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1.  Efficient and Selective Prevention of GVHD by Antigen-Specific Induced Tregs via Linked-Suppression in Mice 
Naturally occurring regulatory T cells (nTregs) suppress the development of GVHD and may spare graft-versus-leukemia (GVL) effect. Because nTreg is a rare population in a healthy individual, the limited source and the non-selective suppression are major hurdles towards the application of nTregs in the control of clinical GVHD after allogeneic HCT. An alternative approach is to generate induced Tregs (iTregs) from naïve CD4 precursors, but the effectiveness of iTregs in the control of GVHD is highly controversial and requires further investigation. The other critical but unsolved issue on Treg therapy is how to achieve antigen (Ag)-specific tolerance that distinguishes GVHD and GVL effect. To address the important issues on the effectiveness of iTregs and Ag-specificity of Tregs, we generated Ag-specific iTregs and tested their potential in the prevention of GVHD in pre-clinical BMT model. CD4+CD25+Foxp3+ iTregs generated from OT-II TCR transgenic T cells specific for OVA target Ag efficiently prevented GVHD induced by polyclonal T effector cells (Teffs) only in the allogeneic recipients that express OVA protein but not in OVA− recipients. The efficacy of these Ag-specific iTregs was significantly higher than polyclonal iTregs. As controls, OT-II CD4+Foxp3− cells had no effect on GVHD development in OVA− recipients and exacerbated GVHD in OVA+ recipients when transplanted together with polyclonal Teffs. Because the iTregs recognize OVA whereas Teffs recognize alloAg bm12, our data reveal for the first time that Tregs prevent GVHD through a linked suppression. Mechanistically, OT-II iTregs expanded extensively, and significantly suppressed expansion and infiltration of Teffs in OVA+ but not in OVA− recipients. These results demonstrate that Ag-specific iTregs can prevent GVHD efficiently and selectively, providing a proof of principle that Ag-specific iTregs may represent a promising cell therapy for their specificity and higher efficacy in allogeneic HCT.
doi:10.1016/j.bbmt.2010.12.710
PMCID: PMC3039088  PMID: 21224010
2.  Phosphatidylinositol 3-Kinase–Independent Signaling Pathways Contribute to ICOS-Mediated T Cell Costimulation in Acute Graft-Versus-Host Disease in Mice 
We and others have previously shown that ICOS plays an important role in inducing acute graft-versus-host disease (GVHD) in murine models of allogeneic bone marrow transplantation. ICOS potentiates TCR-mediated PI3K activation and intracellular calcium mobilization. However, ICOS signal transduction pathways involved in GVHD remain unknown. In this study, we examined the contribution of ICOS-PI3K signaling in the pathogenic potential of T cells using a knock-in mouse strain, ICOS-YF, which selectively lost the ability to activate PI3K. We found that when total T cells were used as alloreactive T cells, ICOS-YF T cells caused less severe GVHD compared with ICOS wild-type T cells, but they induced much more aggressive disease than ICOS knockout T cells. This intermediate level of pathogenic capacity of ICOS-YF T cells was correlated with similar levels of IFN-g–producing CD8 T cells that developed in the recipients of ICOS-WT or ICOS-YF T cells. We further evaluated the role of ICOS-PI3K signaling in CD4 versus CD8 T cell compartment using GVHD models that are exclusively driven by CD4 or CD8 T cells. Remarkably, ICOS-YF CD8 T cells caused disease similar to ICOS wild-type CD8 T cells, whereas ICOS-YF CD4 T cells behaved very similarly to their ICOS knockout counterparts. Consistent with their in vivo pathogenic potential, CD8 T cells responded to ICOS ligation in vitro by PI3K-independent calcium flux, T cell activation, and proliferation. Thus, in acute GVHD in mice, CD4 T cells heavily rely on ICOS-PI3K signaling pathways; in contrast, CD8 T cells can use PI3K-independent ICOS signaling pathways, possibly through calcium.
doi:10.4049/jimmunol.1203485
PMCID: PMC4318500  PMID: 23729441
3.  PKCθ is required for alloreactivity and GVHD but not for immune responses toward leukemia and infection in mice 
The Journal of Clinical Investigation  2009;119(12):3774-3786.
