Experimental Autoimmune Thyroiditis

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Bellur S Prabhakar - One of the best experts on this subject based on the ideXlab platform.

  • ox40l jag1 induced expansion of lineage stable regulatory t cells involves noncanonical nf κb signaling
    Journal of Immunology, 2019
    Co-Authors: Prabhakaran Kumar, Swarali Surendra Lele, Vandhana K Ragothaman, Divya Raghunathan, Shigeru Chiba, Alan L. Epstein, Bellur S Prabhakar
    Abstract:

    Foxp3(+)T regulatory cells (Tregs) control Autoimmune response by suppressing proliferation and effector functions of self-reactive Foxp3(-)CD4(+)/CD8(+) T cells and thereby maintain the critical balance between self-tolerance and autoimmunity. Earlier, we had shown that OX40L-JAG1 cosignaling mediated through their cognate receptors OX40 and Notch3 preferentially expressed on murine Tregs can selectively induce their proliferation in the absence of TCR stimulation. However, the differential molecular mechanisms regulating TCR-independent versus TCR-dependent Treg proliferation and lineage stability of the expanded Tregs remained unknown. In this study, we show that OX40L-JAG1 treatment induced TCR-independent proliferation of Tregs in the thymus and periphery. The use of Src kinase inhibitor permitted us to demonstrate selective inhibition of TCR-dependent T cell proliferation with little to no effect on OX40L-JAG1-induced TCR-independent Treg expansion in vitro, which was critically dependent on noncanonical NF-kappaB signaling. OX40L-JAG1-expanded Tregs showed sustained lineage stability as indicated by stable demethylation marks in Treg signature genes such as Foxp3, Il2ra, Ctla4, Ikzf2, and Ikzf4. Furthermore, OX40L-JAG1 treatment significantly increased CTLA4(+) and TIGIT(+) Tregs and alleviated Experimental Autoimmune Thyroiditis in mice. Relevance of our findings to humans became apparent when human OX40L and JAG1 induced TCR-independent selective expansion of human Tregs in thymocyte cultures and increased human Tregs in the liver tissue of humanized NSG mice. Our findings suggest that OX40L-JAG1-induced TCR-independent Treg proliferation is a conserved mechanism that can be used to expand lineage-stable Tregs to treat Autoimmune diseases.

  • ox40l jagged1 cosignaling by gm csf induced bone marrow derived dendritic cells is required for the expansion of functional regulatory t cells
    Journal of Immunology, 2013
    Co-Authors: Anupama Gopisetty, Chenthamarakshan Vasu, Palash Bhattacharya, Christine Haddad, Joseph C Bruno, Lucio Miele, Bellur S Prabhakar
    Abstract:

    Earlier, we had demonstrated that treatment with low dose of GM-CSF can prevent the development of Experimental Autoimmune Thyroiditis (EAT), Experimental Autoimmune myasthenia gravis, and type 1 diabetes, and could also reverse ongoing EAT and Experimental Autoimmune myasthenia gravis. The protective effect was mediated through the induction of tolerogenic CD11C(+)CD8α(-) dendritic cells (DCs) and consequent expansion of Foxp3(+) regulatory T cells (Tregs). Subsequently, we showed that GM-CSF acted specifically on bone marrow precursors and facilitated their differentiation into tolerogenic dendritic cells (DCs; GM-CSF-induced bone marrow-derived DCs [GM-BMDCs]), which directed Treg expansion in a contact-dependent manner. This novel mechanism of Treg expansion was independent of TCR-mediated signaling but required exogenous IL-2 and cosignaling from DC-bound OX40L. In this study, we observed that OX40L-mediated signaling by GM-BMDCs, although necessary, was not sufficient for Treg expansion and required signaling by Jagged1. Concurrent signaling induced by OX40L and Jagged1 via OX40 and Notch3 receptors expressed on Tregs was essential for the Treg expansion with sustained FoxP3 expression. Adoptive transfer of only OX40L(+)Jagged1(+) BMDCs led to Treg expansion, increased production of IL-4 and IL-10, and suppression of EAT in the recipient mice. These results showed a critical role for OX40L- and Jagged1-induced cosignaling in GM-BMDC-induced Treg expansion.

