28 research outputs found
TH1/TH2 Cytokine profile in relapsing-remitting multiple sclerosis patients treated with Glatiramer acetate or Natalizumab
Background: The balance between T helper cells Th2- and Th1-related cytokines plays a key role in multiple
sclerosis (MS). A shift from a Th1 towards a Th2 cytokine profile could have a beneficial effect on the clinical course
of the disease. The objective of this study was to assess Th2/Th1 cytokine profile in relapsing-remitting MS (RRMS)
patients receiving an immunosuppressive treatment with natalizumab (NAT), or an immunomodulatory treatment
with glatiramer acetate (GA) after one year of treatment.
Methods: This was an observational cross-sectional study. All consecutive patients diagnosed with RRMS who had
received GA or NAT for 12 months were included in the study. We determined serum levels of Th1 and Th2
cytokines (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-13, monocyte chemotactic protein
[MCP]-1, tumor-necrosis factor [TNF]-α, interferon [IFN]-γ and granulocyte macrophage colony stimulating factor
[GM-CSF]) by flow cytometry. Th2/Th1 bias was defined based on the ratio of IL-4, IL-5, IL-6 or IL-10 Th2 cytokines
and proinflammatory INF-γ or TNF-α Th1 cytokines.
Results: Eleven patients under treatment with NAT and 12 patients treated with GA were evaluated. RRMS patients
treated with NAT showed significantly higher levels of IL-6 (p < 0.05), MCP-1 (p < 0.01), and GM-CSF (p < 0.05)
compared to GA patients after one year of treatment. A trend for increasing of IL-12p70, IL-1b, TNF- α and IFN- γ
levels was also found in patients receiving NAT compared to GA patients. IL-4/IFN-γ, IFN-γ/TNF-α and IL-10/IFN-γ
ratios as markers of Th2/Th1 ratio were significantly elevated in GA patients compared to those receiving NAT
(p < 0.05).
Conclusion: In conclusion, our findings suggest that GA promotes a superior Th2-biased anti-inflammatory
response as compared with NAT in the systemic circulation of RRMS patients. Future studies with larger cohorts will
determine whether this immune Th2 shift in GA patients is associated with a beneficial effect on disease outcom
TWEAK promotes peritoneal inflammation
Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing
peritonitis. An improved understanding of the molecular contributors to peritoneal injury and defense may increase the
therapeutic armamentarium to optimize peritoneal defenses while minimizing peritoneal injury. There is no information on
the expression and function of the cytokine TWEAK and its receptor Fn14 during peritoneal injury. Fn14 expression and
soluble TWEAK levels were measured in human PD peritoneal effluent cells or fluids with or without peritonitis. Fn14
expression was also analyzed in peritoneal biopsies from PD patients. Actions of intraperitoneal TWEAK were studied in
mice in vivo. sTWEAK levels were increased in peritoneal effluent in PD peritonitis. Effluent sTWEAK levels correlated with
the number of peritoneal macrophages (r = 0.491, p = 0.002). Potential TWEAK targets that express the receptor Fn14
include mesothelial cells and macrophages, as demonstrated by flow cytometry of peritoneal effluents and by analysis of
peritoneal biopsies. Peritoneal biopsy Fn14 correlated with mesothelial injury, fibrosis and inflammation, suggesting a
potential deleterious effect of TWEAK/Fn14. In this regard, intraperitoneal TWEAK administration to mice promoted
peritoneal inflammation characterized by increased peritoneal effluent MCP-1, Fn14 and Gr1+ macrophages, increased
mesothelial Fn14, MCP-1 and CCL21 expression and submesothelial tissue macrophage recruitment. Taken together these
data suggest that the TWEAK/Fn14 system may promote inflammation and tissue injury during peritonitis and PD.This work was supported by FIS PS09/00447, PI08/1564, PI10/00234, MS12/03262, FEDER funds ISCIII-RETIC REDinREN/RD06/0016, RD12/0021, Comunidad de Madrid (Fibroteam S2010/BMD-2321, S2010/BMD-2378). Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laı´n-Entralgo/CM) to AO,