When used as therapy for hematopoietic malignancies, allogeneic BM transplantation (BMT) relies on the graft-versus-leukemia (GVL) effect to eradicate residual tumor cells through immunologic mechanisms. However, graft-versus-host disease (GVHD), which is initiated by alloreactive donor T cells that recognize mismatched major and/or minor histocompatibility antigens and cause severe damage to hematopoietic and epithelial tissues, is a potentially lethal complication of allogeneic BMT. To enhance the therapeutic potential of BMT, we sought to find therapeutic targets that could inhibit GVHD while preserving GVL and immune responses to infectious agents. We show here that T cell responses triggered in mice by either Listeria monocytogenes or administration of antigen and adjuvant were relatively well preserved in the absence of PKC isoform θ (PKCθ), a key regulator of TCR signaling. In contrast, PKCθ was required for alloreactivity and GVHD induction. Furthermore, absence of PKCθ raised the threshold for T cell activation, which selectively affected alloresponses. Most importantly, PKCθ-deficient T cells retained the ability to respond to virus infection and to induce GVL effect after BMT. These findings suggest PKCθ is a potentially unique therapeutic target required for GVHD induction but not for GVL or protective responses to infectious agents.
doi:10.1172/JCI39692
PMCID: PMC2786796  PMID: 19907075
4.  C-Rel is an essential transcription factor for the development of acute graft-versus-host disease in mice 
European journal of immunology  2013;43(9):2327-2337.
Transcription factor of the Rel/NF-κB family are known to play different roles in immunity and inflammation, although the putative role of c-Rel in transplant tolerance and GVHD remains elusive. We report here that T cells deficient for c-Rel have a dramatically reduced ability to cause acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) using major and minor histocompatibility mismatched murine models. In the study to understand the underlying mechanisms, we found that c-Rel-/- T cells had reduced ability to expand in lymphoid organs and to infiltrate in GVHD target organs in allogeneic recipients. c-Rel-/- T cells were defective in the differentiation into Th1 cells after encountering alloantigens, but were enhanced in the differentiation towards Foxp3+ regulatory T cells (Tregs). Furthermore, c-Rel-/- T cells had largely preserved activity to mediate graft-versus leukemia (GVL) response. Taken together, our findings indicate that c-Rel plays an essential role in T cells in the induction of acute GVHD, and suggest that c-Rel can be a potential target for therapeutic intervention in allogeneic HCT in clinic.
doi:10.1002/eji.201243282
PMCID: PMC3940138  PMID: 23716202
c-Rel; BMT; GVHD
5.  Dynamic Change and Impact of Myeloid Derived Suppressor Cells in Allogeneic Bone Marrow Transplantation in Mice 
Myeloid-derived suppressor cells (MDSCs) are a group of myeloid cells comprised of hematopoietic progenitor cells, immature macrophages, dendritic cells and granulocytes, which accumulate in inflammatory diseases and various cancers. Here, we investigated the dynamic changes and effects of MDSCs in graft-versus-host disease (GVHD) development and/or tumor relapse after syngeneic and allogeneic bone marrow transplantation (BMT). We found that adding functional MDSCs in donor graft alleviated GVHD, whereas removal of MDSCs in vivo exacerbated GVHD. Following T cell-deplete BMT, MDSCs transiently accumulated in the blood and spleen of recipients without GVHD; In contrast, after T cell-replete BMT, the levels of blood MDSCs were constantly elevated in recipients with GVHD. MDSC accumulation positively correlated with the severity of GVHD. Additionally, MDSC accumulation was further increased upon tumor relapse. Although MDSCs isolated from both syngeneic and allogeneic BMT recipients inhibited T-cell proliferation in response to alloantigen stimulation ex vivo, MDSCs from the recipients with GVHD showed much higher suppressive potency compared to those from recipients without GVHD. These results indicate that MDSCs can regulate the immune response in acute GVHD, and possibly tumor relapse, subsequent to allogeneic BMT.
