Spleen Of Collagen-induced Arthritis Mice Research Articles

Oxymatrine ameliorates rheumatoid arthritis by regulation of Tfr/Tfh cell balance via the TLR9-MyD88-STAT3 signaling pathway.

Oxymatrine (OMT) is one of the authentic Chinese herbal medicines which has rich and complex active ingredients. however,the relevant potential targets of oxymatrine on rheumatoid arthritis and the mechanism remains unreported. The aim of this study was to determine the regulation of oxymatrine on rheumatoid arthritis using a collagen-induced arthritis (CIA) mice models and blood samples from RA patients. Our results indicated that Tfr cells in RA patients express low levels of Blimp-1 and CTLA-4. Oxymatrine treatment of CIA mice alleviated joint swelling, reduced the arthritis score, and improved joint damage. While flow cytometry results showed that oxymatrine treatment reduced Tfh cells and B cells, and increased Tfr cells in the spleen of CIA mice. In addition, oxymatrine treatment significantly down-regulated the expression of TLR9（Toll-like Receptors 9), IL-21, MyD88, STAT3, p-STAT3, and CXCR5 in the synovial tissues of CIA mice, and up-regulated the expression of Foxp3, Blimp-1, and CTLA-4. Oxymatrine can alleviate rheumatoid arthritis by regulating the TLR9-MyD88-STAT3 signaling pathway to maintain immune balance between Tfr-Tfh cells. © 2023 Society of Chemical Industry.

Activation of formyl peptide receptor 1 elicits therapeutic effects against collagen-induced arthritis.

Rheumatoid arthritis (RA) is an autoimmune disorder which shows production of autoantibodies, inflammation, bone erosion, swelling and pain in joints. In this study, we examined the effects of an immune‐modulating peptide, WKYMVm, that is an agonist for formyl peptide receptors (FPRs). Administration of WKYMVm into collagen‐induced arthritis (CIA) mice, an animal model for RA, attenuated paw thickness, clinical scores, production of type II collagen‐specific antibodies and inflammatory cytokines. WKYMVm treatment also decreased the numbers of TH1 and TH17 cells in the spleens of CIA mice. WKYMVm attenuated TH1 and TH17 differentiation in a dendritic cell (DC)‐dependent manner. WKYMVm‐induced beneficial effects against CIA and WKYMVm‐attenuated TH1 and TH17 differentiation were reversed by cyclosporin H but not by WRW4, indicating a crucial role of FPR1. We also found that WKYMVm augmented IL‐10 production from lipopolysaccharide‐stimulated DCs and WKYMVm failed to suppress TH1 and TH17 differentiation in the presence of anti‐IL‐10 antibody. The therapeutic administration of WKYMVm also elicited beneficial outcome against CIA. Collectively, we demonstrate that WKYMVm stimulation of FPR1 in DCs suppresses the generation of TH1 and TH17 cells via IL‐10 production, providing novel insight into the function of FPR1 in regulating CIA pathogenesis.

Soufeng sanjie formula alleviates collagen-induced arthritis in mice by inhibiting Th17 cell differentiation

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch), scorpion (dried body of Buthus martensii Karsch), astragali radix (dried root of Astragalus membranaceus (Fisch.) Bge), and black soybean seed coats (seed coats of Glycine max (L.) Merr), is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remains unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice.MethodsFor in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/day) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 days, degree of ankle joint destruction and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Moreover, the expression levels of retinoic acid receptor-related orphan nuclear receptor (ROR) γt and phosphorylated STAT3 (pSTAT3, Tyr705) in the spleen were detected by immunohistochemistry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in CD4+ T cells under Th17 polarization conditions.ResultsSF decreased the arthritis score, ameliorated paw swelling, and reduced cartilage loss in the joint of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG in sera of CIA mice. SF decreased the levels of inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 both in the sera and the joint of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. SF also reduced the expression levels of ROR γt and pSTAT3 (Tyr705) in the spleen of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, IL-17A, and pSTAT3 (Tyr705) under Th17 polarization conditions.ConclusionsOur results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.