Programa Estabilizacio´n Investigadores to LB-C, Miguel Servet to ABS, Sara Borrell to BS, MDSN. The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript
Treatment with Natalizumab in Relapsing–Remitting Multiple Sclerosis Patients Induces Changes in Inflammatory Mechanism
Natalizumab is a widely accepted drug for the relapsing–remitting subtype of multiple sclerosis (RRMS). The present longitudinal exploratory study in RRMS patients analyzes the effects of natalizumab treatment on the levels of pro-inflammatory and anti-inflammatory cytokine protein levels and also the frequency and suppressor function of regulatory T cells. Flow cytometry was used to determine cytokines and regulatory T cell frequency while regulatory T cell suppressor function was assayed in vitro at different time-points after starting with natalizumab. Results showed serum levels of pro-inflammatory interferon gamma and interleukin (IL)-12p70, as well as anti-inflammatory IL-4 and IL-10, were elevated just a few hours or days after first IV infusion of natalizumab. Interestingly, other cytokines like IL-5 or IL-13 were also elevated while pro-inflammatory IL-17, IL-2, and IL-1β increased only after a long-term treatment, suggesting different immune mechanisms. In contrast, we did not observe any effect of natalizumab treatment on regulatory T cell frequency or activity. In conclusion, these results suggest natalizumab has other immunological effects beyond VLA-4 interaction and inhibition of CNS extravasation, the relevance of which is as yet unknown and warrants further investigation
A natural anti-T-cell receptor monoclonal antibody protects against experimental autoimmune encephalomyelitis
AbstractThe therapeutic potential of natural anti-T-cell receptor (TCR) antibodies is largely unknown. We investigated whether passive administration of C1-19, a novel natural anti-TCRVβ8 monoclonal antibody, could interfere with the development of EAE. Treatment with C1-19 prevented myelin basic protein (MBP)-induced EAE in Vβ8-sufficient B10.PL but not in Vβ8-deficient SJL mice. Furthermore, C1-19 reduced disease severity when administrated shortly after disease onset. These protective effects of C1-19 correlated with a Th2 bias of the cytokine response, in the absence of T-cell deletion or anergy. Together, these findings indicate that natural anti-TCR antibodies could function as therapeutic tools in autoimmune inflammatory diseases
Anti-Vβ8 antibodies induce and maintain staphylococcal enterotoxin B-triggered Vβ8<sup>+</sup> T cell anergy
The mechanism involved in the maintenance of staphylococcal enterotoxin B (SEB)-induced T cell anergy is poorly understood. We demonstrated earlier that B cells play an important role in the maintenance of SEB-induced T cell anergy in vivo and in vitro. Here, we demonstrate that B cells are not essential in SEB-induced T cell activation, but are important for the maintenance of T cell memory phenotype and anergy in vivo. Studying the activated B cell repertoire, we observe that SEB treatment increases serum anti-Vβ8 antibody titer as detected by enzyme-linked immunosorbent assay using soluble Vβ8 chains as antigens, and by staining of a Vβ8-expressing thymoma. These antibodies disappear gradually after immunization with SEB, whereas the capacity of the T cells to respond to SEB in vitro is restored. Anti-Vβ8 monoclonal antibody treatment causes Vβ8+ T cell unresponsiveness to SEB in vitro (anergy), without affecting CD4Vβ8+ T cell frequency. Together, these results suggest a new mechanism to explain the maintenance of SEB-induced T cell anergy, which is depen dent on B cells and on anti-Vβ8 antibody that specifically interacts with Vβ8+ T cells.</p
Pharmacological modulation of peritoneal injury induced by dialysis fluids: Is it an option?