doi:10.1016/j.bbmt.2013.01.008
PMCID: PMC4011929  PMID: 23376089
6.  Adoptive transfer of Tc1 or Tc17 cells elicits anti-tumor immunity against established melanoma through distinct mechanisms1 
Adoptive cell transfer (ACT) of ex vivo activated autologous tumor-reactive T cells is currently one of the most promising approaches for cancer immunotherapy. Recent studies provided some evidence that Th17/Tc17 cells may exhibit potent anti-tumor activity, but the specific mechanisms have not been completely defined. In the present study, we used a murine melanoma lung-metastasis model and tested the therapeutic effects of gp100-specific polarized Tc1 or Tc17 cells combined with autologous BMT after total TBI. BMT combined with ACT of anti-tumor (gp100-specific) Tc17 cells significantly suppressed the growth of established melanoma, whereas Tc1 cells induced long-term tumor regression. After ACT, Tc1 cells maintained their phenotype to produce IFNγ but not IL-17. However, although Tc17 cells largely preserved their ability to produce IL-17, a subset secreted IFNγ or both IFNγ and IL-17, indicating the plasticity of Tc17 cells in vivo. Furthermore, after ACT the Tc17 cells had a long-lived effector T cell phenotype (CD127hi/KLRG-1low) as compared to Tc1 cells. Mechanistically, Tc1 cells mediated anti-tumor immunity primarily through the direct effect of IFNγ on tumor cells. In contrast, despite the fact that some Tc17 cells also secreted IFNγ, Tc17-mediated anti-tumor immunity was independent of the direct effects of IFNγ on the tumor. Nevertheless, IFNγ played a critical role by creating a microenvironment that promoted Tc17-mediated anti-tumor activity. Taken together, these studies demonstrate that both Tc1 and Tc17 cells can mediate effective anti-tumor immunity through distinct effector mechanisms, but Tc1 cells are superior to Tc17 cells in mediating tumor regression.
doi:10.4049/jimmunol.1201989
PMCID: PMC3563723  PMID: 23315072
7.  T helper17 Cells Are Sufficient But Not Necessary to Induce Acute Graft-Versus-Host Disease 
T helper (Th)1 cells were considered responsible for the induction of graft-versus-host disease (GVHD), but recently the concept has been challenged. Th17 cells play a critical role in mediating autoimmune diseases, but their role in the pathogenesis of GVHD remains unclear. Herein we compare the ability of in vitro generated Th1 and Th17 cells from C57BL/6 mice to induce GVHD in lethally irradiated BALB/c recipients. Allogeneic Th17 cells had superior expansion and infiltration capabilities in GVHD target organs, which correlated with their increased pathogenicity when compared with naïve or Th1 controls. Th17 cells caused no pathology in the syngeneic recipients, indicating that antigen-activation was required for their pathogenicity. Polarized Th17 cells could not maintain their phenotype in vivo as they produced a significant amount of interferon (IFN)-γ after being transplanted into allogeneic recipients; however, IFN-γ was not required for Th17 cell-induced GVHD. Further, we evaluated the pathogenesis of Th17 cells in GVHD by using polyclonal nonprimed CD4 T cells in a clinically relevant allogeneic bone marrow transplantation (BMT) setting. We found that disruption of Th17-differentiation alone by targeting RORγt (Th17-specific transcription factor) had no significant effect on GVHD development. We conclude that Th17 cells are sufficient but not necessary to induce GVHD.
doi:10.1016/j.bbmt.2009.09.023
PMCID: PMC3876952  PMID: 19804837
Th1; Th17; BMT; GVHD
8.  LBH589 enhances T-cell activation in vivo and accelerates graft-versus-host disease in mice 
Histone deacetylase inhibitors (HDACi) are a new class of compounds that induce acetylation of histone lysine tails in chromatin and modify gene expression. The FDA approved HDACi, Vorinostat or suberoylanilide hydroxamic acid (SAHA), has been shown to inhibit tumor cell growth and the production of pro-inflammatory cytokines. In preclinical allogeneic transplantation models, SAHA induces graft-versus-host disease (GVHD) amelioration in treated mice without impairing graft-versus-leukemia (GVL). LBH589 (Panobinostat), a structurally novel cinnamic hydroxamic acid class, is an HDACi more potent than SAHA. In the current work, we tested the hypothesis that LBH589 would be highly effective in the prevention of GVHD. Using mouse model of allogeneic bone marrow transplantation (BMT), we unexpectedly found that treatment with LBH589 accelerated GVHD, in contrast to the treatment with SAHA that alleviated GVHD. Accelerated GVHD in the recipients treated with LBH589 was associated with elevated Th1 cytokines in recipient serum, enhanced CXCR3 expression on donor T cells, and T-cell infiltration in the liver. The current study highlights the distinct effects of pan HDACi on allogeneic BMT, and alerts that LBH589 (Panobinostat) could have adverse effect on GVHD, and possibly on other inflammatory diseases.
