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There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.
Jide Tian; Blake Middleton; Daniel Kaufman. GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice. Viruses 2021, 13, 966 .
AMA StyleJide Tian, Blake Middleton, Daniel Kaufman. GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice. Viruses. 2021; 13 (6):966.
Chicago/Turabian StyleJide Tian; Blake Middleton; Daniel Kaufman. 2021. "GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice." Viruses 13, no. 6: 966.
Most multiple sclerosis (MS) patients given currently available disease-modifying drugs (DMDs) experience progressive disability. Accordingly, there is a need for new treatments that can limit the generation of new waves T cell autoreactivity that drive disease progression. Notably, immune cells express GABAA-receptors (GABAA-Rs) whose activation has anti-inflammatory effects such that GABA administration can ameliorate disease in models of type 1 diabetes, rheumatoid arthritis, and COVID-19. Here, we show that oral GABA, which cannot cross the blood–brain barrier (BBB), does not affect the course of murine experimental autoimmune encephalomyelitis (EAE). In contrast, oral administration of the BBB-permeable GABAA-R-specific agonist homotaurine ameliorates monophasic EAE, as well as advanced-stage relapsing–remitting EAE (RR-EAE). Homotaurine treatment beginning after the first peak of paralysis reduced the spreading of Th17 and Th1 responses from the priming immunogen to a new myelin T cell epitope within the CNS. Antigen-presenting cells (APC) isolated from homotaurine-treated mice displayed an attenuated ability to promote autoantigen-specific T cell proliferation. The ability of homotaurine treatment to limit epitope spreading within the CNS, along with its safety record, makes it an excellent candidate to help treat MS and other inflammatory disorders of the CNS.
Jide Tian; Min Song; Daniel L. Kaufman. Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis. Scientific Reports 2021, 11, 1 -8.
AMA StyleJide Tian, Min Song, Daniel L. Kaufman. Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis. Scientific Reports. 2021; 11 (1):1-8.
Chicago/Turabian StyleJide Tian; Min Song; Daniel L. Kaufman. 2021. "Homotaurine limits the spreading of T cell autoreactivity within the CNS and ameliorates disease in a model of multiple sclerosis." Scientific Reports 11, no. 1: 1-8.
Despite the availability of vaccines for COVID-19, serious illness and death induced by coronavirus infection will remain a global health burden because of vaccination hesitancy, possible virus mutations, and the appearance of novel coronaviruses. Accordingly, there is a need for new approaches to limit severe illness stemming from coronavirus infections. Cells of the immune system and lung epithelia express receptors for GABA (GABA-Rs), a widely used neurotransmitter within the CNS. GABA-R agonists have anti-inflammatory effects and can limit acute lung injury. We previously showed that GABA treatment effectively reduced disease severity and death rates in mice following infection with a coronavirus (MHV-1) which provides a potentially lethal model of COVID-19. Here, we report that GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit pulmonary coronavirus replication. Histopathological analysis revealed that GABA treatment reduced lung inflammatory infiltrates and damages. Since GABA is safe for human consumption, inexpensive, and available worldwide, it is a promising candidate to help treat COVID-19.
Jide Tian; Blake Middleton; Daniel L. Kaufman. GABA administration limits viral replication and pneumonitis in a mouse model of COVID-19. 2021, 1 .
AMA StyleJide Tian, Blake Middleton, Daniel L. Kaufman. GABA administration limits viral replication and pneumonitis in a mouse model of COVID-19. . 2021; ():1.
Chicago/Turabian StyleJide Tian; Blake Middleton; Daniel L. Kaufman. 2021. "GABA administration limits viral replication and pneumonitis in a mouse model of COVID-19." , no. : 1.
Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit β-cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.
Jide Tian; Blake Middleton; Victoria Seunghee Lee; Hye Won Park; Zhixuan Zhang; Bokyoung Kim; Catherine Lowe; Nancy Nguyen; Haoyuan Liu; Ryan S. Beyer; Hannah W. Chao; Ryan Chen; Davis Mai; Karen Anne O’Laco; Min Song; Daniel L. Kaufman. GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice. Biomedicines 2021, 9, 43 .
AMA StyleJide Tian, Blake Middleton, Victoria Seunghee Lee, Hye Won Park, Zhixuan Zhang, Bokyoung Kim, Catherine Lowe, Nancy Nguyen, Haoyuan Liu, Ryan S. Beyer, Hannah W. Chao, Ryan Chen, Davis Mai, Karen Anne O’Laco, Min Song, Daniel L. Kaufman. GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice. Biomedicines. 2021; 9 (1):43.
Chicago/Turabian StyleJide Tian; Blake Middleton; Victoria Seunghee Lee; Hye Won Park; Zhixuan Zhang; Bokyoung Kim; Catherine Lowe; Nancy Nguyen; Haoyuan Liu; Ryan S. Beyer; Hannah W. Chao; Ryan Chen; Davis Mai; Karen Anne O’Laco; Min Song; Daniel L. Kaufman. 2021. "GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice." Biomedicines 9, no. 1: 43.
