Suppression of Autoimmune Diabetes by Soluble Galectin-1 (original) (raw)
Related papers
Nature Medicine, 2001
Type 1 diabetes (T1D) in non-obese diabetic (NOD) mice may be favored by immune dysregulation leading to the hyporesponsiveness of regulatory T cells and activation of effector T-helper type 1 (Th1) cells 1. The immunoregulatory activity of natural killer T (NKT) cells is well documented 2,3 , and both interleukin (IL)-4 and IL-10 secreted by NKT cells have important roles in mediating this activity 4,5. NKT cells are less frequent and display deficient IL-4 responses in both NOD mice 6,7 and individuals at risk for T1D (ref. 8), and this deficiency may lead to T1D (refs. 1,6-9). Thus, given that NKT cells respond to the α-galactosylceramide (α-GalCer) glycolipid in a CD1d-restricted manner by secretion of Th2 cytokines 10-12 , we reasoned that activation of NKT cells by α-GalCer might prevent the onset and/or recurrence of T1D. Here we show that α-GalCer treatment, even when initiated after the onset of insulitis, protects female NOD mice from T1D and prolongs the survival of pancreatic islets transplanted into newly diabetic NOD mice. In addition, when administered after the onset of insulitis, α-GalCer and IL-7 displayed synergistic effects, possibly via the ability of IL-7 to render NKT cells fully responsive to α-GalCer. Protection from T1D by α-GalCer was associated with the suppression of both T-and B-cell autoimmunity to islet β cells and with a polarized Th2-like response in spleen and pancreas of these mice. These findings raise the possibility thatα-GalCer treatment might be used therapeutically to prevent the onset and recurrence of human T1D.
Dendritic Cells Expressing Transgenic Galectin-1 Delay Onset of Autoimmune Diabetes in Mice
The Journal of Immunology, 2006
are the APC that initiate the T cell response that triggers T1D. However, DC also participate in T cell tolerance, and genetic engineering of DC to modulate T cell immunity is an area of active research. Galectin-1 (gal-1) is an endogenous lectin with regulatory effects on activated T cells including induction of apoptosis and down-regulation of the Th1 response, characteristics that make gal-1 an ideal transgene to transduce DC to treat T1D. We engineered bone marrow-derived DC to synthesize transgenic gal-1 (gal-1-DC) and tested their potential to prevent T1D through their regulatory effects on activated T cells. NOD-derived gal-1-DC triggered rapid apoptosis of diabetogenic BDC2.
Regulatory Natural Killer T Cells Protect against Spontaneous and Recurrent Type 1 Diabetes
Annals of the New York Academy of Sciences, 2006
Autoimmune diseases, especially type 1 diabetes (T1D), may be caused by dysregulation of the immune system, which leads to hyporesponsiveness of regulatory T helper 2 (Th2) cells and promotion of autoimmune Th1 cells. Natural killer T (NKT) cells, which comprise a minor subpopulation of T cells, play a critical role in immunoregulation as a result of a rapid burst of IL-4 and IFN-␥ secretion. These cells are functionally and numerically deficient in individuals at risk of T1D, as well as in nonobese diabetic (NOD) mice. It is conceivable that protection from T1D may be achieved by correction of this deficiency. Alpha-galactosylceramide (␣-GalCer) specifically binds to NKT cells in a CD1-dependent manner and stimulates these cells to proliferate and to produce various cytokines, including IFN-␥, IL-4, and IL-10. In this review, we present evidence that a multiple-dose ␣-GalCer treatment regimen, which is known to promote a dominant Th2 environment, can prevent the onset of spontaneous and cyclophosphamide (CY)-accelerated T1D. This protection is associated with elevated IL-4 and IL-10 in the spleen and pancreas of protected female NOD mice. Concomitantly, IFN-␥ levels are reduced in both tissues. More importantly, the protective effect of ␣-GalCer in CY-accelerated T1D is abrogated by the in vivo blockade of IL-10 activity. We also show that ␣-GalCer treatment significantly prolongs syngeneic islet graft survival in recipient diabetic NOD mice. These findings raise the possibility that ␣-GalCer treatment may be used therapeutically to prevent the onset and recurrence of human T1D.