doi:10.1016/j.bbmt.2012.06.002
PMCID: PMC3417119  PMID: 22698484
9.  Role of CD28, CTLA4 and ICOS costimulation in Acute Graft-versus-Host Disease in Mice 
T cells deficient for CD28 have reduced ability to expand and survive, but still cause graft-versus-host disease (GVHD). Inducible costimulator (ICOS), the third member of the CD28 family, is expressed on antigen-activated T cells and has unique roles in T-cell activation and effector function. We hypothesized that ICOS contributes to the development of GVHD in the absence of B7:CD28/CTLA4 costimulation. In this study, we evaluated the roles of CD28, CTLA4 and ICOS in the pathogenesis of acute GVHD under myeloablative allogeneic bone marrow transplantation (BMT). Unexpectedly, we found that blocking CD28 and CTLA4 signals using the clinically relevant reagent, CTLA4-Ig, results in the enhancement of GVHD severity mediated by CD4+ T cells, and such treatment does not add any benefit to blockade of ICOS. In contrast, selectively blocking CD28 and ICOS but not CTLA4 prevents GVHD more effectively than blocking either CD28 or ICOS alone. Taken together, these results indicate that CD28 and ICOS are synergistic in promoting GVHD, whereas the CTLA4-signal is required for T-cell tolerance regardless of ICOS signaling. Thus, blocking CD28 and ICOS while sparing CTLA4 represents a promising approach for abrogating pathogenic T-cell responses after allogeneic BMT.
doi:10.1016/j.bbmt.2011.01.018
PMCID: PMC3131782  PMID: 21447398
10.  Bim is required for T-cell allogeneic responses and graft-versus-host disease in vivo  
Bim, a BH3-only Bcl-2-family protein, is essential for T-cell negative selection in the thymus as well as for the death of activated T cells in the periphery. The role of Bim has been extensively studied in T-cell responses to self-antigens and viral infections. Recent findings on Bim in autoimmunity triggered our interest in investigating whether Bim may play a role in another disease with inflammatory symptoms as graft-versus-host disease (GVHD). Here we report that Bim is required for optimal T-cell responses to alloantigens in vivo and for the development of GVHD. Using murine models of allogeneic bone marrow transplantation (BMT), we found that donor T cells deficient for Bim are impaired in the induction of GVHD primarily due to a significant defect in T cell activation and expansion in vivo. Upon TCR engagement, Bim-/- T cells exhibited selective defects in CD69 expression and phosphorylation of PLCγ1. Our studies uncover a novel aspect of Bim function in T-cell activation with important implications in understanding the mechanisms of T-cell activation and tolerance under allogeneic transplantation.
PMCID: PMC3301434  PMID: 22432091
Bim; T cells; proliferation; apoptosis; alloantigen; GVHD; GVL; and BMT
11.  CD28 Controls Differentiation of Regulatory T Cells from Naive CD4 T Cells1 
CD28 is required for the development of regulatory T cells (Tregs; CD4+CD25+Foxp3+) in the thymus and also contributes to their survival and homeostasis in the periphery. We studied whether and how CD28 and ICOS control the differentiation of Tregs from naive T cells. By using wild-type, CD28-, ICOS-, or CD28/ICOS-double knockout mice on C57BL/6 background as T cell sources, we found that CD28 is essential, whereas ICOS is dispensable, for the development and homeostasis of Tregs. Furthermore, the differentiation of Tregs from naive CD4+CD25− T cells in vivo also depends on CD28. The requirement of CD28 for Treg differentiation was mediated by IL-2, because neutralization of IL-2 with its specific mAb-blocked Treg differentiation from wild-type CD4+CD25− T cells and addition of IL-2 restored Treg differentiation from CD28−/− T cells. Other common γ-chain cytokines, IL-4, IL-7, or IL-15, do not share such a role with IL-2. Although CD28 is required for the differentiation of Tregs from naive T cells, already generated Tregs do not depend on CD28 to exert their suppressive function. Our study reveals a new aspect of CD28 function in regulating T cell response.
PMCID: PMC2688779  PMID: 18684917
12.  CD28 ligation induces transplantation tolerance by IFN-γ–dependent depletion of T cells that recognize alloantigens 
Journal of Clinical Investigation  2004;113(11):1624-1630.