Immune Function and Mechanism of Costimulating Molecules PD-1 and OX40 in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a T lymphocyte-mediated autoimmune disease, although its immune mechanism has not been fully studied. In this study, healthy controls (HC), osteoarthritis patients (OA), and RA patients were enrolled, and mice were evenly divided into control, collagen-induced arthritis (CIA), PD-1 Fc/CIA (PD-1 Fc membrane fusion protein administered to CIA mice), OX40 Fc/CIA (OX40 Fc membrane fusion protein administered to CIA mice), and PD-1 Fc + OX40 Fc/CIA groups. The expressions of programmed death-1 (PD-1) and OX40 in CD4+ T lymphocytes and the levels of sPD-1, immunoglobulin, and proinflammatory factors in patients and mice were measured. The results showed that the expression levels of PD-1 and OX40 in CD4+ T lymphocytes separated from the peripheral blood and synovial fluid of RA patients and the spleen of CIA mice were observably elevated. The levels of soluble PD-1, interleukin (IL)-2, IL-4, IL-5, IL-17, and interferon-γ (IFN-γ) in RA patients obviously increased. In animal experiments, PD-1 Fc not only increased the serum levels of immunoglobulin G (IgG), IgG1, and IgG2a in CIA mice, but also increased the levels of IL-4, IL-2, IL-5, IL-17, and IFN-γ in mouse spleen cells and joint tissues, which, however, were reversed by OX40 Fc. In conclusion, OX40 inhibition could reverse the progression of RA caused by PD-1 blocking, and PD-1 might be a potential target for RA. Clinical Trials.gov ID: HGH2018012203.

α-Difluoromethylornithine suppresses inflammatory arthritis by impairing myeloid-derived suppressor cells

ObjectivesThe chemopreventive drug α-difluoromethylornithine (DFMO) has been shown to have an antinociceptive effect on mechanical allodynia in inflammatory arthritis by directly inhibiting ornithine decarboxylase (ODC) and decreasing polyamine production in inflammatory sites. However, little is known about the effect of DFMO on the immune system of inflammatory arthritis. Here, we investigated the effect of DFMO in a well-established collagen-induced arthritis (CIA) mouse model and explored its effect on the immune system. MethodsThe effect of DFMO on the frequency of myeloid-derived suppressor cells (MDSCs) in the spleens of CIA mice and their associations with disease severity, tissue inflammation and the levels of proinflammatory T-helper (Th) 17 cells in lymphoid tissues were investigated. The effects of DFMO on disease severity and Th17 cells were compared with those of antibody depletion of MDSCs. The arthritis severity was also evaluated by adoptive transfer of MDSCs derived from DFMO- or dH2O-treated mice. ResultsIn this study, we showed that both MDSCs and Th17 cells were significantly expanded in CIA mice. Treatment by DFMO at the onset of CIA suppressed the development of arthritis and decreased the frequency of MDSCs and Th17 cells. MDSC depletion by anti-Gr-1 mAb achieved a similar result, while combination treatment of both methods did not achieve a significant difference compared to either of the single treatments. In addition, the adoptive transfer of MDSCs derived from dH2O-treated mice with CIA restored the arthritis severity of CIA in mice treated with anti-Gr-1 mAb, while the transfer of MDSCs from DFMO-treated mice did not have such an effect. ConclusionsOur results identified DFMO as a potential therapeutic drug for the treatment of inflammatory arthritis.

The effect of the cholinergic anti-inflammatory pathway on collagen-induced arthritis involves the modulation of dendritic cell differentiation

BackgroundThe cholinergic anti-inflammatory pathway (CAP) has a strong anti-inflammatory effect on collagen-induced arthritis (CIA), a classic animal model of rheumatoid arthritis (RA). However, the underlying immune regulatory mechanism remains unclear. Here, we investigated the effect of the CAP on arthritis development and the involvement of dendritic cells (DCs).MethodsForty DBA/1 mice were randomly divided into five groups: a control group (sham vagotomy+ phosphate-buffered saline; shamVGX+PBS), a CIA group (shamVGX+CIA + PBS), a vagotomy group (VGX + CIA + PBS), a GTS-21 (4 mg/kg) group (shamVGX+CIA + GTS-4), and a GTS-21 (8 mg/kg) group (shamVGX+CIA + GTS-8). The vagotomy group underwent left cervical vagotomy 4 days before arthritis induction, whereas the sham-vagotomy group underwent vagus nerve exposure. Mice were pretreated with GTS-21 by intraperitoneal injection on the day of surgery. The degree of arthritis was measured by using the arthritis score, hematoxylin and eosin staining, and TRAP (tartrate-resistant acid phosphatase) staining. Flow cytometry was used to detect the expression of CD80 and major histocompatibility complex II (MHC II) on CD11c+ DCs in the spleen. Luminex was used to detect the serum concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and IL-10. Immunohistochemistry was used to detect CD11c expression in the synovium. The effects of GTS-21 on DC differentiation and maturation were examined in vitro by treating bone marrow–derived DCs with GTS-21 and assessing differentiation and maturation. Flow cytometry was used to analyze CD80 and MHC II expression on the surface of DCs.ResultsGTS-21 treatment ameliorated clinical arthritis in a mouse model of CIA in vivo, decreasing the secretion of pro-inflammatory cytokines in the serum and downregulating CD80 and MHC II expression on DCs in the spleen of CIA mice. GTS-21 treatment strongly suppressed the infiltration of DCs into the synovium. Vagotomy itself did not exacerbate the severity of arthritis in CIA mice. In vitro, GTS-21 (10 μmol/L) significantly downregulated CD80 and MHC II in bone marrow–derived immature DCs and this effect was blocked by the α7-nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA). However, GTS-21 had no effects on mature DCs.ConclusionsThe present study provides new insight into the mechanism underlying the effects of the CAP on RA and indicates that the immunosuppressive effect of GTS-21 may be mediated by the inhibition of DC differentiation.

