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Accelerated Type 1 Diabetes Induction in Mice by Adoptive Transfer of Diabetogenic CD4+ T Cells
Published on: May 6, 2013
Retinoids differentially regulate the progression of autoimmune diabetes in three preclinical models in mice
Stanislava Stosić-Grujicić1, Tamara Cvjetićanin, Ivana Stojanović
1Department of Immunology, Institute for Biological Research Sinisa Stanković, Belgrade University, Bulevar Despota Stefana 142, 11060 Belgrade, Serbia. duta@eunet.rs
Abstract:
Retinoids have a variety of biological activities, including immunomodulatory action in a number of inflammatory and autoimmune conditions. Considering the pathogenesis of type 1 diabetes mellitus (T1D), in this study we examined the potential role for retinoids, etretinate and all-trans-retinoic acid (ATRA) in preclinical models of human T1D. When administered prophylactically to CBA/H mice made diabetic with multiple low doses of streptozotocin (MLD-STZ), both drugs effectively prevented clinical signs of diabetes. Prevention of T1D was associated with reduced emergence of primed (autoreactive) CD4(+) CD25(+) T cells, but not with the emergence of Foxp3(+) Treg in the peripheral compartments. Moreover, the animals receiving ATRA exhibited reduced Th1/Th17 response and nitric oxide (NO) production in the peripheral lymphoid tissues, thus shifting the balance towards the anti-inflammatory cytokines. In NOD mice with spontaneous form of diabetes, ATRA prophylaxis, starting at a time point immediately before T1D onset, markedly reduced hyperglycemia and incidence of the disease. However, administration of ATRA to NOD mice in which the proportion and function of CD4(+)Foxp3(+) Treg cells was abrogated by cyclophosphamide (CY), failed to permit progression to T1D. These findings suggest that effectiveness of T1D suppression by retinoids depends on the presence of Tregs which down-modulate immunoinflammatory events at the second "check-point" and allow diabetes progression.
Insights
Retinoids like etretinate and all-trans-retinoic acid (ATRA) show promise in preventing type 1 diabetes (T1D) by modulating immune responses. Their effectiveness in preclinical models depends on the presence of regulatory T cells (Tregs).
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Retinoids possess immunomodulatory properties relevant to inflammatory and autoimmune diseases.
- Type 1 diabetes (T1D) involves complex autoimmune pathogenesis.
- Understanding T1D's immune triggers is crucial for therapeutic development.
Purpose of the Study:
- To investigate the potential of retinoids, specifically etretinate and all-trans-retinoic acid (ATRA), in preclinical models of T1D.
- To elucidate the mechanisms underlying retinoid-mediated prevention of T1D.
- To determine the role of regulatory T cells (Tregs) in retinoid efficacy for T1D.
Main Methods:
- Prophylactic administration of etretinate and ATRA to streptozotocin-induced diabetic CBA/H mice.
- Assessment of clinical diabetes signs, immune cell populations (CD4+CD25+ T cells, Foxp3+ Tregs), and cytokine profiles (Th1/Th17, NO).
- Treatment of non-obese diabetic (NOD) mice with ATRA before T1D onset, including experiments with cyclophosphamide (CY)-induced Treg abrogation.
Main Results:
- Both etretinate and ATRA prevented clinical T1D in MLD-STZ treated mice.
- T1D prevention was linked to reduced autoreactive T cells but not increased Tregs.
- ATRA treatment decreased Th1/Th17 responses and nitric oxide (NO) production.
- ATRA prophylaxis reduced hyperglycemia and T1D incidence in spontaneous NOD mouse models.
- ATRA's protective effect was lost when Tregs were abrogated by CY.
Conclusions:
- Retinoids, including ATRA, can effectively prevent T1D in preclinical models.
- The immunomodulatory effects of retinoids involve suppressing inflammatory responses and shifting cytokine balance.
- The therapeutic efficacy of retinoids in T1D is dependent on the presence and function of regulatory T cells (Tregs).
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