Administration of an agonistic anti-CD28 mAb paradoxically inhibits donor T cell expansion and prevents graft-versus-host disease (GVHD) in mice. Here we examined the mechanism of anti-CD28–mediated immunosuppression and found that anti-CD28 mAb activated, rather than blocked, CD28-mediated signaling in vivo. Anti-CD28 treatment prevented GVHD by selectively depleting alloantigen-activated donor T cells through apoptosis but spared the T cells that did not recognize recipient alloantigens. Overexpression of Bcl-xL did not protect T cells from depletion and did not affect GVHD prevention after anti-CD28 treatment. Depletion of activated T cells mediated through CD28 did not depend on the expression of death receptors Fas and TNF receptors type I and II, but both the depletion of activated T cells and the suppressive effect of anti-CD28 mAb on GVHD lethality required donor-derived IFN-γ production. This study demonstrates that agonistic Ab’s specific for the CD28 costimulatory molecule may be used as novel therapeutic agents to abrogate pathogenic T cell responses by selective depletion of activated T cells.
doi:10.1172/JCI200420940
PMCID: PMC419490  PMID: 15173889
13.  Modified shock index and mortality rate of emergency patients 
BACKGROUND:
This study aimed to determine whether modified shock index (MSI) is associated with mortality that is superior to heart rate, blood pressure, or the shock index (SI) in emergency patients.
METHODS:
A retrospective database review was performed on 22 161 patients who presented to Peking Union Medical College Hospital Emergency Department and received intravenous fluids from January 1 to December 31, 2009. We gathered data of the patients on age, gender, vital signs, levels of consciousness, presenting complaints, and SI and MSI were calculated for all patients.
RESULTS:
Multivariate regression analysis was performed to determine the correlation between risk factors and outcome. There is a significant correlation between emergency patient mortality rate and patient’s vital signs obtained at the triage desk (HR>120 beats/min, systolic BP<90 mmHg, diastolic BP<60 mmHg). MSI is a stronger predictor of emergency patient mortality compared to heart rate and blood pressure alone, whereas SI does not have a significant correlation with emergency patient mortality rate.
CONCLUSION:
MSI is a clinically significant predictor of mortality in emergency patients. It may be better than using heart rate and blood pressure alone. SI is not significantly correlated with the mortality rate of the emergency patient.
doi:10.5847/wjem.j.issn.1920-8642.2012.02.006
PMCID: PMC4129788  PMID: 25215048
Emergency department; Modified shock index; Mortality rate; Predictor; Multivariate regression analysis
14.  Evaluation and treatment of altered mental status patients in the emergency department: Life in the fast lane 
BACKGROUND:
Altered mental status (AMS) is a very common emergency case, but the exact etiology of many AMS patients is unknown. Patients often manifest vague symptoms, thus, AMS diagnosis and treatment are highly challenging for emergency physicians. The aim of this study is to provide a framework for the assessment of AMS patients. This assessment should allow providers to better understand the etiology of mental status changes and therefore improve diagnostic skills and management.
METHODS:
This is a prospective cohort observational study. We recruited all adult patients with undifferentiated AMS at a single center tertiary care academic emergency department over 24 months (June 2009 to June 2011). Demographic characteristics, clinical manifestations, assessment approaches, causative factors, emergency treatments and outcomes were collected prospectively.
RESULTS:
In 1934 patients with AMS recruited, accounting for 0.93% of all emergency department (ED) patients, 1 026 (53.1%) were male, and 908 (46.9%) female. Their average age was 51.95±15.71 years. Etiologic factors were neurological (n=641; 35.0%), pharmacological and toxicological (n=421; 23.0%), systemic and organic (n=266; 14.5%), infectious (n=167; 9.1%), endocrine/metabolic (n=145; 7.9%), psychiatric (n=71; 3.9%), traumatic (n=38; 2.1%), and gynecologic and obstetric (n=35; 1.9%). Total mortality rate was 8.1% (n=156). The death rate was higher in elderly patients (≥60) than in younger patients (10.8% vs. 6.9%, P=0.003).
