) or methylprednisolone group (n = 10). The animals were anesthetized and after 30 min of ventilation, they had their left lung blocked. Ventilation was continued via right lung for 3 h. The left lung was then unblocked. Following another 30 min of bilateral ventilation, the animals were euthanized and both lungs were harvested. The methylprednisolone group had a single dose (2 mg·kg?1) of methylprednisolone given i.v. 45–60 min prior to onset of one‐lung ventilation. Physiological parameters (PaO2, resistance, and compliance) and markers of inflammation (tumor necrosis factor [TNF]‐α, interleukin [IL]‐1β, IL‐6, and IL‐8) were measured at baseline and every 30 min thereafter. Lung tissue homogenates from both collapsed and ventilated lungs were analyzed for TNF‐α, IL‐1β, IL‐6, and IL‐8. Results: The methylprednisolone group had higher partial pressure of oxygen (P = 0.01), lower plasma levels of TNF‐α (P = 0.03) and IL‐6 (P = 0.001) when compared with control group. Lung tissue homogenate in the methylprednisolone group had lower levels of TNF‐α (P < 0.05), IL‐1β (P < 0.05), and IL‐8 (P < 0.05) in both the collapsed and the ventilated lungs. Conclusions: In a piglet model of one‐lung ventilation, use of prophylactic methylprednisolone prior to collapse of the lung improves lung function and decreases systemic pro‐inflammatory response. In addition, in the piglets who received methylprednisolone, there were reduced levels of inflammatory mediators in both the collapsed and ventilated lungs.  相似文献   

15.
Background: Erythropoietin (EPO) is a cytokine with organ‐protective properties. We hypothesized that EPO could attenuate acute renal dysfunction and inflammation in a porcine model of ischemia–reperfusion (IR). Furthermore, we aimed to characterize the impact of EPO on systemic and renal hemodynamics, and renal oxygen consumption. Methods: Twenty‐four pigs were randomly assigned to three groups: (1) EPO (5000 IU/kg) administered intravenously before IR (n=9), (2) placebo administered before IR (n=9), or (3) sham group, anesthetized and operated on only (n=6). IR was induced by clamping the left renal artery for 45 min. Hemodynamics and renal blood flow (RBF) were analyzed continuously. Glomerular filtration rate (GFR), renal oxygen consumption, and plasma cytokines (IL‐1β, IL‐6, IL‐8, IL‐10, and TNF‐α) were analyzed hourly. Renal biopsies were analyzed for cytokine content and apoptosis. Results: GFR was higher during reperfusion in the EPO group than in the placebo group (P<0.01). No differences between the IR groups were found in hemodynamics, RBF, oxygen consumption, or renal apoptosis. The levels of TNF‐α in the plasma (P=0.036) and the levels of TNF‐α and IL‐10 in the renal cortex (P=0.04 and P=0.01, respectively) were lower in the EPO group compared with the sham group. Conclusion: EPO attenuated the renal dysfunction as estimated as GFR. This effect was not related to changes in the hemodynamics. The immunomodulatory effects of EPO were manifested as decreased levels of TNF‐α and IL‐10 in renal biopsies and TNF‐α levels in plasma.  相似文献   

16.
Although borderline changes (BL ) suspicious for acute T‐cell‐mediated rejection represent a diagnostic category, its clinical relevance is questioned leading to heterogeneous therapeutic management. We hypothesized that measuring IL ‐6 secretion by peripheral blood mononuclear cells identifies patients with ongoing graft damage. We examined the association between secreted IL ‐6 and the change in estimated glomerular filtration rate at 6 months after the biopsy (ΔeGFR ). We then conducted phenotypic and functional studies on patient and mouse innate immune cells in the blood and the kidney. In a training set, ΔeGFR was strongly associated with IL ‐6 levels, showing a clinically meaningful decline of 4.6 ± 1.5 ml /min per increase in log10 IL ‐6 (P = 0.001). These results were consistent after adjustment and were reproduced in a validation cohort. Phenotyping of peripheral blood cells revealed that the main source of IL ‐6 was CD 14+CD 16?CCR 2+HLA‐DR +CD 86+CD 11c+ inflammatory monocytes. There was a significant correlation between IL ‐6 secretion and interstitial dendritic cell density in the biopsy. Finally, characterization of mouse kidney dendritic cells revealed that they share features with macrophages and function as effector cells secreting IL ‐6. In conclusion, measuring IL ‐6 secreted by peripheral blood cells can be useful in the management of patients with BL in the absence of a concurrent inflammatory condition.  相似文献   