  • gm csf induced cd11c cd8a dendritic cells facilitate foxp3 and il 10 regulatory t cell expansion resulting in suppression of Autoimmune Thyroiditis
    International Immunology, 2009
    Co-Authors: Balaji B Ganesh, Donald Cheatem, Chenthamarakshan Vasu, Jian Rong Sheng, Bellur S Prabhakar
    Abstract:

    GM-CSF plays an essential role in the differentiation of dendritic cells (DCs). Our studies have shown that GM-CSF treatment can induce semi-mature DCs and CD4+CD25+ regulatory T cells (Tregs) and suppress ongoing autoimmunity in mouse models. In this study, we examined the differences in the potential of GM-CSF to exert tolerogenic function on CD8a+ and CD8a- sub-populations of DCs in vivo. We show that GM-CSF modulates CD8a-, but not CD8a+ DCs in vivo, by inhibiting the surface expression of activation markers MHC II and CD80 and production of inflammatory cytokines such as IL-12 and IL-1beta. Self-antigen [mouse thyroglobulin (mTg)] presentation by GM-CSF-exposed CD8a- DCs to T cells from mTg-primed mice induced a profound increase in the frequency of forkhead box P3 (FoxP3)-expressing T cells compared with antigen presentation by GM-CSF-exposed CD8a+ DCs and control CD8a+ and CD8a- DCs. This tolerogenic property of GM-CD8a- DCs was abrogated when IL-12 was added. GM-CSF-exposed CD8a- DCs could also induce secretion of significantly higher amounts of IL-10 by T cells from mTg-primed mice. Importantly, adoptive transfer of CD8a- DCs from GM-CSF-treated SCID mice, but not untreated mice, into wild-type CBA/J mice prevented the development of Experimental Autoimmune Thyroiditis (EAT) in the recipient animals upon immunization with mTg. Collectively, our results show that GM-CSF renders CD8a- DCs tolerogenic, and these DCs induce Foxp3+ and IL-10+ Tregs.

  • il 10 producing cd4 cd25 regulatory t cells play a critical role in granulocyte macrophage colony stimulating factor induced suppression of Experimental Autoimmune Thyroiditis
    Journal of Immunology, 2005
    Co-Authors: Eryn Gangi, Chenthamarakshan Vasu, Donald Cheatem, Bellur S Prabhakar
    Abstract:

    Our earlier study showed that GM-CSF has the potential not only to prevent, but also to suppress, Experimental Autoimmune Thyroiditis (EAT). GM-CSF-induced EAT suppression in mice was accompanied by an increase in the frequency of CD4 + CD25 + regulatory T cells that could suppress mouse thyroglobulin (mTg)-specific T cell responses in vitro, but the underlying mechanism of this suppression was not elucidated. In this study we show that GM-CSF can induce dendritic cells (DCs) with a semimature phenotype, an important characteristic of DCs, which are known to play a critical role in the induction and maintenance of regulatory T cells. Adoptive transfer of CD4 + CD25 + T cells from GM-CSF-treated and mTg-primed donors into untreated, but mTg-primed, recipients resulted in decreased mTg-specific T cell responses. Furthermore, lymphocytes obtained from these donors and recipients after adoptive transfer produced significantly higher levels of IL-10 compared with mTg-primed, untreated, control mice. Administration of anti-IL-10R Ab into GM-CSF-treated mice abrogated GM-CSF-induced suppression of EAT, as indicated by increased mTg-specific T cell responses, thyroid lymphocyte infiltration, and follicular destruction. Interestingly, in vivo blockade of IL-10R did not affect GM-CSF-induced expansion of CD4 + CD25 + T cells. However, IL-10-induced immunosuppression was due to its direct effects on mTg-specific effector T cells. Taken together, these results indicated that IL-10, produced by CD4 + CD25 + T cells that were probably induced by semimature DCs, is essential for disease suppression in GM-CSF-treated mice.

  • selective induction of dendritic cells using granulocyte macrophage colony stimulating factor but not fms like tyrosine kinase receptor 3 ligand activates thyroglobulin specific cd4 cd25 t cells and suppresses Experimental Autoimmune Thyroiditis
    Journal of Immunology, 2003
    Co-Authors: Chenthamarakshan Vasu, Rukiye Nazan E Dogan, Mark J Holterman, Bellur S Prabhakar
    Abstract:

    fms-like tyrosine kinase receptor 3-ligand (Flt3-L) and GM-CSF cause expansion of different subsets of dendritic cells and skew the immune response toward predominantly Th1 and Th2 type, respectively. In the present study, we investigated their effects on Experimental Autoimmune Thyroiditis in CBA/J mice. Relative to mouse thyroglobulin (mTg) immunized controls, mTg-immunized mice treated with Flt3-L showed more severe Thyroiditis characterized by enhanced lymphocytic infiltration of the thyroid, and IFN-γ and IL-2 production. In contrast, mice treated with GM-CSF, either before or after immunization with mTg, showed suppressed T cell response to mTg and failed to develop Thyroiditis. Lymphocytes from these mice, upon activation with mTg in vitro, produced higher levels of IL-4 and IL-10. Additionally, GM-CSF-treated mice showed an increase in the frequency of CD4+/CD25+ T cells, which suppressed the mTg-specific T cell response. Neutralization of IL-10, but not IL-4, or depletion of CD4+/CD25+ cells resulted in increased mTg-specific in vitro T cell proliferation suggesting that IL-10 produced by the Ag-specific CD4+/CD25+ regulatory T cells might be critical for disease suppression. These results indicate that skewing immune response toward Th2, through selective activation of dendritic cells using GM-CSF, may have therapeutic potential in Th1 dominant Autoimmune diseases including Hashimoto’s Thyroiditis.

Yi Chi M Kong - One of the best experts on this subject based on the ideXlab platform.

  • efficacy of hla drb1 03 01 and h2e transgenic mouse strains to correlate pathogenic thyroglobulin epitopes for Autoimmune Thyroiditis
    Journal of Autoimmunity, 2011
    Co-Authors: Yi Chi M Kong, Gerald P Morris, Nicholas K Brown, Jeffrey C Flynn, Daniel J Mccormick, Vladimir Brusic, Chella S David
    Abstract:

    Thyroglobulin (Tg), a homodimer of 660 kD comprising 2748 amino acids, is the largest autoantigen known. The prevalence of Autoimmune thyroid disease, including Hashimoto's Thyroiditis and Graves' disease, has provided the impetus for identifying pathogenic T cell epitopes from human Tg over two decades. With no known dominant epitopes, the search has long been a challenge for investigators. After identifying HLA-DRB1∗03:01 (HLA-DR3) and H2E(b) as susceptibility alleles for Tg-induced Experimental Autoimmune Thyroiditis in transgenic mouse strains, we searched for naturally processed T cell epitopes with MHC class II-binding motif anchors and tested the selected peptides for pathogenicity in these mice. The thyroiditogenicity of one peptide, hTg2079, was confirmed in DR3 transgenic mice and corroborated in clinical studies. In H2E(b)-expressing transgenic mice, we identified three T cell epitopes from mouse Tg, mTg179, mTg409 and mTg2342, based on homology to epitopes hTg179, hTg410 and hTg2344, respectively, which we and others have found stimulatory or pathogenic in both DR3- and H2E-expressing mice. The high homology among these peptides with shared presentation by DR3, H2E(b) and H2E(k) molecules led us to examine the binding pocket residues of these class II molecules. Their similar binding characteristics help explain the pathogenic capacity of these T cell epitopes. Our approach of using appropriate human and murine MHC class II transgenic mice, combined with the synthesis and testing of potential pathogenic Tg peptides predicted from computational models of MHC-binding motifs, should continue to provide insights into human Autoimmune thyroid disease.

  • Autoimmune Thyroiditis a model uniquely suited to probe regulatory t cell function
    Journal of Autoimmunity, 2009
    Co-Authors: Yi Chi M Kong, Gerald P Morris, Nicholas K Brown, Jeffrey C Flynn, Yan Yan, Chella S David
    Abstract:

    Murine Experimental Autoimmune Thyroiditis (EAT) is a model for Hashimoto's Thyroiditis that has served as a prototype of T cell-mediated autoimmunity for more than three decades. Key roles for MHC restriction and autoantigen influence on susceptibility to autoimmunity have been demonstrated in EAT. Moreover, it has served a unique role in investigations of self tolerance. In the early 1980s, self tolerance and resistance to EAT induction could be enhanced by increasing circulating levels of the autoantigen, thyroglobulin (Tg), by exogenous addition as well as endogenous release. This observation, directly linking circulating self antigen to self tolerance, led to subsequent investigations of the role of regulatory T cells (Tregs) in self tolerance. These studies revealed that protection against autoimmunity, in both naive and tolerized mice, was mediated by thymically-derived CD4(+)CD25(+)Foxp3(+) Tregs. Moreover, these naturally-existing Tregs required proper costimulation, in context with autoantigen presentation, to maintain and enhance self tolerance. In particular was the selected use of MHC- and heterologous Tg-restricted models from both conventional and transgenic mice. These models helped to elucidate the complex interplay between autoantigen presentation and MHC class II-mediated T cell selection in the development of Treg and autoreactive T cell repertoires determining susceptibility to autoimmunity. Here we describe these investigations in further detail, providing a context for how EAT has helped shape our understanding of self tolerance and autoimmunity.