There is an urgent need for new treatments to prevent and ameliorate severe illness and death induced by SARS-CoV-2 infection in COVID-19 patients. The coronavirus mouse hepatitis virus (MHV)-1 causes pneumonitis in mice which shares many pathological characteristics with human SARS-CoV infection. Previous studies have shown that the amino acid gamma-aminobutyric acid (GABA) has anti-inflammatory effects. We tested whether oral treatment with GABA could modulate the MHV-1 induced pneumonitis in susceptible A/J mice. As expected, MHV-1-inoculated control mice became severely ill (as measured by weight loss, clinical score, and the ratio of lung weight to body weight) and >60% of them succumbed to the infection. In contrast, mice that received GABA immediately after MHV-1 inoculation became only mildly ill and all of them recovered. When GABA treatment was initiated after the appearance of illness (3 days post-MHV-1 infection), we again observed that GABA treatment significantly reduced the severity of illness and greatly increased the frequency of recovery. Therefore, the engagement of GABA receptors (GABA-Rs) prevented the MHV-1 infection-induced severe pneumonitis and death in mice. Given that GABA-R agonists, like GABA and homotaurine, are safe for human consumption, stable, inexpensive, and available worldwide, they are promising candidates to help prevent severe illness stemming from SARS-CoV-2 infection and other coronavirus strains.
Jide Tian; Blake Milddleton; Daniel L. Kaufman. GABA administration prevents severe illness and death following coronavirus infection in mice. 2020, 1 .
AMA StyleJide Tian, Blake Milddleton, Daniel L. Kaufman. GABA administration prevents severe illness and death following coronavirus infection in mice. . 2020; ():1.
Chicago/Turabian StyleJide Tian; Blake Milddleton; Daniel L. Kaufman. 2020. "GABA administration prevents severe illness and death following coronavirus infection in mice." , no. : 1.
Immune cells express γ-aminobutyric acid receptors (GABA-R), and GABA administration can inhibit effector T cell responses in models of autoimmune disease. The pharmacokinetic properties of GABA, however, may be suboptimal for clinical applications. The amino acid homotaurine is a type A GABA-R (GABAA-R) agonist with good pharmacokinetics and appears safe for human consumption. In this study, we show that homotaurine inhibits in vitro T cell proliferation to a similar degree as GABA but at lower concentrations. In vivo, oral homotaurine treatment had a modest ability to reverse hyperglycemia in newly hyperglycemic NOD mice but was ineffective after the onset of severe hyperglycemia. In severely diabetic NOD mice, the combination of homotaurine and low-dose anti-CD3 treatment significantly increased 1) disease remission, 2) the percentages of splenic CD4+and CD8+ regulatory T cells compared with anti-CD3 alone, and 3) the frequencies of CD4+ and CD8+ regulatory T cells in the pancreatic lymph nodes compared with homotaurine monotherapy. Histological examination of their pancreata provided no evidence of the large-scale GABAA-R agonist–mediated replenishment of islet β-cells that has been reported by others. However, we did observe a few functional islets in mice that received combined therapy. Thus, GABAA-R activation enhanced CD4+and CD8+ regulatory T cell responses following the depletion of effector T cells, which was associated with the preservation of some functional islets. Finally, we observed that homotaurine treatment enhanced β-cell replication and survival in a human islet xenograft model. Hence, GABAA-R agonists, such as homotaurine, are attractive candidates for testing in combination with other therapeutic agents in type 1 diabetes clinical trials.
Jide Tian; Hoa Dang; Karen Anne O’Laco; Min Song; Bryan-Clement Tiu; Spencer Gilles; Christina Zakarian; Daniel L. Kaufman. Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice. ImmunoHorizons 2019, 3, 498 -510.
AMA StyleJide Tian, Hoa Dang, Karen Anne O’Laco, Min Song, Bryan-Clement Tiu, Spencer Gilles, Christina Zakarian, Daniel L. Kaufman. Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice. ImmunoHorizons. 2019; 3 (10):498-510.
Chicago/Turabian StyleJide Tian; Hoa Dang; Karen Anne O’Laco; Min Song; Bryan-Clement Tiu; Spencer Gilles; Christina Zakarian; Daniel L. Kaufman. 2019. "Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice." ImmunoHorizons 3, no. 10: 498-510.