Antigen-Specific Regulatory T Cells and Low Dose of IL-2 in Treatment of Type 1 Diabetes
Frontiers in Immunology, 2016
Regulatory T cells (Tregs) play an important role in preventing effector T-cell (Teff) targeting of self-antigens that can lead to tissue destruction in autoimmune settings, including type 1 diabetes (T1D). Autoimmunity is caused in part by an imbalance between Teff and Tregs. Early attempts to treat with immunosuppressive agents have led to serious side effects, thus requiring a more targeted approach. Low-dose IL-2 (LD IL-2) can provide immunoregulation with few side effects by preferentially acting on Tregs to drive tolerance. The concept of LD IL-2 as a therapeutic approach is supported by data in mouse models where autoimmunity is cured and further strengthened by success in human clinical studies in hepatitis C virus-induced vasculitis, chronic graft-versus-host disease, and Alopecia areata. Treatment will require identification of a safe therapeutic window, which is a difficult task given that patients are reported to have deficient or defective IL-2 production or signaling and have experienced mild activation of NK cells and eosinophils with LD IL-2 therapy. In T1D, an LD IL-2 clinical trial concluded that Tregs can be safely expanded in humans; however, the study was not designed to address efficacy. Antigen-specific therapies have also aimed at regulation of the autoimmune response but have been filled with disappointment despite an extensive list of diverse islet antigens tested in humans. This approach could be enhanced through the addition of LD IL-2 to the antigenic treatment regimen to improve the frequency and function of antigen-specific Tregs, without global immunosuppression. Here, we will discuss the use of LD IL-2 and islet antigen to enhance antigen-specific Tregs in T1D and focus on what is known about their immunological impact, their safety, and potential efficacy, and need for better methods to identify therapeutic effectiveness.
The rise, fall, and resurgence of immunotherapy in type 1 diabetes
Pharmacological Research, 2014
Despite considerable effort to halt or delay destruction of -cells in autoimmune type 1 diabetes (T1D), success remains elusive. Over the last decade, we have seen a proliferation of knowledge on the pathogenesis of T1D that emerged from studies performed in non-obese diabetic (NOD) mice. However, while results of these preclinical studies appeared to hold great promise and boosted patients' hopes, none of these approaches, once tested in clinical settings, induced remission of autoimmune diabetes in individuals with T1D. The primary obstacles to translation reside in the differences between the human and murine autoimmune responses and in the contribution of many environmental factors associated with the onset of disease. Moreover, inaccurate dosing as well as inappropriate timing and uncertain length of drug exposure have played a central role in the negative outcomes of such therapeutic interventions. In this review, we summarize the most important approaches tested thus far in T1D, beginning with the most successful preclinical studies in NOD mice and ending with the latest disappointing clinical trials in humans. Finally, we highlight recent stem cell-based trials, for which expectations in the scientific community and among individuals with T1D are high.
Cellular Immunology, 2011
Galectins are a group of β-galactoside-binding mammalian lectins that play important roles in the regulation of the immune response by promoting T cell tolerance, blunting Th1 and Th17 responses and suppressing autoimmune inflammation. However, the synthesis of these molecules by different T helper (Th) subsets and in the context of human type 1 diabetes (T1D) has not yet been studied. Our results show that Th17 polarising conditions induce the synthesis of higher levels of galectin-1 compared to Th1-polarised lymphocytes. In the context of human diabetes, peripheral blood mononuclear cells (PBMCs) from T1D patients, either unstimulated or after stimulation, secreted significantly lower amounts of galectin-1 in vitro compared to healthy donors. The reduced galectin-1 synthesis observed in this autoimmune disease occurs in a dominant pro-inflammatory cytokine milieu and it is mainly due to the lower synthesis by monocytes. Surprisingly, CD4+ T helper cells from these patients secreted similar levels of galectin-1 compared to healthy donors, probably mediated by Th17 cytokines. In conclusion, CD4+ T helper lymphocytes from T1D patients produce normal levels of the immunoregulator galectin-1 but its reduced synthesis by monocytes helps to maintain a skewed pro-inflammatory response.► The Th17 cell subset secrete higher levels of galectin-1 compared to Th1 cells. ► Immune cells from diabetic patients secrete lower levels of galectin-1. ► Monocytes and Th1 cells are responsible for this reduced secretion in diabetes. ► Treg from T1D patients have lower levels of surface-bound galectin-1.
Immune intervention in type 1 diabetes
Seminars in Immunology, 2011
Type 1 diabetes (T1D) is a chronic autoimmune disease that results in the specific immune destruction of insulin producing beta cells. Currently there is no cure for T1D and treatment for the disease consists of lifelong administration of insulin. Immunotherapies aimed at preventing beta cell destruction in T1D patients with residual c-peptide or in individuals developing T1D are being evaluated. Networks of researchers such as TrialNet and the Immune Tolerance Network in the U.S. and similar networks in Europe have been established to evaluate such immunotherapies. This review focuses on immune intervention for the prevention and amelioration of human T1D with a focus on potential immune suppressive, antigen specific and environmental therapies.