  • naturally existing cd4 cd25 foxp3 regulatory t cells are required for tolerance to Experimental Autoimmune Thyroiditis induced by either exogenous or endogenous autoantigen
    Journal of Autoimmunity, 2009
    Co-Authors: Gerald P Morris, Nicholas K Brown, Yi Chi M Kong
    Abstract:

    Murine Experimental Autoimmune Thyroiditis (EAT) is a model for Hashimoto's Thyroiditis, an organ-specific Autoimmune disease characterized by mononuclear cell infiltration and destruction of the thyroid gland. Susceptibility to EAT is MHC-linked, and influenced by CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs). Treg depletion enables Thyroiditis induction with mouse thyroglobulin (mTg) in traditionally-resistant mice and mTg-induced, Treg-mediated tolerance protects against EAT induction in genetically-susceptible mice. Here, we demonstrate the existence of naturally-existing CD4(+)CD25(+)Foxp3(+) Tregs (nTregs) influencing Thyroiditis development in naive susceptible mice and that induction of Thyroiditis in these mice involves overcoming peripheral homeostatic immune suppression by nTregs. Additionally we demonstrate that nTregs are required for induction of antigen-specific tolerance, indicating that induced EAT tolerance is a result of activation of naturally-existing nTregs rather than de novo generation of induced Tregs (iTregs). Examination of several potential costimulatory molecules previously described as involved in peripheral activation of Tregs demonstrates a critical role indeed for CTLA-4 in the activation of nTregs leading to development of EAT tolerance and providing a mechanism for mTg-induced Treg activation during tolerance induction. Together, these data reinforce the important role of Tregs in mediating self-tolerance, and illuminate a potential mechanism for their therapeutic expansion in induced tolerance.

  • depletion of cd4 cd25 regulatory t cells exacerbates sodium iodide induced Experimental Autoimmune Thyroiditis in human leucocyte antigen dr3 drb1 0301 transgenic class ii knock out non obese diabetic mice
    Clinical and Experimental Immunology, 2007
    Co-Authors: Jeffrey C Flynn, C Meroueh, D P Snower, Chella S David, Yi Chi M Kong
    Abstract:

    Both genetic and environmental factors contribute to Autoimmune disease development. Previously, we evaluated genetic factors in a humanized mouse model of Hashimoto's Thyroiditis (HT) by immunizing human leucocyte antigen DR3 (HLA-DR3) and HLA-DQ8 transgenic class II-knock-out non-obese diabetic (NOD) mice. DR3+ mice were susceptible to Experimental Autoimmune Thyroiditis (EAT) induction by both mouse thyroglobulin (mTg) and human (h) Tg, while DQ8+ mice were weakly susceptible only to hTg. As one environmental factor associated with HT and tested in non-transgenic models is increased sodium iodide (NaI) intake, we examined the susceptibility of DR3+ and/or DQ8+ mice to NaI-induced disease. Mice were treated for 8 weeks with NaI in the drinking water. At 0 x 05% NaI, 23% of DR3+, 0% of DQ8+ and 20% of DR3+DQ8+ mice had thyroid destruction. No spleen cell proliferation to mTg was observed. Most mice had undetectable anti-mTg antibodies, but those with low antibody levels usually had Thyroiditis. At 0.3% NaI, a higher percentage of DR3+ and DR3+DQ8+ mice developed destructive Thyroiditis, but it was not statistically significant. However, when DR3+ mice had been depleted of CD4+CD25+ regulatory T cells prior to NaI treatment, destructive Thyroiditis (68%) and serum anti-mTg antibodies were exacerbated further. The presence of DQ8 molecules does not alter the susceptibility of DR3+DQ8+ mice to NaI-induced Thyroiditis, similar to earlier findings with mTg-induced EAT. Susceptibility of DR3+ mice to NaI-induced EAT, in both the presence and absence of regulatory T cells, demonstrates the usefulness of HLA class II transgenic mice in evaluating the roles of environmental factors and immune dysregulation in Autoimmune thyroid disease.