CONCLUSIONS:
Patients with AMS pose a challenge for ED physicians. The most frequently encountered diagnostic categories causing AMS were primary CNS disorders, intoxication, organ system dysfunction, and endocrine/metabolic diseases. AMS has a high fatality rate in the ED. AMS is an important warning signal for ED patients because of its potentially fatal and reversible effects. Prompt evaluation and treatment are essential to decreasing morbidity and mortality associated with AMS.
doi:10.5847/wjem.j.issn.1920-8642.2012.04.006
PMCID: PMC4129809  PMID: 25215076
Altered mental status; Emergency department; Demographic characteristics; Clinical feature; Assessment; Etiology; Mortality; Algorithm
15.  Targeting PKCθ in alloreactivity and graft-versus-host-disease: unanswered questions and therapeutic potential 
Protein kinase C isoform θ (PKCθ) is a key modulator of TCR signaling and mediates activation of NF-κB, NF-AT, and AP-1 transcription factors. Although in vitro studies of PKCθ-/- T cells have shown impaired activation responses, in vivo studies indicate that PKCθ requirement is not universal. While PKCθ is important in induction of experimentally induced autoimmune diseases in mice and generation of Th2 responses, it is not essential for induction of T cell proliferative and cytotoxic responses against influenza virus, LCMV, and vaccinia virus. The context-specific involvement of PKCθ in T cell responses suggests that inhibition of PKCθ may be beneficial in some but not all situations. In the bone marrow transplantation (BMT) setting, we have shown that graft-versus-host-disease (GVHD) cannot be induced in the absence of PKCθ. However, graft-versus-leukemia effects and T cell ability to clear virus infection remains intact. Therefore, PKCθ is a potential therapeutic target in BMT, inhibition of which may prevent GVHD while retaining anti-tumor and anti-infection responses.
doi:10.3389/fimmu.2012.00259
PMCID: PMC3418525  PMID: 22912640
alloreactivity; graft-versus-host-disease; protein kinase C; T cell activation; anti-tumor effect
16.  Ethylenecarbodiimide-coupled allogeneic antigen presenting cells induce human CD4+ regulatory T cells 
Clinical immunology (Orlando, Fla.)  2008;129(3):381-393.
Adoptive transfer of naturally occurring CD4+CD25+ regulatory T cells can tolerize transplantation alloresponses in animal models. However isolation of these cells in sufficient numbers from humans is cumbersome and prone to contamination with alloreactive CD25+ T-cells. Incubation of ethylenecarbodiimide-coupled antigen presenting cells (APC) with naïve T-cells and antigen has been shown to induce tolerance in various experimental models. We therefore investigated whether ECDI-coupled allogeneic APC were able to induce an expandable human CD4+ Treg population.
CD4+ and CD4+CD25− cells cultured for five days with ECDI-treated human PBMC exhibited potent suppressive capacity in a mixed lymphocyte reaction. Induction of these ECDI-Tregs was associated with up-regulation of Foxp3 mRNA and protein expression and they maintained high expression of CD62L and CD27 as well as low CD127 expression. ECDI-treated APC displayed reduced expression of the co-stimulatory signaling molecules CD40 and CD80, and failed to stimulate proliferation and cytokine secretion in co-cultured CD4+ T cells. Restimulation in the presence of rapamycin and hrIL-2 led to expansion of ECDI-Tregs with increasing Foxp3 levels and suppressive activity significantly higher than expanded naturally occurring CD4+CD25+ Tregs.
In summary these findings support the hypothesis that ECDI-coupled APC can convert naïve CD4+ T cells into functional Tregs with different phenotypic characteristics than naturally occurring CD4+CD25+ Tregs. These inducible Tregs could provide a novel approach that might facilitate the translation of ex vivo generated and expanded Tregs into clinical settings.
doi:10.1016/j.clim.2008.07.027
PMCID: PMC3033601  PMID: 18819845
ECDI; Treg; Rapamycin; GVHD
17.  Plasmin Plays an Essential Role in Amplification of Psoriasiform Skin Inflammation in Mice 
PLoS ONE  2011;6(2):e16483.
Background
Although increased levels of plasminogen activators have been found in psoriatic lesions, the role of plasmin converted from plasminogen by plasminogen activators in pathogenesis of psoriasis has not been investigated.