Anthocyanin Extracted from Black Soybean Seed Coats Prevents Autoimmune Arthritis by Suppressing the Development of Th17 Cells and Synthesis of Proinflammatory Cytokines by Such Cells, via Inhibition of NF-κB.

IntroductionOxidative stress plays a role in the pathogenesis of rheumatoid arthritis (RA). Anthocyanin is a plant antioxidant. We investigated the therapeutic effects of anthocyanin extracted from black soybean seed coats (AEBS) in a murine model of collagen-induced arthritis (CIA) and human peripheral blood mononuclear cells (PBMCs) and explored possible mechanisms by which AEBS might exert anti-arthritic effects.Material and MethodsCIA was induced in DBA/1J mice. Cytokine levels were measured via enzyme-linked immunosorbent assays. Joints were assessed in terms of arthritis incidence, clinical arthritis scores, and histological features. The extent of oxidative stress in affected joints was determined by measuring the levels of nitrotyrosine and inducible nitric oxide synthase. NF-κB activity was assayed by measuring the ratio of phosphorylated IκB to total IκB via Western blotting. Th17 cells were stained with antibodies against CD4, IL-17, and STAT3. Osteoclast formation was assessed via TRAP staining and measurement of osteoclast-specific mRNA levels.ResultsIn the CIA model, AEBS decreased the incidence of arthritis, histological inflammation, cartilage scores, and oxidative stress. AEBS reduced the levels of proinflammatory cytokines in affected joints of CIA mice and suppressed NF-κB signaling. AEBS decreased Th17 cell numbers in spleen of CIA mice. Additionally, AEBS repressed differentiation of Th17 cells and expression of Th17-associated genes in vitro, in both splenocytes of naïve DBA/1J mice and human PBMCs. In vitro, the numbers of both human and mouse tartrate-resistant acid phosphatase+ (TRAP) multinucleated cells fell, in a dose-dependent manner, upon addition of AEBS.ConclusionsThe anti-arthritic effects of AEBS were associated with decreases in Th17 cell numbers, and the levels of proinflammatory cytokines synthesized by such cells, mediated via suppression of NF-κB signaling. Additionally, AEBS suppressed osteoclastogenesis and reduced oxidative stress levels.

Myeloid-Derived Suppressor Cells Protect Mouse Models from Autoimmune Arthritis via Controlling Inflammatory Response

Myeloid-derived suppressor cells (MDSCs) have been reported to participate in immune suppression and autoimmune disorders. However, its role in autoimmune arthritis remains to be determined. We explored whether adoptive transfer of MDSCs in vivo would block joint inflammation and histological damage using collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) models. CD11b(+) Gr-1(+) MDSCs were isolated from the single cells from the spleens of CIA mice on day 41 or AIA mice on day 35. MDSCs (2 × 10(6)) were then transferred to AIA and CIA mice via tail vein before arthritis establishment at indicated time points. Phosphate buffered saline (PBS) was injected as control. Arthritis was evaluated by severity score and histology. The levels of TNF-α, IL-6, IL-17 and IL-10 in the serum and joints were detected by enzyme-linked immunosorbent assay (ELISA). The number of Th17 cells and macrophages in draining lymph nodes and joint tissues was assessed by flow cytometric analysis. Adoptive transfer of MDSCs significantly reduced the clinical score of arthritis, alleviated joint inflammation and histological damage both in AIA and CIA models compared with PBS-treated control groups. The levels of TNF-α, IL-6, IL-17, and IL-10 in the serum and joints were down-regulated by transfer of MDSCs. In addition, adoptive transfer of MDSCs significantly reduced the number of Th17 cells and macrophages in draining lymph nodes and joint tissues. Altogether, we demonstrate that adoptive transfer of MDSCs prevented autoimmune arthritis in mouse models of RA through inhibiting Th17 cells and macrophages. These new findings provide insights into the inhibitory functions of MDSCs and MDSCs may be used as a cell-based biotherapy in RA.