FIS (PS09/00447, PI09/00641, PI08/1564); ISCIII-RETIC REDinREN/RD06/0016; Fondecyt 1080083; Comunidad de Madrid/FRACM/S-BIO0283/2006; Ministerio de Ciencia e Innovación (SAF 2007/63648, SAF 2010-21249); CAM S-GEN-0247/2006Peer Reviewe
TGF-Beta Blockade Increases Renal Inflammation Caused by the C-Terminal Module of the CCN2
The CCN family member 2 (CCN2, also known as
connective tissue growth factor) may behave as a risk
biomarker and a potential therapeutic target for renal
disease. CCN2 participates in the regulation of
inflammation and fibrosis. TGF-β is considered
the main fibrogenic cytokine; however, in some
pathological settings TGF-β also has
anti-inflammatory properties. CCN2 has been proposed
as a downstream profibrotic mediator of TGF-β,
but data on TGF-β role in CCN2 actions are
scarce. Our aim was to evaluate the effect of
TGF-β blockade in CCN2-mediated experimental
renal damage. Systemic administration of the
C-terminal module of CCN2 to mice caused sustained
renal inflammation. In these mice, TGF-β
blockade, using an anti-TGF-β neutralizing
antibody, significantly increased renal expression of
the NGAL (a kidney injury biomarker), kidney
infiltration by monocytes/macrophages, and
upregulation of MCP-1 expression. The
anti-inflammatory effect of TGF-β seems to be
mediated by a dysregulation of the systemic Treg
immune response, shown by decreased levels of
circulating CD4+/Foxp3+Treg
cells. Our experimental data support the idea that
TGF-β exerts anti-inflammatory actions in the
kidney and suggest that it is not an optimal
therapeutic target
A Nanoconjugate Apaf-1 Inhibitor Protects Mesothelial Cells from Cytokine-Induced Injury
The definitive version is available at: htpp://dx.doi.org/10.1371/journal.pone.0006634BACKGROUND: Inflammation may lead to tissue injury. We have studied the modulation of inflammatory milieu-induced tissue injury, as exemplified by the mesothelium. Peritoneal dialysis is complicated by peritonitis episodes that cause loss of mesothelium. Proinflammatory cytokines are increased in the peritoneal cavity during peritonitis episodes. However there is scarce information on the modulation of cell death by combinations of cytokines and on the therapeutic targets to prevent desmesothelization. METHODOLOGY: Human mesothelial cells were cultured from effluents of stable peritoneal dialysis patients and from omentum of non-dialysis patients. Mesothelial cell death was studied in mice with S. aureus peritonitis and in mice injected with tumor necrosis factor alpha and interferon gamma. Tumor necrosis factor alpha and interferon gamma alone do not induce apoptosis in cultured mesothelial cells. By contrast, the cytokine combination increased the rate of apoptosis 2 to 3-fold over control. Cell death was associated with the activation of caspases and a pancaspase inhibitor prevented apoptosis. Specific caspase-8 and caspase-3 inhibitors were similarly effective. Co-incubation with both cytokines also impaired mesothelial wound healing in an in vitro model. However, inhibition of caspases did not improve wound healing and even impaired the long-term recovery from injury. By contrast, a polymeric nanoconjugate Apaf-1 inhibitor protected from apoptosis and allowed wound healing and long-term recovery. The Apaf-1 inhibitor also protected mesothelial cells from inflammation-induced injury in vivo in mice. CONCLUSION: Cooperation between tumor necrosis factor alpha and interferon gamma contributes to mesothelial injury and impairs the regenerative capacity of the monolayer. Caspase inhibition attenuates mesothelial cell apoptosis but does not facilitate regeneration. A drug targeting Apaf-1 allows protection from apoptosis as well as regeneration in the course of inflammation-induced tissue injury.Grant support: ISCIII (01/0199, 06/0046, ISCIII-RETIC REDinREN/RD06/0016, Comunidad de Madrid/FRACM/S-BIO0283/2006, Sociedad Espanola de Nefrologia, and Fresenius Medical Care, Programa Intensificacion Actividad Investigadora Sistema Nacional de Salud ISCIII/CM to AO, MEC (BIO2004-998 and BIO2007-60066) to EPP, MEC (CTQ2007-60601) and GVA (GV07/070) to MJV. BS and ACU were supported by Fundacion Conchita Rabago and AB by Fondo de Investigaciones Sanitarias (FIS).Peer reviewe