The effectiveness of a pentop computer when teaching multiplication facts to three middle school students with mild intellectual disabilities was examined. A multiple probe design was used to assess ...the students learning of one and two digit multiplication facts over a 2-3 week intervention period. During the intervention phase, students used a FLYTM Pentop Computer (LeapFrogC) to practice multiplication problems. Following intervention, students were assessed on their ability to solve multiplication problems without the tool. The results indicated that all three students improved in the percentage of correct math facts completed and support the use of the pentop computer when teaching multiplication to students with mild intellectual disabilities. Limitations and suggestions for future research are discussed. (Contains 1 figure and 2 tables.)
Abstract
Full development of IL-17 producing CD4
+
T helper cells (T
H
17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered ...functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in T
H
17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for T
H
17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased T
H
17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3
+
T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human T
H
17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming T
H
17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of T
H
17-mediated autoimmunity.
Abstract
Dysregulated TH17 immune responses have been associated with the pathogenesis of several autoimmune diseases. While full development of TH17 cells requires both nuclear receptors RORα and ...RORγt, most of the work surrounding TH17 cells has focused on the lineage defining transcription factor RORγt. However, TH17 cells are not absent in RORγ−/− mice, suggesting that RORα plays an important role. Despite this, RORα is considered redundant to RORγt and little is known about its function in TH17 cells. The aim of this study was to determine whether RORα played a significant role in TH17 cell development and TH17-driven inflammatory disorders.
Using molecular, genetic, and pharmacological approaches our data suggests that RORα has non-redundant functions to RORγt driving TH17 cell development. Loss or overexpression of RORα in CD4+ T cells significantly decreased or increased IL-17A, respectively, despite no change in RORγt expression. Using two mouse models of autoimmunity known to be TH17 driven experimental autoimmune encephalomyelitis (EAE) and adoptive transfer model of colitis, we found that loss of RORα significantly inhibited the development of EAE and colitis, largely as a consequence of decreased frequencies of pro-inflammatory TH17 cells and increased frequencies of anti-inflammatory Foxp3+ T regulatory cells. Finally, using a RORα-selective small molecule that we developed, we found that modulation of RORα activity significantly inhibited the development of autoimmunity. Our data suggests that RORα plays a non-redundant role to RORγt in TH17 cell development. Studies focusing on assessing RORα activity alone or along with RORγt may lend novel insight into future therapeutic design for TH17-mediated autoimmunity.
Abstract
While RORγt has been well characterized as the lineage defining transcription factor for TH17 cell development, TH17 cells are not absent in Rorc-deficient mice, suggesting other factors may ...be required. RORα, a close family member of RORγt, is also expressed during TH17 cell development but is considered functionally redundant, thus little is known about its function in TH17 cells. Using mouse models of autoimmunity and chronic inflammation, we show that expression of RORα is required for TH17 pathogenicity. T-cell specific deletion of RORα significantly abrogated the development of experimental autoimmune encephalomyelitis (EAE) and colitis, due to decreased development of TH17 cells and expression of homing receptors required for cells to gain access to sites of inflammation. These results were accompanied by increased Foxp3+T regulatory cells. Using a RORα-selective small molecule that we developed, we found that modulation of RORα activity largely phenocopied our genetic data, inhibiting the development of EAE, colitis, and relapse in a relapsing remitting model of multiple sclerosis. Importantly, treatment with a RORα modulator did not affect thymic cellularity. Finally, modulation of RORα activity inhibited the development of human TH17 cells and pro-inflammatory cytokine expression from subsets of CD4+CCR6+memory T cells. Our results establish that RORα has non-redundant functions to RORγt driving TH17 cell development and identifies RORα as a potential therapeutic target for the treatment of TH17-mediated autoimmunity.
Full development of IL-17 producing CD4
T helper cells (T
17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally ...redundant to RORγt; therefore, the function and therapeutic value of RORα in T
17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for T
17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased T
17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3
T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human T
17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming T
17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of T
17-mediated autoimmunity.
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