  • tolerance to Autoimmune Thyroiditis cd4 cd25 regulatory t cells influence susceptibility but do not supersede mhc class ii restriction
    Frontiers in Bioscience, 2006
    Co-Authors: Gerald P Morris, Yi Chi M Kong
    Abstract:

    Murine Experimental Autoimmune Thyroiditis (EAT), a model of Hashimoto's Thyroiditis, has served for more than three decades as a prototypical model of T cell-mediated autoimmunity. Early investigations demonstrated a clear correlation between genetic factors, particularly the H2A locus of the MHC class II region, and susceptibility to Autoimmune Thyroiditis. Early studies also demonstrated that susceptibility to EAT induction could be modulated by manipulation of circulating levels of thyroglobulin (Tg), the principal thyroid antigen, resulting in the strengthening of self-tolerance. This antigen-specific induced tolerance is mediated by thymus-derived cells, and subsequent investigations revealed that the suppressive function is located in the (CD4+)CD25+ T cell subset, similar to findings in other models. We have demonstrated that these (CD4+)CD25+ regulatory T cells (Treg) influence susceptibility to Thyroiditis in naive, as well as mTg-tolerized mice. Here, we describe the influence of both Treg and MHC class II haplotype, independently, as well in combination, and describe our recent utilization of MHC class II transgenic mice to directly compare the extent of their influences.

Sung Hwa Hong - One of the best experts on this subject based on the ideXlab platform.

  • characteristics of mouse adipose tissue derived stem cells and therapeutic comparisons between syngeneic and allogeneic adipose tissue derived stem cell transplantation in Experimental Autoimmune Thyroiditis
    Cell Transplantation, 2014
    Co-Authors: Eun Wha Choi, Il Seob Shin, So Young Park, Eun Ji Yoon, Sung Keun Kang, Sung Hwa Hong
    Abstract:

    Previously, we found that the intravenous administration of human adipose tissue-derived mesenchymal stem cells was a promising therapeutic option for Autoimmune Thyroiditis even when the cells were transplanted into a xenogeneic model without an immunosuppressant. Therefore, we explored the comparison between the therapeutic effects of syngeneic and allogeneic adipose tissue-derived stem cells on an Experimental Autoimmune Thyroiditis mouse model. Experimental Autoimmune Thyroiditis was induced in C57BL/6 mice by immunization with porcine thyroglobulin. Adipose tissue-derived stem cells derived from C57BL/6 mice (syngeneic) or BALB/c mice (allogeneic) or saline as a vehicle control were administered intravenously four times weekly. Blood and tissue samples were collected 1 week after the last transplantation. Adipose tissue-derived stem cells from mice were able to differentiate into multiple lineages in vitro; however, mouse adipose tissue-derived stem cells did not have immunophenotypes identical to those from humans. Syngeneic and allogeneic administrations of adipose tissue-derived stem cells reduced thyroglobulin autoantibodies and the inflammatory immune response, protected against lymphocyte infiltration into the thyroid, and restored the Th1/Th2 balance without any adverse effects. However, different humoral immune responses were observed for infused cells from different stem cell sources. The strongest humoral immune response was induced by xenogeneic transplantation, followed by allogeneic and syngeneic administration, in that order. The stem cells were mostly found in the spleen, not the thyroid. This migration might be because the stem cells primarily function in systemic immune modulation, due to being given prior to disease induction. In this study, we confirmed that there were equal effects of adipose tissue-derived stem cells in treating Autoimmune Thyroiditis between syngeneic and allogeneic transplantations.

  • transplantation of ctla4ig gene transduced adipose tissue derived mesenchymal stem cells reduces inflammatory immune response and improves th1 th2 balance in Experimental Autoimmune Thyroiditis
    Journal of Gene Medicine, 2011
    Co-Authors: Eun Wha Choi, Il Seob Shin, So Young Park, Ji Hyun Park, Eun Ji Yoon, Sung Keun Kang, Jeong Chan Ra, Hwa Young Youn, Sung Hwa Hong
    Abstract:

    Background Autoimmune Thyroiditis is one of common organ-specific Autoimmune disease. The aim of this study was to observe the effect of adipose tissue derived mesenchymal stem cells (ATMSC) and CTLA4Ig gene-transduced ATMSC on Autoimmune Thyroiditis. Methods Experimental Autoimmune Thyroiditis was induced by immunization with thyroglobulin. Animals were divided into three groups: (i) a half million of human ATMSC, (ii) a half million of murine CLTA4Ig gene-transduced human ATMSC (CTLA4Ig-MSC), or (iii) normal saline (as control), which were administered intravenously four times within a 3-week period. Blood and tissue samples were collected 1 week after the last cell transplantation. Results The absorbance of serum thyroglobulin autoantibody (TgAA) in the CTLA4Ig-MSC group was considerably lower than those in other groups. In culture supernatant of LPS-stimulated spleen cells, both of the MSC-treated groups showed significantly lower absorbances of TgAA than the control. Flow cytometric analysis of spleen cells revealed a significant decrease in the proportion of CD3+ and CD11b in the CTLA4Ig-MSC group compared to the other groups. Lymphocyte infiltration in the thyroid glands was also dramatically decreased in both of MSC-treated groups. Cytokine analysis showed that ATMSC decreased the production of proinflammatory cytokines and improved the Th1/Th2 balance by down-regulating Th1 cytokines. Conclusion Although CTLA4Ig-MSC transplantation had better result in reduction of serum TgAA, both of ATMSC and CTLA4Ig-MSC transplantations are promising treatments for Autoimmune Thyroiditis judging from the results of histopathology and cytokine analysis. They may be attractive candidates for treating organ-specific Autoimmune disease. Copyright © 2011 John Wiley & Sons, Ltd.

James R Baker - One of the best experts on this subject based on the ideXlab platform.

  • tumor necrosis factor related apoptosis inducing ligand inhibits Experimental Autoimmune Thyroiditis by the expansion of cd4 cd25 regulatory t cells
    Endocrinology, 2009
    Co-Authors: Su He Wang, Gwo Hsiao Chen, Yongyi Fan, Mary Van Antwerp, James R Baker
    Abstract:

    There have been several reports that TNF-related apoptosis-inducing ligand (TRAIL) has the ability to suppress the development of Experimental Autoimmune diseases, including a mouse model of Experimental Autoimmune encephalomyelitis, a rabbit model of rheumatoid arthritis, type 1 diabetes mellitus, in mice and Experimental Autoimmune Thyroiditis (EAT) in mice. However, the mechanism underlying TRAIL effect is not well defined. In the present study, we specifically examined TRAIL effects on CD4+CD25+ regulatory T cells. CD4+CD25+ T cells prepared from mouse thyroglobulin (mTg)-immunized CBA/J mice proliferate in the presence of TRAIL and dendritic cells in vitro. These CD4+CD25+ T cells included both CD4+CD25+CD45RBLow (regulatory) and CD4+CD25+CD45RBHigh (effector) T cells. Our results demonstrated that mTg-immunized mice treated with TRAIL showed significant increases in the number of CD4+CD25+CD45RBLow T cells compared with mice immunized with mTg alone. CD4+CD25+CD45RBLow T cells expressed much higher ...

  • a unique combination of inflammatory cytokines enhances apoptosis of thyroid follicular cells and transforms nondestructive to destructive Thyroiditis in Experimental Autoimmune Thyroiditis
    Journal of Immunology, 2002
    Co-Authors: Su He Wang, James D Bretz, Ellen Phelps, Emese Mezosi, Patricia Arscott, Saho Utsugi, James R Baker
    Abstract:

    Treatment of cultured primary human thyroid cells with IFN-γ and TNF-α uniquely allows the induction of Fas-mediated apoptosis. To investigate the role of this cytokine combination in vivo, CBA/J mice were immunized with thyroglobulin and then injected with IFN-γ and TNF-α. Compared with control animals, mice treated with IFN-γ and TNF-α showed significantly sustained lymphocytic infiltration in the thyroid, which was associated with the destruction of portions of the follicular architecture at wk 6 after initial immunization. Furthermore, the number of apoptotic thyroid follicular cells was increased only in the thyroids from mice treated with the IFN-γ and TNF-α. We also analyzed the function of the Fas pathway in vivo in cytokine-treated mice by using an agonist anti-Fas Ab injected directly into the thyroid. Minimal apoptosis of thyroid epithelial cells was observed unless the mice were pretreated with IFN-γ and TNF-α. These data demonstrate that this unique combination of inflammatory cytokines facilitates the apoptotic destruction of thyroid follicular cells in Experimental Autoimmune Thyroiditis, in a manner similar to what is observed in Hashimoto’s Thyroiditis in humans.

Chenthamarakshan Vasu - One of the best experts on this subject based on the ideXlab platform.