17.
Resident muscularis macrophages initiate an inflammatory cascade during ischemia/reperfusion that is associated with dysmotility and the activation of immunologic processes. We hypothesized that these muscularis macrophages may also play a potential immunologic role for acute allograft rejection in intestinal transplantation. Orthotopic SBTx (BN‐Lew) was performed without immunosuppression. Animals were sacrificed 7 days after SBTx. The role of resident macrophages was evaluated by transplantation of macrophage‐depleted and gadolinium chloride‐treated gut. Leukocyte infiltration was investigated in muscularis whole mounts by immunohistochemistry. Mediator mRNA expression was determined by Real‐Time‐RT‐PCR. Apoptosis was evaluated by TUNEL. Smooth muscle contractility was assessed in a standard organ bath. In comparison to vehicle‐treated grafts, macrophage‐depleted grafts exhibited significantly lower mediator mRNA peak expression (IL‐6, IL‐2, IL‐10, MCP‐1, iNOS, TNFα, IFNγ, FasL), leukocyte infiltrates (ED1‐ and ED2 positive monocytes and macrophages, neutrophils, CD4+ and CD8+ lymphocytes), apoptosis rates and an improved histologic rejection grading. Vehicle‐treated grafts showed a 77% decrease in smooth muscle contractility compared to naïve controls, while macrophage‐depleted gut exhibited only a 51% decrease in contractile activity. Transplantation of macrophage‐depleted gut attenuates the functionally relevant molecular and cellular immunologic response within the graft muscularis in acute allograft rejection. Resident macrophages participate in initiating these processes.  相似文献   

18.
Acute infections with bovine viral diarrhoea virus (BVDV), a major pathogen of cattle, are often asymptomatic or produce only mild clinical symptoms. However, they may play an important role in the bovine respiratory disease complex by exerting a marked immunosuppressive effect, as a result of the death of the immunocompetent cell populations involved in controlling innate and adaptive immune responses, together with a marked reduction of both cytokine expression and co‐stimulatory molecule synthesis. Although experimental research and field studies have shown that acute BVDV infection enhances susceptibility to secondary infection, the precise mechanism involved in BVDV‐induced immunosuppression remains unclear. The present study is aimed at measuring a range of blood parameters in a single group of fourteen calves infected with non‐cytopathic BVDV‐1. Focus has been put on those related to the cell‐mediated immune response just as leucocyte populations and lymphocyte subpopulations, serum concentrations of cytokines (IL‐1β, TNF‐α, IFN‐γ, IL‐12, IL‐4 and IL‐10) and acute phase proteins [haptoglobin, serum amyloid A (SAA), fibrinogen and albumin], as well as BVDV‐specific antibodies and viremia. After non‐cytopathic BVDV‐1 infection, clinical signs intensity was never more than moderate coinciding with the presence of viremia and leucocyte and lymphocyte depletion. An early increase in TNF‐α, IFN‐γ and IL‐12 levels in contrast to IL‐1β was observed in line with a raise in haptoglobin and SAA levels on the latest days of the study. As regards IL‐4 levels, no evidence was found of any changes. However, a slight increase in IL‐10 was observed, matching up the TNF‐α decline during the acute phase response. These findings would help to increase our knowledge of the immune mechanisms involved in acute infection with non‐cytopathic BVDV‐1 strains, suggesting the existence of a clear tendency towards a type 1 immune response, thereby enhancing resistance against viral infections.  相似文献   