THU0112 Myeloid-Derived Suppressor Cells have Regulatory Roles in Mouse Collagen-Induced Arthritis

BackgroundMyeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. MDSCs are characterized by the co-expression of the myeloid differentiation antigens Gr-1 and CD11b...

Accumulation of CD4+CD28-PD-1lowOX40+ T cells and its clinical significance in rheumatoid and collagen-induced arthritis

Event Abstract Back to Event Accumulation of CD4+CD28-PD-1lowOX40+ T cells and its clinical significance in rheumatoid and collagen-induced arthritis Juean Jiang1, Cuiping Liu1, Yongjing Chen2, Jianhua Jiang1, Ranran Zhu2, Ting Wang2, Min Wu3 and Xueguang Zhang1* 1 The First Affiliated Hospital of Soochow University, China 2 Soochow University, China 3 The Third Affiliated Hospital of Soochow University, China CD4+CD28- T cells play a key role in the immunopathogenesis of rheumatoid arthritis (RA). Co-inhibitory molecule of PD-1 has a crucial role in suppression of T cell responses. However, presence of PD-1 and absence of CD28 do not induce CD4+ T cells into apoptosis in RA. In this study, we characterized a novel CD4+CD28-PD-1lowOX40+ T cells subset and investigated its clinical significance in rheumatoid and collagen-induced arthritis (CIA). Peripheral blood samples were collected from RA, osteoarthritis and healthy subjects. CIA was induced in DBA/1 mice. After separation of mononuclear cells from peripheral blood of the patients or spleen of CIA mice, CD4+CD28-PD-1lowOX40+ T cells were examined by flow cytometry. In RA patients and CIA mice, there were increased expressions of PD-1 and OX40 on CD4+ T cells, with PD-L1 and OX40L expressions augmented on monocytes and B cells. Analyses showed that CD4+CD28-PD-1lowOX40+ T cells were accumulated and closely correlated with clinicopathological features of RA patients and CIA mice. Moreover, immunosuppressive therapy significantly reduced the percentage of CD4+CD28-PD-1lowOX40+ T cells. Additionally, CD4+CD28-PD-1low T cells displayed a phenotype of CD45RAlowCD45ROhighCD25low. In summary, low PD-1 and enhanced OX40 expression implied longevity and persistent activation of these T cells both in RA patients and CIA mice. A phenotype of memory T cells and fine correlations with clinicopathological features suggested that these T cells may be involved in the immunopathogenesis of RA and CIA. Interventions with pathological functions of this T cells subset may provide a new therapeutic interesting in RA. Acknowledgements This study was supported by the National Natural Science Foundation of China (Grants: 30930085, 81001337 and 31170834), the Research and Innovation Project for College Graduates of Jiangsu Province (Grant: CXLX11_0077), and Science and Technology Support Program of Suzhou City (Grant: SS201246). Keywords: Rheumatoid arthritis, Autoreactive T cells, CD28, PD-1, OX40 Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Jiang J, Liu C, Chen Y, Jiang J, Zhu R, Wang T, Wu M and Zhang X (2013). Accumulation of CD4+CD28-PD-1lowOX40+ T cells and its clinical significance in rheumatoid and collagen-induced arthritis. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00742 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Xueguang Zhang, The First Affiliated Hospital of Soochow University, Suzhou, China, xueguangzh@126.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Juean Jiang Cuiping Liu Yongjing Chen Jianhua Jiang Ranran Zhu Ting Wang Min Wu Xueguang Zhang Google Juean Jiang Cuiping Liu Yongjing Chen Jianhua Jiang Ranran Zhu Ting Wang Min Wu Xueguang Zhang Google Scholar Juean Jiang Cuiping Liu Yongjing Chen Jianhua Jiang Ranran Zhu Ting Wang Min Wu Xueguang Zhang PubMed Juean Jiang Cuiping Liu Yongjing Chen Jianhua Jiang Ranran Zhu Ting Wang Min Wu Xueguang Zhang Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Taurine chloramine inhibits osteoclastogenesis and splenic lymphocyte proliferation in mice with collagen-induced arthritis