There has been considerable debate as to whether obesity can act as an accelerator of type 1 diabetes (T1D). We assessed this possibility using transgenic mice (MIP-TF mice) whose ß-cells express enhanced green fluorescent protein (EGFP). Infecting these mice with EGFP-expressing murine herpes virus-68 (MHV68-EGFP) caused occasional transient elevation in their blood glucose, peri-insulitis, and Th1 responses to EGFP which did not spread to other ß-cell antigens. We hypothesized that obesity-related systemic inflammation and ß-cell stress could exacerbate the MHV68-EGFP-induced ß-cell autoreactivity. We crossed MIP-TF mice with Avy mice which develop obesity and provide models of metabolic disease alongside early stage T2D. Unlike their MIP-TF littermates, MHV68-EGFP-infected Avy/MIP-TF mice developed moderate intra-insulitis and transient hyperglycemia. MHV68-EGFP infection induced a more pronounced intra-insulitis in older, more obese, Avy/MIP-TF mice. Moreover, in MHV68-EGFP-infected Avy/MIP-TF mice, Th1 reactivity spread from EGFP to other ß-cell antigens. Thus, the spreading of autoreactivity among ß-cell antigens corresponded with the transition from peri-insulitis to intra-insulitis and occurred in obese Avy/MIP-TF mice but not lean MIP-TF mice. These observations are consistent with the notion that obesity-associated systemic inflammation and ß-cell stress lowers the threshold necessary for T cell autoreactivity to spread from EGFP to other ß-cell autoantigens.
Jing Yong; Jide Tian; Hoa Dang; Ting-Ting Wu; Mark A. Atkinson; Ren Sun; Daniel L. Kaufman. Increased risk for T cell autoreactivity to ß-cell antigens in the mice expressing the Avy obesity-associated gene. Scientific Reports 2019, 9, 4269 .
AMA StyleJing Yong, Jide Tian, Hoa Dang, Ting-Ting Wu, Mark A. Atkinson, Ren Sun, Daniel L. Kaufman. Increased risk for T cell autoreactivity to ß-cell antigens in the mice expressing the Avy obesity-associated gene. Scientific Reports. 2019; 9 (1):4269.
Chicago/Turabian StyleJing Yong; Jide Tian; Hoa Dang; Ting-Ting Wu; Mark A. Atkinson; Ren Sun; Daniel L. Kaufman. 2019. "Increased risk for T cell autoreactivity to ß-cell antigens in the mice expressing the Avy obesity-associated gene." Scientific Reports 9, no. 1: 4269.
A major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat β-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote β-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased β-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from β-cells to increase β-cell survival and replication. Treatment with both the PAM and GABA further enhanced human β-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process.
Jide Tian; Hoa Dang; Nataliya Karashchuk; Irvin Xu; Daniel L. Kaufman. A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells. Journal of Diabetes Research 2019, 2019, 1 -7.
AMA StyleJide Tian, Hoa Dang, Nataliya Karashchuk, Irvin Xu, Daniel L. Kaufman. A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells. Journal of Diabetes Research. 2019; 2019 ():1-7.
Chicago/Turabian StyleJide Tian; Hoa Dang; Nataliya Karashchuk; Irvin Xu; Daniel L. Kaufman. 2019. "A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells." Journal of Diabetes Research 2019, no. : 1-7.
There is a need for treatments that can safely promote regulatory lymphocyte responses. T cells express GABA receptors (GABAA-Rs) and GABA administration can inhibit Th1-mediated processes such as type 1 diabetes and rheumatoid arthritis in mouse models. Whether GABAA-R agonists can also inhibit Th17-driven processes such as experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), is an open question. GABA does not pass through the blood-brain barrier (BBB) making it ill-suited to inhibit the spreading of autoreactivity within the CNS. Homotaurine is a BBB-permeable amino acid that antagonizes amyloid fibril formation and was found to be safe but ineffective in long-term Alzheimer’s disease clinical trials. Homotaurine also acts as GABAA-R agonist with better pharmacokinetics than that of GABA. Working with both monophasic and relapsing-remitting mouse models of EAE, we show that oral administration of homotaurine can (1) enhance CD8+CD122+PD-1+ and CD4+Foxp3+ Treg, but not Breg, responses, (2) inhibit autoreactive Th17 and Th1 responses, and (3) effectively ameliorate ongoing disease. These observations demonstrate the potential of BBB-permeable GABAA-R agonists as a new class of treatment to enhance CD8+ and CD4+ Treg responses and limit Th17 and Th1-medaited inflammation in the CNS.
Jide Tian; Hoa Dang; Martin Wallner; Richard Olsen; Daniel L. Kaufman. Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis. Scientific Reports 2018, 8, 1 -8.
AMA StyleJide Tian, Hoa Dang, Martin Wallner, Richard Olsen, Daniel L. Kaufman. Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis. Scientific Reports. 2018; 8 (1):1-8.
Chicago/Turabian StyleJide Tian; Hoa Dang; Martin Wallner; Richard Olsen; Daniel L. Kaufman. 2018. "Homotaurine, a safe blood-brain barrier permeable GABAA-R-specific agonist, ameliorates disease in mouse models of multiple sclerosis." Scientific Reports 8, no. 1: 1-8.