  • ox40l jagged1 cosignaling by gm csf induced bone marrow derived dendritic cells is required for the expansion of functional regulatory t cells
    Journal of Immunology, 2013
    Co-Authors: Anupama Gopisetty, Chenthamarakshan Vasu, Palash Bhattacharya, Christine Haddad, Joseph C Bruno, Lucio Miele, Bellur S Prabhakar
    Abstract:

    Earlier, we had demonstrated that treatment with low dose of GM-CSF can prevent the development of Experimental Autoimmune Thyroiditis (EAT), Experimental Autoimmune myasthenia gravis, and type 1 diabetes, and could also reverse ongoing EAT and Experimental Autoimmune myasthenia gravis. The protective effect was mediated through the induction of tolerogenic CD11C(+)CD8α(-) dendritic cells (DCs) and consequent expansion of Foxp3(+) regulatory T cells (Tregs). Subsequently, we showed that GM-CSF acted specifically on bone marrow precursors and facilitated their differentiation into tolerogenic dendritic cells (DCs; GM-CSF-induced bone marrow-derived DCs [GM-BMDCs]), which directed Treg expansion in a contact-dependent manner. This novel mechanism of Treg expansion was independent of TCR-mediated signaling but required exogenous IL-2 and cosignaling from DC-bound OX40L. In this study, we observed that OX40L-mediated signaling by GM-BMDCs, although necessary, was not sufficient for Treg expansion and required signaling by Jagged1. Concurrent signaling induced by OX40L and Jagged1 via OX40 and Notch3 receptors expressed on Tregs was essential for the Treg expansion with sustained FoxP3 expression. Adoptive transfer of only OX40L(+)Jagged1(+) BMDCs led to Treg expansion, increased production of IL-4 and IL-10, and suppression of EAT in the recipient mice. These results showed a critical role for OX40L- and Jagged1-induced cosignaling in GM-BMDC-induced Treg expansion.

  • gm csf induced cd11c cd8a dendritic cells facilitate foxp3 and il 10 regulatory t cell expansion resulting in suppression of Autoimmune Thyroiditis
    International Immunology, 2009
    Co-Authors: Balaji B Ganesh, Donald Cheatem, Chenthamarakshan Vasu, Jian Rong Sheng, Bellur S Prabhakar
    Abstract:

    GM-CSF plays an essential role in the differentiation of dendritic cells (DCs). Our studies have shown that GM-CSF treatment can induce semi-mature DCs and CD4+CD25+ regulatory T cells (Tregs) and suppress ongoing autoimmunity in mouse models. In this study, we examined the differences in the potential of GM-CSF to exert tolerogenic function on CD8a+ and CD8a- sub-populations of DCs in vivo. We show that GM-CSF modulates CD8a-, but not CD8a+ DCs in vivo, by inhibiting the surface expression of activation markers MHC II and CD80 and production of inflammatory cytokines such as IL-12 and IL-1beta. Self-antigen [mouse thyroglobulin (mTg)] presentation by GM-CSF-exposed CD8a- DCs to T cells from mTg-primed mice induced a profound increase in the frequency of forkhead box P3 (FoxP3)-expressing T cells compared with antigen presentation by GM-CSF-exposed CD8a+ DCs and control CD8a+ and CD8a- DCs. This tolerogenic property of GM-CD8a- DCs was abrogated when IL-12 was added. GM-CSF-exposed CD8a- DCs could also induce secretion of significantly higher amounts of IL-10 by T cells from mTg-primed mice. Importantly, adoptive transfer of CD8a- DCs from GM-CSF-treated SCID mice, but not untreated mice, into wild-type CBA/J mice prevented the development of Experimental Autoimmune Thyroiditis (EAT) in the recipient animals upon immunization with mTg. Collectively, our results show that GM-CSF renders CD8a- DCs tolerogenic, and these DCs induce Foxp3+ and IL-10+ Tregs.

  • il 10 producing cd4 cd25 regulatory t cells play a critical role in granulocyte macrophage colony stimulating factor induced suppression of Experimental Autoimmune Thyroiditis
    Journal of Immunology, 2005
    Co-Authors: Eryn Gangi, Chenthamarakshan Vasu, Donald Cheatem, Bellur S Prabhakar
    Abstract:

    Our earlier study showed that GM-CSF has the potential not only to prevent, but also to suppress, Experimental Autoimmune Thyroiditis (EAT). GM-CSF-induced EAT suppression in mice was accompanied by an increase in the frequency of CD4 + CD25 + regulatory T cells that could suppress mouse thyroglobulin (mTg)-specific T cell responses in vitro, but the underlying mechanism of this suppression was not elucidated. In this study we show that GM-CSF can induce dendritic cells (DCs) with a semimature phenotype, an important characteristic of DCs, which are known to play a critical role in the induction and maintenance of regulatory T cells. Adoptive transfer of CD4 + CD25 + T cells from GM-CSF-treated and mTg-primed donors into untreated, but mTg-primed, recipients resulted in decreased mTg-specific T cell responses. Furthermore, lymphocytes obtained from these donors and recipients after adoptive transfer produced significantly higher levels of IL-10 compared with mTg-primed, untreated, control mice. Administration of anti-IL-10R Ab into GM-CSF-treated mice abrogated GM-CSF-induced suppression of EAT, as indicated by increased mTg-specific T cell responses, thyroid lymphocyte infiltration, and follicular destruction. Interestingly, in vivo blockade of IL-10R did not affect GM-CSF-induced expansion of CD4 + CD25 + T cells. However, IL-10-induced immunosuppression was due to its direct effects on mTg-specific effector T cells. Taken together, these results indicated that IL-10, produced by CD4 + CD25 + T cells that were probably induced by semimature DCs, is essential for disease suppression in GM-CSF-treated mice.