Taurine chloramine (TauCl) is produced by activated neutrophils in the inflammatory joint cavities of rheumatoid arthritis and is known to have anti-inflammatory and anti-arthritic effects. However, the mechanisms underlying the anti-arthritic effect of TauCl have not been elucidated. Here, we investigated that mechanism using a collagen-induced arthritis (CIA) mouse model. DBA/1J mice were immunized with bovine type II collagen to induce CIA and were given daily subcutaneous injections of TauCl from the day of first collagen immunization. Severity of arthritis was scored by paw swelling and the arthritis score system. At the 8th week, mice were sacrificed for histological examination using hematoxylin and eosin, safranin-O and tartrate-resistant acid phosphatase (TRAP) staining. Effects of TauCl on osteoclastogenesis from bone marrow-derived preosteoclasts and proliferation of the lymphocytes obtained from spleens of CIA mice were determined. TauCl significantly attenuated the severity of paw swelling and reduced arthritis score in CIA mice. TauCl treated CIA mice showed significant reductions of synovial inflammation, cartilage damage and bone erosion. The number of TRAP-positive cells in the joints of TauCl treated CIA mice was reduced. TauCl inhibited osteoclastogenesis from the RANKL treated bone marrow-derived preosteoclasts in a dose-dependent manner. TauCl also inhibited the proliferation of splenic lymphocytes obtained from CIA mice. In conclusion, TauCl attenuated the severity of CIA by inhibiting lymphocyte proliferation and osteoclastogenesis. Combined our results suggest that TauCl produced endogenously in inflamed joints may suppress the development of rheumatoid arthritis and that TauCl may be used for therapeutic treatment of rheumatoid arthritis.

CD8alpha+ dendritic cells enhance the antigen-specific CD4+ T-cell response and accelerate development of collagen-induced arthritis

To investigate the role of CD8α + DCs in the development of collagen-induced arthritis (CIA). The immunogenic properties of CD8α + and CD8α − DC subsets were investigated by mixed-lymphocyte reaction and cytokine enzyme-linked immunoassay. CII-pulsed CD8α + DCs or CD8α − DCs with CD4 + T cells from CIA mice were adoptively transferred onto the hind footpad of DBA mice. The onset of arthritis and the arthritis index were examined for 14 weeks after adoptive transfer. Expression of MHC-II and CD80 but not CD86 and CD40 was higher in CD8α + DCs than in CD8α − DCs from the spleens of CIA mice. Culturing CD8α + DCs with CD4 + T cells significantly increased the proliferative response of CD4 + T cells in the presence of CII. The production of interleukin (IL)-12p70, IL-17, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α was slightly increased in CD8α + DCs than in CD8α − DCs. DBA/1 mice that were adoptively transferred with CII-pulsed CD8α + DCs and CD4 + T cells into the footpads showed accelerated onset of CIA compared to control group. By contrast, CD8α − DCs showed a partial inhibitory effect on CIA. These findings show that CD8α + DCs accelerated the onset of CIA when aoptively transferred with CD4 + T cells and that CD8α + DCs provoke the development of CIA probably by stimulating the immune responses of CII-reactive CD4 + T cells and by increasing the production of inflammatory cytokines.

Expression of Co-stimulatory Molecules and STAT/SOCS Signaling Factors in the Splenocytes of Mice Tolerized against Arthritis by Oral Administration of Type II Collagen

Oral administration of antigen has long been used in the induction of immune tolerance in various animal models of autoimmune diseases including rheumatoid arthritis (RA). Alleveation of arthritogenic symptoms has been reported from RA patients who received oral administration of type II collagen (CII) without side effects, however its rather inconsistent therapeutic efficacy and variation among patients calls for more detailed investigation on the mechanism of oral tolerance to be settled as regular treatment for RA. In an attempt to understand the immunogenic processes underpinning tolerance induction by orally administered CII, we analyzed changes in the expression of costimulatory molecules and STAT/SOCS signaling messengers in the mouse model of collagen induced arthritis (CIA). We found thatin the spleen of CIA mice, that has been undergone repeated oral feeding of CII prior to the induction of arthritis, showed increased promortion of CTLA4 expressing lymphocytes than in the spleen of PBS fed control. On the other hand, cells expressing CD28 or ICOS were decreased in the spleen of tolerized mice. Tolerance induction by oral CII administration also enhanced the expression of STAT6 in both RNA and protein level, while not affecting the expression of STAT3. The expression of SOCS3, which hasbeen known to transmit STAT-mediated signals from Th2 type cytokines, remained unchanged in the spleen of tolerized mice. Interestingly transcript of SOCS1, which has been associated with Th1 related pathways, was only visible in the spleen of tolerized but not of control mice, suggesting that as in the case of IL-6 signaling, it may exert a feed back inhibition toward the Th1 type stimulation. (Im m u ne N etw ork 2003 ;3(3):248-254)