The activation ofβ-cell’s A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs) can promote their survival and replication, and the activation ofα-cell GABAA-Rs promotes their conversion intoβ-cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptimal for the long-term treatment of diabetes due to their pharmacological properties or potential side-effects on the central nervous system (CNS). Lesogaberan (AZD3355) is a peripherally restricted high-affinity GABAB-R-specific agonist, originally developed for the treatment of gastroesophageal reflux disease (GERD) that appears to be safe for human use. This study tested the hypothesis that lesogaberan could be repurposed to promote human islet cell survival andβ-cell replication.Treatment with lesogaberan significantly enhanced replication of human islet cellsin vitro, which was abrogated by a GABAB-R antagonist. Immunohistochemical analysis of human islets that were grafted into immune-deficient mice revealed that oral treatment with lesogaberan promoted humanβ-cell replication and islet cell survivalin vivoas effectively as GABA (which activates both GABAA-Rs and GABAB-Rs), perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation.
Jide Tian; Hoa Dang; Angela Hu; Willem Xu; Daniel L. Kaufman. Repurposing Lesogaberan to Promote Human Islet Cell Survival andβ-Cell Replication. Journal of Diabetes Research 2017, 2017, 1 -7.
AMA StyleJide Tian, Hoa Dang, Angela Hu, Willem Xu, Daniel L. Kaufman. Repurposing Lesogaberan to Promote Human Islet Cell Survival andβ-Cell Replication. Journal of Diabetes Research. 2017; 2017 ():1-7.
Chicago/Turabian StyleJide Tian; Hoa Dang; Angela Hu; Willem Xu; Daniel L. Kaufman. 2017. "Repurposing Lesogaberan to Promote Human Islet Cell Survival andβ-Cell Replication." Journal of Diabetes Research 2017, no. : 1-7.
A key goal of diabetes research is to develop treatments to safely promote human ß-cell replication. It has recently become appreciated that activation of γ-aminobutyric acid receptors (GABA-Rs) on ß-cells can promote their survival and replication. A number of positive allosteric modulators (PAMs) that enhance GABA's actions on neuronal GABAA-Rs are in clinical use. Repurposing these GABAA-R PAMs to help treat diabetes is theoretically appealing because of their safety and potential to enhance the ability of GABA, secreted from ß-cells, or exogenously administered, to promote ß-cell replication and survival. Here, we show that clinically applicable GABAA-R PAMs can increase significantly INS-1 ß-cell replication, which is enhanced by exogenous GABA application. Furthermore, a GABAA-R PAM promoted human islet cell replication in vitro. This effect was abrogated by a GABAA-R antagonist. The combination of a PAM and low levels of exogenous GABA further increased human islet cell replication. These findings suggest that PAMs may potentiate the actions of GABA secreted by islet ß-cells on GABAA-Rs and provide a new class of drugs for diabetes treatment. Finally, our findings may explain a past clinical observation of a GABAA-R PAM reducing HbA1c levels in diabetic patients.
Jide Tian; Hoa Dang; Blake Middleton; Daniel L. Kaufman. Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication. Scientific Reports 2017, 7, 374 .
AMA StyleJide Tian, Hoa Dang, Blake Middleton, Daniel L. Kaufman. Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication. Scientific Reports. 2017; 7 (1):374.
Chicago/Turabian StyleJide Tian; Hoa Dang; Blake Middleton; Daniel L. Kaufman. 2017. "Clinically applicable GABA receptor positive allosteric modulators promote ß-cell replication." Scientific Reports 7, no. 1: 374.
Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic NOD mice, perhaps because too few β-cells remain by the time that ABT-induced regulatory responses arise and spread. We hypothesized that combining a fast-acting anti-inflammatory agent with an ABT could limit pathogenic responses while ABT-induced regulatory responses arose and spread. γ-Aminobutyric acid (GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg) responses, and promote β-cell replication in mice. We examined the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia, while GABA monotherapy restored normoglycemia for a short period. Combined treatment restored normoglycemia in the long term with apparent permanent remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4- and IL-10-secreting T-cell responses that spread to other β-cell autoantigens. GABA monotherapy induced moderate IL-10 (but not IL-4) responses to β-cell autoantigens. Combined treatment synergistically reduced spontaneous type 1 T-helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses, and insulitis, but enhanced IL-10 and Treg responses and promoted β-cell replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic T-cell responses, induce Treg responses, promote β-cell replication, and effectively restore normoglycemia in newly diabetic NOD mice. Since these treatments appear safe for humans, they hold promise for type 1 diabetes intervention.
Jide Tian; Hoa Dang; An Viet Nguyen; Zheying Chen; Daniel L. Kaufman. Combined Therapy With GABA and Proinsulin/Alum Acts Synergistically to Restore Long-term Normoglycemia by Modulating T-Cell Autoimmunity and Promoting -Cell Replication in Newly Diabetic NOD Mice. Diabetes 2014, 63, 3128 -3134.