19.
Genetic modification of pigs (e.g. transgenic expression of human complement regulatory molecules or inactivation of α1,3galactosyltransferase) enabled the development of promising strategies to overcome hyperacute rejection after pig‐to‐primate xenotransplantation. However, cellular rejection still remains a hurdle for successful xenograft survival. Cellular rejection of porcine cells in xenotransplantation models is mediated by macrophages, T cells and NK cells. Activation of human monocytes by pig cells is partly due to the incapacity of porcine ligands to bind the inhibitory receptor SIRPα (signal regulatory protein α). Thus, one approach to impair the ability of human macrophages to phagocyte porcine cells is the overexpression of the human ligand for SIRPα in porcine cells. To inhibit human NK cell reactivity after xenotranslantation transgenic expression of HLA‐E in pigs has been shown to be a promising concept. Cells from these pigs were partially protected from lysis by human NK cells. Our group focuses on manipulation of human anti‐pig T cell responses by negative costimulatory signals. Thus, we asked whether overexpression of PD‐L1 on porcine cells can (i) downregulate human anti‐pig cellular responses in vitro, and (ii) inhibit rat anti‐pig cellular immune responses in vivo. Pig cells overexpressing PD‐L1 triggered reduced proliferation and low amounts of IL‐2, IFNγ, TNF‐alpha, IL‐4, and IL‐5 in human CD4+ T cells compared to control pig cells. The concentration of IL‐10, however, was increased. In long‐term cultures of human CD4+ T cells and PD‐L1 transfectants a high frequency of CD4+ CD25high FoxP3+ cells showed up which had the capacity to suppress the activation of conventional CD4+ T cells. Cytotoxic CD8+ T cells and NK cells lysed pig control cells very efficiently. In contrast, PD‐L1 transfected pig cells were partially protected from lysis by human effector cells. Overexpression of PD‐L1 on porcine cells was not sufficient to prevent rejection after transplantation under the rat kidney capsule. However, in rats that had been grafted with PD‐L1 expressing cells we observed reduced cellular infiltrates in the kidneys and lower antibody responses compared to rats grafted with control cells. Together these observations support the assumption that PD‐1/PD‐Ligand pathways are interesting targets to prevent cellular immune responses after xenotransplantation. PD‐L overexpression might not only impede the initiation of an anti‐pig T cell response by suppressing CD4+ T cells but may also protect pig cells from destruction by cytotoxic effectors. Supported by the Deutsche Forschungsgemeinschaft (Transregio Forschergruppe “Xenotransplantation”, FOR 535).  相似文献   

20.
Reduced HLA‐DR expression on monocytes has been suggested as a predictive marker of immunosuppression following very high risk surgery, but there are few reports in lower risk surgery. In 32 patients undergoing low to intermediate risk surgery, blood samples were analysed by flow cytometry for HLA‐DR expression and numbers in both CD14high and CD14lowCD16+ monocyte subsets. The numbers of CD14high monocytes increased at 24 h (mean (SD), 5.0 (2.2) vs 7.6 (3.9) × 105 cells.ml?1; p < 0.01) while CD14lowCD16+ monocytes decreased (0.68 (0.36) vs 0.44 (0.36) × 105 cells.ml?1; p < 0.01). HLA‐DR expression was significantly reduced in both subsets by 24 h (mean (SD) fluorescent intensity 440 (310) vs 160 (130) for CD14high and 1000 (410) vs 560 (380) for CD14lowCD16+ subsets; p < 0.01). This reduction of monocyte HLA‐DR expression 24 h following lower risk surgery raises questions about the purported clinical utility of this biomarker as an early predictor of postoperative complications. Our results also suggest that surgery induces significant trafficking (i.e. mobilisation, margination and extravasation) of monocyte subsets, and that monocyte HLA‐DR depression is the result of a down‐regulatory phenomenon (decreased protein expression on each cell) rather than the differential trafficking of monocyte subsets.  相似文献   

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