  • selective induction of dendritic cells using granulocyte macrophage colony stimulating factor but not fms like tyrosine kinase receptor 3 ligand activates thyroglobulin specific cd4 cd25 t cells and suppresses Experimental Autoimmune Thyroiditis
    Journal of Immunology, 2003
    Co-Authors: Chenthamarakshan Vasu, Rukiye Nazan E Dogan, Mark J Holterman, Bellur S Prabhakar
    Abstract:

    fms-like tyrosine kinase receptor 3-ligand (Flt3-L) and GM-CSF cause expansion of different subsets of dendritic cells and skew the immune response toward predominantly Th1 and Th2 type, respectively. In the present study, we investigated their effects on Experimental Autoimmune Thyroiditis in CBA/J mice. Relative to mouse thyroglobulin (mTg) immunized controls, mTg-immunized mice treated with Flt3-L showed more severe Thyroiditis characterized by enhanced lymphocytic infiltration of the thyroid, and IFN-γ and IL-2 production. In contrast, mice treated with GM-CSF, either before or after immunization with mTg, showed suppressed T cell response to mTg and failed to develop Thyroiditis. Lymphocytes from these mice, upon activation with mTg in vitro, produced higher levels of IL-4 and IL-10. Additionally, GM-CSF-treated mice showed an increase in the frequency of CD4+/CD25+ T cells, which suppressed the mTg-specific T cell response. Neutralization of IL-10, but not IL-4, or depletion of CD4+/CD25+ cells resulted in increased mTg-specific in vitro T cell proliferation suggesting that IL-10 produced by the Ag-specific CD4+/CD25+ regulatory T cells might be critical for disease suppression. These results indicate that skewing immune response toward Th2, through selective activation of dendritic cells using GM-CSF, may have therapeutic potential in Th1 dominant Autoimmune diseases including Hashimoto’s Thyroiditis.

  • Targeted engagement of CTLA-4 prevents Autoimmune Thyroiditis
    2003
    Co-Authors: Chenthamarakshan Vasu, Bellur S Prabhakar, Seema R. Gorla, Mark J Holterman
    Abstract:

    The CTLA-4-mediated signal is a critical step in the down-modulation of immune responses. The therapeutic potential of this signal to induce tissue-speci®c tolerance was investigated by using an anti-CTLA-4 antibody that was coupled to an antibody speci®c for the thyrotropin receptor. After in vivo administration, this bispeci®c antibody (BiAb) accumulated in the thyroid and prevented development of Experimental Autoimmune Thyroiditis (EAT) in mice immunized with mouse thyroglobulin (mTg). Lymphocytes from BiAb-treated mice showed a signi®cant reduction in their ability to proliferate, and to produce IL-2, IFN-g and tumor necrosis factor (TNF)-a, in response to mTg re-stimulation compared to lymphocytes from untreated mice. Moreover, BiAb-treated mice showed suppressed anti-mTg antibody response, lymphocytic in®ltration of the thyroid and follicular destruction. The BiAb targeted to the thyroid most likely facilitated engagement of CTLA-4, resulting in an increase in the number of CD4 + CD25 + T cells. These regulatory T cells suppressed in vitro mTg-speci®c T cell responses, which were associated with an enhanced transforming growth factor (TGF)-b1 production. Neutralization of TGF-b1 increased mTg-speci®c in vitro proliferation of, and IL-2 production by, T cells from BiAb-treated mice. Our data suggest that engagement of CTLA-4 expressed on activated autoreactive T cells in close proximity to the thyroid can increase the number of regulatory T cells and their ability to produce TGF-b1, with a concomitant reduction in IFN-g and TNF-a, resulting in suppression of EAT

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Experimental Autoimmune Thyroiditis - 15 days free trial to Access Experts & Abstracts