AMA StyleJide Tian, Hoa Dang, An Viet Nguyen, Zheying Chen, Daniel L. Kaufman. Combined Therapy With GABA and Proinsulin/Alum Acts Synergistically to Restore Long-term Normoglycemia by Modulating T-Cell Autoimmunity and Promoting -Cell Replication in Newly Diabetic NOD Mice. Diabetes. 2014; 63 (9):3128-3134.
Chicago/Turabian StyleJide Tian; Hoa Dang; An Viet Nguyen; Zheying Chen; Daniel L. Kaufman. 2014. "Combined Therapy With GABA and Proinsulin/Alum Acts Synergistically to Restore Long-term Normoglycemia by Modulating T-Cell Autoimmunity and Promoting -Cell Replication in Newly Diabetic NOD Mice." Diabetes 63, no. 9: 3128-3134.
γ-Aminobutyric acid (GABA) has been shown to inhibit apoptosis of rodent β-cells in vitro. In this study, we show that activation of GABAA receptors (GABAA-Rs) or GABAB-Rs significantly inhibits oxidative stress–related β-cell apoptosis and preserves pancreatic β-cells in streptozotocin-rendered hyperglycemic mice. Moreover, treatment with GABA, or a GABAA-R– or GABAB-R–specific agonist, inhibited human β-cell apoptosis following islet transplantation into NOD/scid mice. Accordingly, activation of GABAA-Rs and/or GABAB-Rs may be a useful adjunct therapy for human islet transplantation. GABA-R agonists also promoted β-cell replication in hyperglycemic mice. While a number of agents can promote rodent β-cell replication, most fail to provide similar activities with human β-cells. In this study, we show that GABA administration promotes β-cell replication and functional recovery in human islets following implantation into NOD/scid mice. Human β-cell replication was induced by both GABAA-R and GABAB-R activation. Hence, GABA regulates both the survival and replication of human β-cells. These actions, together with the anti-inflammatory properties of GABA, suggest that modulation of peripheral GABA-Rs may represent a promising new therapeutic strategy for improving β-cell survival following human islet transplantation and increasing β-cells in patients with diabetes.
Jide Tian; Hoa Dang; Zheying Chen; Alice Guan; Yingli Jin; Mark A. Atkinson; Daniel L. Kaufman. -Aminobutyric Acid Regulates Both the Survival and Replication of Human -Cells. Diabetes 2013, 62, 3760 -3765.
AMA StyleJide Tian, Hoa Dang, Zheying Chen, Alice Guan, Yingli Jin, Mark A. Atkinson, Daniel L. Kaufman. -Aminobutyric Acid Regulates Both the Survival and Replication of Human -Cells. Diabetes. 2013; 62 (11):3760-3765.
Chicago/Turabian StyleJide Tian; Hoa Dang; Zheying Chen; Alice Guan; Yingli Jin; Mark A. Atkinson; Daniel L. Kaufman. 2013. "-Aminobutyric Acid Regulates Both the Survival and Replication of Human -Cells." Diabetes 62, no. 11: 3760-3765.
We previously showed that, in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), vaccination with bacillus Calmette‐Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination's neuroprotective effects in this model. We found that a dose of 1 × 106 cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG‐vaccinated vs. unvaccinated MPTP‐treated mice, but without a significant increase in substantia nigra tyrosine hydroxylase‐staining neurons. Previous studies showed that BCG can induce regulatory T cells (Tregs) and that Tregs are neuroprotective in models of neurodegenerative diseases. However, MPTP is lymphotoxic, so it was unclear whether Tregs were maintained after MPTP treatment and whether a relationship existed between Tregs and the preservation of striatal DA system integrity. We found that, 21 days post‐MPTP treatment, Treg levels in mice that had received BCG prior to MPTP were threefold greater than those in MPTP‐only‐treated mice and elevated above those in saline‐only‐treated mice, suggesting that the persistent BCG infection continually promoted Treg responses. Notably, the magnitude of the Treg response correlated positively with both striatal DA levels and DAT ligand binding. Therefore, BCG vaccine‐mediated neuroprotection is associated with Treg levels in this mouse model. Our results suggest that BCG‐induced Tregs could provide a new adjunctive therapeutic approach to ameliorating pathology associated with PD and other neurodegenerative diseases.
Goran Laćan; Hoa Dang; Blake Middleton; Marcus A. Horwitz; Jide Tian; William P. Melega; Daniel L. Kaufman. Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Journal of Neuroscience Research 2013, 91, 1292 -1302.
AMA StyleGoran Laćan, Hoa Dang, Blake Middleton, Marcus A. Horwitz, Jide Tian, William P. Melega, Daniel L. Kaufman. Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Journal of Neuroscience Research. 2013; 91 (10):1292-1302.
Chicago/Turabian StyleGoran Laćan; Hoa Dang; Blake Middleton; Marcus A. Horwitz; Jide Tian; William P. Melega; Daniel L. Kaufman. 2013. "Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease." Journal of Neuroscience Research 91, no. 10: 1292-1302.