Methodology/Principal Findings
Here we examined the contribution of plasmin to amplification of inflammation in patients with psoriasis. We found that plasminogen was diminished, but that the amount and activity of its converted product plasmin were markedly increased in psoriasis. Moreover, annexin II, a receptor for plasmin was dramatically increased in both dermis and epidermis in psoriasis. Plasmin at sites of inflammation was pro-inflammatory, eliciting production of inflammatory factors, including CC chemokine ligand 20 (CCL20) and interleukin-23 (IL-23), that was mediated by the nuclear factor-kappaB (NF-κB) signaling pathway and that had an essential role in the recruitment and activation of pathogenic C-C chemokine receptor type 6 (CCR6)+ T cells. Moreover, intradermal injection of plasmin or plasmin together with recombinant monocyte/macrophage chemotactic protein-1 (MCP-1) resulted in induction of psoriasiform skin inflammation around the injection sites with several aspects of human psoriasis in mice.
Conclusions/Significance
Plasmin converted from plasminogen by plasminogen activators plays an essential role in amplification of psoriasiform skin inflammation in mice, and targeting plasmin receptor - annexin II - may harbor therapeutic potential for the treatment of human psoriasis.
doi:10.1371/journal.pone.0016483
PMCID: PMC3032787  PMID: 21311769
18.  Role of corticotrophin releasing hormone in cerebral infarction-related gastrointestinal barrier dysfunction 
BACKGROUND:
Corticotrophin releasing hormone (CRH) is believed to mediate stress-induced behaviors, implying a broader, integrative role for the hormone in the psychological stress response, and studies on CRH in physical stress are few. This study was undertaken to investigate whether CRH plays an important role in cerebral infarction-related gastrointestinal barrier dysfunction.
METHODS:
Thirty male Wistar rats were randomly divided into a pseudo-operation group (group C, n=10), a cerebral infarction group (group I, n=10), and a cerebral infarction + ic α-helical-CRH (9-41) group (group Aic, n=10). Urine samples were collected to determine the levels of epinephrine, norepinephrine, cortisol, and sucrose. At 24 hours after establishment of the models, blood samples were taken to determine the activity of diamine oxidase (DAO) and the concentration of D-lactic acid (D-lac). The stomach was taken to determine gastric Guth score, and the hypothalamus was also taken to determine tissue CRH protein expression using Western blotting.
RESULTS:
The hypothalamus CRH protein, the indicators of stress, the plasma DAO activity and plasma D-lac, urine sucrose exertion and gastric Guth score in group I were higher than those in groups Aic and C.
CONCLUSIONS:
After cerebral infarction, CRH in the hypothalamus was increased, the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system were activated, gastrointestinal permeability was increased, and gastrointestinal barrier function was destroyed. CRH receptor antagonist alleviated the gastrointestinal barrier function.
PMCID: PMC4129739  PMID: 25214985
Corticotrophin releasing hormone; Cerebral infarction; Gastrointestinal barrier; Stress
19.  TGF-β–dependent suppressive function of Tregs requires wild-type levels of CD18 in a mouse model of psoriasis 
The Journal of Clinical Investigation  2008;118(7):2629-2639.
Dysfunctional Tregs have been identified in individuals with psoriasis. However, their role in the pathogenesis of the disease remains unclear. Here we explored the effect of diminished CD18 (β2 integrin) expression on the function of CD4+CD25+CD127– Tregs using the Cd18 hypomorphic (Cd18hypo) PL/J mouse model of psoriasis that closely resembles the human disease. We found that reduced CD18 expression impaired cell-cell contact between Tregs and DCs. This led to dysfunctional Tregs, which both failed to suppress the pathogenic T cells and promoted the onset and severity of the disease. This failure was TGF-β–dependent, as Tregs derived from Cd18hypo PL/J mice had diminished TGF-β1 expression. Adoptive transfer of Tregs expressing wild-type levels of CD18 into affected Cd18hypo PL/J mice resulted in a substantial improvement of the psoriasiform skin disease, which did not occur upon coinjection of the cells with TGF-β–specific neutralizing antibody. Our data indicate a primary dysfunction of Cd18hypo Tregs, allowing subsequent hyperproliferation of pathogenic T cells in the Cd18hypo PL/J mouse model of psoriasis. This study may provide a step forward in our understanding of the unique role of CD18 expression levels in avoiding autoimmunity.
doi:10.1172/JCI34916
PMCID: PMC2398739  PMID: 18521187

Results 1-19 (19)