Cutting Edge: Anti-Inflammatory Properties of Low Levels of IFN-γ

Flaishon, Liat; Topilski, Ian; Shoseyov, David; Hershkoviz, Rami; Fireman, Elizabeth; Levo, Y; Marmor, Sylvia; Shachar, Idit

doi:10.4049/jimmunol.168.8.3707

Cited by 76 publications

(74 citation statements)

References 24 publications

(26 reference statements)

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“…Our studies to determine the potential in vivo mechanisms underlying the inhibition of diabetes development by the tetramer ϩ T cells showed that these regulatory T cells could block the migration of the diabetogenic BDC2.5 T cells into lymph nodes of recipient mice. This blocking effect may be reminiscent of the findings described in a recent report that low-dose IFN-␥ exerts anti-inflammatory properties, such as suppression of T cell trafficking (55). Therefore, incubation of T cells in vitro with a low concentration of IFN-␥ blocked the migration of treated T cells into lymph nodes after they were adoptively transferred into recipient mice.…”

Section: Discussionsupporting

confidence: 48%

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Chen

Lee

Yun

et al. 2003

The Journal of Immunology

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Autoantigen-based immunotherapy can modulate autoimmune diabetes, perhaps due to the activation of Ag-specific regulatory T cells. Studies of these regulatory T cells should help us understand their roles in diabetes and aid in designing a more effective immunotherapy. We have used class II MHC tetramers to isolate Ag-specific T cells from nonobese diabetic (NOD) mice and BALB/c mice treated with glutamic acid decarboxylase 65 peptides (p206 and p221). Based on their cytokine secretion profiles, immunization of NOD mice with the same peptide induced different T cell subsets than in BALB/c mice. Treatment of NOD mice induced not only Th2 cells but also IFN-γ/IL-10-secreting T regulatory type 1 (Tr1) cells. Adoptive transfer experiments showed that isolated tetramer+ T cells specific for p206 or p221 could inhibit diabetes development. These cells were able to suppress the in vitro proliferation of other NOD mouse T cells without cell-cell contact. They performed their regulatory functions probably by secreting cytokines, and Abs against these cytokines could block their suppressive effect. Interestingly, the presence of both anti-IL-10 and anti-IFN-γ could enhance the target cell proliferation, suggesting that Tr1 cells play an important role. Further in vivo experiments showed that the tetramer+ T cells could block diabetogenic T cell migration into lymph nodes. Therefore, treatment of NOD mice with autoantigen could induce Th2 and Tr1 regulatory cells that can suppress the function and/or block the migration of other T cells, including diabetogenic T cells, and inhibit diabetes development.

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Section: Discussionsupporting

confidence: 48%

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Chen

Lee

Yun

et al. 2003

The Journal of Immunology

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“…In contrast to the proinflammatory effects of IFN-␥ at relatively high concentrations, low-dose IFN-␥ appears to exert global suppressive effects on T cell trafficking and may have an antiinflammatory effect (47). In some autoimmune disease models, such as experimental autoimmune encephalomyelitis and collagen-induced arthritis (48), disease incidence and severity are frequently increased in IFN-␥-deficient animals.…”