We studied cultured hippocampal neurons from embryonic wildtype, major histocompatibility complex class I (MHCI) heavy chain-deficient (KbDb−/−) and NSE-Db (which have elevated neuronal MHCI expression) C57BL/6 mice. KbDb−/− neurons displayed slower neuritogenesis and establishment of polarity, while NSE-Db neurons had faster neurite outgrowth, more primary neurites, and tended to have accelerated polarization. Additional studies with ß2M−/− neurons, exogenous ß2M, and a self-MHCI monomer suggest that free heavy chain cis interactions with other surface molecules can promote neuritogenesis while tripartite MHCI interactions with classical MHCI receptors can inhibit axon outgrowth. Together with the results of others, MHCI appears to differentially modulate neuritogenesis and synaptogenesis.
Tina Bilousova; Hoa Dang; Willem Xu; Sarah Gustafson; Yingli Jin; Lalinda Wickramasinghe; Tony Won; Gabriela Bobarnac; Blake Middleton; Jide Tian; Daniel L. Kaufman. Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization. Journal of Neuroimmunology 2012, 247, 1 -8.
AMA StyleTina Bilousova, Hoa Dang, Willem Xu, Sarah Gustafson, Yingli Jin, Lalinda Wickramasinghe, Tony Won, Gabriela Bobarnac, Blake Middleton, Jide Tian, Daniel L. Kaufman. Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization. Journal of Neuroimmunology. 2012; 247 (1):1-8.
Chicago/Turabian StyleTina Bilousova; Hoa Dang; Willem Xu; Sarah Gustafson; Yingli Jin; Lalinda Wickramasinghe; Tony Won; Gabriela Bobarnac; Blake Middleton; Jide Tian; Daniel L. Kaufman. 2012. "Major histocompatibility complex class I molecules modulate embryonic neuritogenesis and neuronal polarization." Journal of Neuroimmunology 247, no. 1: 1-8.
Antigen-based therapies (ABTs) very effectively prevent the development of type 1 diabetes (T1D) when given to young nonobese diabetic (NOD) mice, however, they have little or no ability to reverse hyperglycemia in newly diabetic NOD mice. More importantly, ABTs have not yet demonstrated an ability to effectively preserve residual ß-cells in individuals newly diagnosed with type 1 diabetes (T1D). Accordingly, there is great interest in identifying new treatments that can be combined with ABTs to safely protect ß-cells in diabetic animals. The activation of γ-aminobutyric acid (GABA) receptors (GABA-Rs) on immune cells has been shown to prevent T1D, experimental autoimmune encephalomyelitis (EAE) and rheumatoid arthritis in mouse models. Based on GABA's ability to inhibit different autoimmune diseases and its safety profile, we tested whether the combination of ABT with GABA treatment could prolong the survival of transplanted ß-cells in newly diabetic NOD mice. Newly diabetic NOD mice were untreated, or given GAD/alum (20 or 100 µg) and placed on plain drinking water, or water containing GABA (2 or 6 mg/ml). Twenty-eight days later, they received syngenic pancreas grafts and were monitored for the recurrence of hyperglycemia. Hyperglycemia reoccurred in the recipients given plain water, GAD monotherapy, GABA monotherapy, GAD (20 µg)+GABA (2 mg/ml), GAD (20 µg)+GABA (6 mg/ml) and GAD (100 µg)+GABA (6 mg/ml) about 1, 2-3, 3, 2-3, 3-8 and 10-11 weeks post-transplantation, respectively. Thus, combined GABA and ABT treatment had a synergistic effect in a dose-dependent fashion. These findings suggest that co-treatment with GABA (or other GABA-R agonists) may provide a new strategy to safely enhance the efficacy of other therapeutics designed to prevent or reverse T1D, as well as other T cell-mediated autoimmune diseases.
Jide Tian; Hoa Dang; Daniel L. Kaufman. Combining Antigen-Based Therapy with GABA Treatment Synergistically Prolongs Survival of Transplanted ß-Cells in Diabetic NOD Mice. PLOS ONE 2011, 6, e25337 .
AMA StyleJide Tian, Hoa Dang, Daniel L. Kaufman. Combining Antigen-Based Therapy with GABA Treatment Synergistically Prolongs Survival of Transplanted ß-Cells in Diabetic NOD Mice. PLOS ONE. 2011; 6 (9):e25337.
Chicago/Turabian StyleJide Tian; Hoa Dang; Daniel L. Kaufman. 2011. "Combining Antigen-Based Therapy with GABA Treatment Synergistically Prolongs Survival of Transplanted ß-Cells in Diabetic NOD Mice." PLOS ONE 6, no. 9: e25337.
The neurobiological activities of classical major histocompatibility class I (MHCI) molecules are just beginning to be explored. To further examine MHCI's actions during the formation of neuronal connections, we cultured embryonic mouse retina explants a short distance from wildtype thalamic explants, or thalami from transgenic mice (termed “NSE-Db”) whose neurons express higher levels of MHCI. While retina neurites extended to form connections with wildtype thalami, we were surprised to find that retina neurite outgrowth was very stunted in regions proximal to NSE-Db thalamic explants, suggesting that a diffusible factor from these thalami inhibited retina neurite outgrowth. It has been long known that MHCI-expressing cells release soluble forms of MHCI (sMHCI) due to the shedding of intact MHCI molecules, as well as the alternative exon splicing of its heavy chain or the action proteases which cleave off it's transmembrane anchor. We show that the diffusible inhibitory factor from the NSE-Db thalami is sMHCI. We also show that COS cells programmed to express murine MHCI release sMHCI that inhibits neurite outgrowth from nearby neurons in vitro. The neuroinhibitory effect of sMHCI could be blocked by lowering cAMP levels, suggesting that the neuronal MHCI receptor's signaling mechanism involves a cyclic nucleotide-dependent pathway. Our results suggest that MHCI may not only have neurobiological activity in its membrane-bound form, it may also influence local neurons as a soluble molecule. We discuss the involvement of complement proteins in generating sMHCI and new theoretical models of MHCI's biological activities in the nervous system.
Lorraine R. Washburn; Dan Zekzer; Shoshana Eitan; Yuxin Lu; Hoa Dang; Blake Middleton; Christopher J. Evans; Jide Tian; Daniel L. Kaufman. A Potential Role for Shed Soluble Major Histocompatibility Class I Molecules as Modulators of Neurite Outgrowth. PLOS ONE 2011, 6, e18439 .
AMA StyleLorraine R. Washburn, Dan Zekzer, Shoshana Eitan, Yuxin Lu, Hoa Dang, Blake Middleton, Christopher J. Evans, Jide Tian, Daniel L. Kaufman. A Potential Role for Shed Soluble Major Histocompatibility Class I Molecules as Modulators of Neurite Outgrowth. PLOS ONE. 2011; 6 (3):e18439.
Chicago/Turabian StyleLorraine R. Washburn; Dan Zekzer; Shoshana Eitan; Yuxin Lu; Hoa Dang; Blake Middleton; Christopher J. Evans; Jide Tian; Daniel L. Kaufman. 2011. "A Potential Role for Shed Soluble Major Histocompatibility Class I Molecules as Modulators of Neurite Outgrowth." PLOS ONE 6, no. 3: e18439.
Studies of mice deficient in classical major histocompatability complex class I (MHCI) revealed that MHCI plays an important role in neurodevelopment in the central nervous system. We previously studied the effects of recombinant MHCI molecules on wildtype retina explants and observed that MHCI can inhibit retina neurite outgrowth, with self-MHCI molecules having greater inhibitory effect than non-self MHCI molecules. Here, we examined classical MHCI's effects on axon outgrowth from neurons of the peripheral nervous system (PNS). We used the embryonic dorsal root ganglia (DRG) explant model since their neurons express MHCI and because DRG explants have been widely used to assess the effects of molecules on axonal outgrowth from PNS neurons. We observed that picomolar levels of a recombinant self-MHCI molecule, but not non-self MHCI molecules, inhibited axon outgrowth from DRG explants. This differential sensitivity to self- vs. non-self MHCI suggests that early in development, self-MHCI may “educate” PNS neurons to express appropriate MHCI receptors, as occurs during natural killer cell development. Furthermore, we observed that a MHCI tetramer stained embryonic DRG neurons, indicating the expression of classical MHCI receptors. These results suggest that MHCI and MHCI receptors play roles during early stages of PNS development and may provide new targets of therapeutic strategies to promote neuronal outgrowth after PNS injury.
Zhongqi-Phyllis Wu; Tina Bilousova; Nathalie Escande-Beillard; Hoa Dang; Terry Hsieh; Jide Tian; Daniel L. Kaufman. Major histocompatibility complex class I-mediated inhibition of neurite outgrowth from peripheral nerves. Immunology Letters 2011, 135, 118 -123.
AMA StyleZhongqi-Phyllis Wu, Tina Bilousova, Nathalie Escande-Beillard, Hoa Dang, Terry Hsieh, Jide Tian, Daniel L. Kaufman. Major histocompatibility complex class I-mediated inhibition of neurite outgrowth from peripheral nerves. Immunology Letters. 2011; 135 (1-2):118-123.
Chicago/Turabian StyleZhongqi-Phyllis Wu; Tina Bilousova; Nathalie Escande-Beillard; Hoa Dang; Terry Hsieh; Jide Tian; Daniel L. Kaufman. 2011. "Major histocompatibility complex class I-mediated inhibition of neurite outgrowth from peripheral nerves." Immunology Letters 135, no. 1-2: 118-123.