Section: Discussionmentioning

confidence: 99%

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Kim

Tarbell

Sanna

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Glutamic acid decarboxylase (GAD) 65 is one of the major pancreatic antigens targeted by self-reactive T cells in type I diabetes mellitus. T cells specific for GAD65 are among the first to enter inflamed islets and may be important for the initiation of autoimmune diabetes. However, we previously reported that nonobese diabetic (NOD) mice transgenic for a T cell antigen receptor (TCR) specific for one of the immunodominant epitopes of GAD65, peptide 286-300 (G286), are protected from insulitis and diabetes. To examine whether other GAD65-reactive T cells share this phenotype, we have generated TCR transgenic NOD mice for a second immunodominant epitope of GAD65, peptide 206-220 (G206). As in G286 mice, G206 mice do not develop islet inflammation or diabetes. When adoptively transferred along with diabetogenic T cells, activated G206 T cells significantly delayed the onset of diabetes in NOD.scid recipients. Both G206 and G286 T cells produce immunoregulatory cytokines IFN-␥ and IL-10 at low levels when activated by cognate antigens. These data suggest that GAD65-specific T cells may play a protective role in diabetes pathogenesis by regulating pathogenic T cell responses. A better understanding of the functions of autoreactive T cells in type I diabetes will be necessary for choosing desirable targets for immunotherapy.T ype I diabetes mellitus in humans is an autoimmune disease that results from the selective destruction of pancreatic ␤-cells by T cells (1, 2). The nonobese diabetic (NOD) mouse develops spontaneous autoimmune diabetes that shares many characteristics with the human disease (1, 3, 4). The principal islet cell antigens targeted by autoreactive T cells in NOD mice include insulin (5), glutamic acid decarboxylase 65 (GAD65) (6), 65-kDa heat shock protein (7), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) (8). Among these, T cell responses to GAD65 and insulin are detected early preceding the onset of clinical disease (3-5 weeks of age in the NOD mouse) (9-11). This result has led to the speculation that GAD65 may be among the first autoantigens targeted by T cells that initiate the diabetes pathogenesis.The hypothesis for a pathogenic role of GAD65 is supported by a GAD65-specific T cell clone that induces insulitis and diabetes upon adoptive transfer (12) and by the finding that prevention of GAD65 expression in the pancreatic islets by GAD antisense cDNA prevented diabetes (13). In contrast, induction of deletional T cell tolerance by widespread expression of a GAD65 transgene did not alter diabetes pathogenesis (14) but exacerbated the disease (15). In addition, several GAD65-specific T cell clones, lines, and T cell antigen receptor (TCR) transgenic mice were not pathogenic and exhibited a diabetesdelaying capacity (16-18). Thus, it appears that GAD65 may not be a required initiating antigen for diabetes pathogenesis but rather induces a protective response.To further examine the functions of GAD65-reactive T cells in the pathogenesis of diabetes, we have ge...

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“…Similarly, low-dose IFN␥ has been demonstrated to prevent migration of T cells and B cells (48)(49)(50). IFN␥ might suppress inflammation only if administered at a very precise dosage level, and SGL-S23 may thus have greater utility as an inhibitor of inflammatory arthritis.…”

Section: Discussionmentioning

confidence: 99%

Activation of invariant natural killer T cells by synthetic glycolipid ligands suppresses autoantibody‐induced arthritis

Kaieda

Tomi

Oki

et al. 2007

Arthritis & Rheumatism

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Objective. Stimulation of invariant natural killer T (iNKT) cells with SGL-S23, a novel synthetic glycolipid analog of ␣-galactosylceramide with an elongated sphingosine chain, has been shown to strongly suppress K/BxN serum transfer arthritis. This study was designed to evaluate the protective effects of SGL-S23 in an effector phase of arthritis.Methods. To induce arthritis, C57BL/6 mice were injected with 150 l of serum from K/BxN mice (KRN TCR-transgenic mice crossed with nonobese diabetic mice). Subsequently, synthetic glycolipid ligands were administered intraperitoneally twice, either 3 times starting on day 0 (the day of K/BxN serum injection) or twice starting on day 3. Neutralizing antibody against interferon-␥ (IFN␥) interleukin-4 (IL-4), IL-10, or transforming growth factor ␤ was administered 4 hours before injection of SGL-S23. Recombinant IFN␥ was administered subcutaneously every day. The severity of arthritis was monitored using a macroscopic scoring system. Cytokine production and plasma histamine levels were measured by enzyme-linked immunosorbent assay.Results. SGL-S23 strongly suppressed K/BxN serum transfer arthritis by inhibiting inflammatory cell infiltration and subsequent destruction of cartilage and bone. The inhibitory effect mediated by SGL-S23 was abolished by neutralization of IFN␥. Systemic administration of IFN␥ prevented the development of inflammatory arthritis. Histamine release was suppressed by administration of SGL-S23 or IFN␥. Degranulated mast cells in the synovium were significantly reduced in SGL-S23-treated mice, suggesting that suppression of mast cell activation contributed to the inhibition of arthritis.Conclusion. These findings suggest that activation of iNKT cells with glycolipid ligands holds promise with regard to the treatment of autoimmune diseases such as rheumatoid arthritis. SGL-S23 has clinical benefit over ␣-galactosylceramide since it induces a weaker cytokine production response in iNKT cells, therefore reducing potential side effects caused by excessive cytokine release.

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Cutting Edge: Anti-Inflammatory Properties of Low Levels of IFN-γ

Cited by 76 publications

References 24 publications

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes

Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells

Activation of invariant natural killer T cells by synthetic glycolipid ligands suppresses autoantibody‐induced arthritis

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