OBJECTIVE β-Cells that express an imaging reporter have provided powerful tools for studying β-cell development, islet transplantation, and β-cell autoimmunity. To further expedite diabetes research, we generated transgenic C57BL/6 “MIP-TF” mice that have a mouse insulin promoter (MIP) driving the expression of a trifusion (TF) protein of three imaging reporters (luciferase/enhanced green fluorescent protein/HSV1-sr39 thymidine kinase) in their β-cells. This should enable the noninvasive imaging of β-cells by charge-coupled device (CCD) and micro-positron emission tomography (PET), as well as the identification of β-cells at the cellular level by fluorescent microscopy. RESEARCH DESIGN AND METHODS MIP-TF mouse β-cells were multimodality imaged in models of type 1 and type 2 diabetes. RESULTS MIP-TF mouse β-cells were readily identified in pancreatic tissue sections using fluorescent microscopy. We show that MIP-TF β-cells can be noninvasively imaged using microPET. There was a correlation between CCD and microPET signals from the pancreas region of individual mice. After low-dose streptozotocin administration to induce type 1 diabetes, we observed a progressive reduction in bioluminescence from the pancreas region before the appearance of hyperglycemia. Although there have been reports of hyperglycemia inducing proinsulin expression in extrapancreatic tissues, we did not observe bioluminescent signals from extrapancreatic tissues of diabetic MIP-TF mice. Because MIP-TF mouse β-cells express a viral thymidine kinase, ganciclovir treatment induced hyperglycemia, providing a new experimental model of type 1 diabetes. Mice fed a high-fat diet to model early type 2 diabetes displayed a progressive increase in their pancreatic bioluminescent signals, which were positively correlated with area under the curve–intraperitoneal glucose tolerance test (AUC-IPGTT). CONCLUSIONS MIP-TF mice provide a new tool for monitoring β-cells from the single cell level to noninvasive assessments of β-cells in models of type 1 diabetes and type 2 diabetes.
Jing Yong; Julia Rasooly; Hoa Dang; Yuxin Lu; Blake Middleton; Zesong Zhang; Larry Hon; Mohammad Namavari; David B. Stout; Mark A. Atkinson; Jide Tian; Sanjiv Sam Gambhir; Daniel L. Kaufman. Multimodality Imaging of -Cells in Mouse Models of Type 1 and 2 Diabetes. Diabetes 2011, 60, 1383 -1392.
AMA StyleJing Yong, Julia Rasooly, Hoa Dang, Yuxin Lu, Blake Middleton, Zesong Zhang, Larry Hon, Mohammad Namavari, David B. Stout, Mark A. Atkinson, Jide Tian, Sanjiv Sam Gambhir, Daniel L. Kaufman. Multimodality Imaging of -Cells in Mouse Models of Type 1 and 2 Diabetes. Diabetes. 2011; 60 (5):1383-1392.
Chicago/Turabian StyleJing Yong; Julia Rasooly; Hoa Dang; Yuxin Lu; Blake Middleton; Zesong Zhang; Larry Hon; Mohammad Namavari; David B. Stout; Mark A. Atkinson; Jide Tian; Sanjiv Sam Gambhir; Daniel L. Kaufman. 2011. "Multimodality Imaging of -Cells in Mouse Models of Type 1 and 2 Diabetes." Diabetes 60, no. 5: 1383-1392.
Current treatments for rheumatoid arthritis (RA) have long-term side effects such that new treatments are needed that can safely help manage the disease. There is a growing appreciation that GABA receptors (GABA-Rs) on immune cells provide new targets that can be used to modulate immune cell activity. Here, we show for the first time that activation of peripheral GABA-Rs can inhibit the development of disease in the collagen-induced arthritis (CIA) mouse model of RA. Mice that received oral GABA had a reduced incidence of CIA, and those mice that did develop CIA had milder symptoms. T cells from GABA-treated mice displayed reduced proliferative responses to collagen and their APC had a reduced ability to promote the proliferation of collagen-reactive T cells. Thus, GABA downregulated both T-cell autoimmunity and APC activity. Collagen-reactive T cells from GABA-treated mice displayed reduced recall responses in the presence of GABA ex vivo, indicating that GABA consumption did not desensitize these cells to GABA. GABA-treated mice had reduced collagen-reactive IgG2a, but not IgG1 antibodies, consistent with reduced Th1 help. The levels of serum anti-collagen IgG2a antibodies were correlated significantly with the CIA disease scores of individual mice. Our results suggest that activation of peripheral GABA-Rs may provide a new modality to modulate T cell, B cell, and APC activity and help ameliorate RA and other inflammatory diseases.
Jide Tian; Jing Yong; Hoa Dang; Daniel L. Kaufman. Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis. Autoimmunity 2011, 44, 465 -470.
AMA StyleJide Tian, Jing Yong, Hoa Dang, Daniel L. Kaufman. Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis. Autoimmunity. 2011; 44 (6):465-470.
Chicago/Turabian StyleJide Tian; Jing Yong; Hoa Dang; Daniel L. Kaufman. 2011. "Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis." Autoimmunity 44, no. 6: 465-470.