Islet-Specific Expression of CXCL10 Causes Spontaneous Islet Infiltration and Accelerates Diabetes Development (original) (raw)
Related papers
Diabetes, 2016
Type 1 diabetes (T1D) results from the autoimmune destruction of insulin-producing β-cells in the pancreas. Thereby, the chemokine CXC-motif ligand 10 (CXCL10) plays an important role in the recruitment of autoaggressive lymphocytes to the islets of Langerhans. Transplantation of isolated islets as a promising therapy for T1D has been hampered by early graft rejection. Here, we investigated the influence of CXCL10 on the autoimmune destruction of islet isografts using RIP-LCMV mice expressing a lymphocytic choriomeningitis virus (LCMV) protein in the β-cells. RIP-LCMV islets express CXCL10 after isolation and maintain CXCL10 production after engraftment. Thus, we isolated islets from either normal or CXCL10-deficient RIP-LCMV mice and transferred them under the kidney capsule of diabetic RIP-LCMV mice. We found that the autoimmune destruction of CXCL10-deficient islet isografts was significantly reduced. The autoimmune destruction was also diminished in mice administered with an ant...
Diabetes, 2013
Cytotoxic T lymphocytes (CTLs) constitute a major effector population in pancreatic islets from patients suffering from type 1 diabetes (T1D) and thus represent attractive targets for intervention. Some studies have suggested that blocking the interaction between the chemokine CXCL10 and its receptor CXCR3 on activated CTLs potently inhibits their recruitment and prevents b-cell death. Since recent studies on human pancreata from T1D patients have indicated that both ligand and receptor are abundantly present, we reevaluated whether their interaction constitutes a pivotal node within the chemokine network associated with T1D. Our present data in a viral mouse model challenge the notion that specific blockade of the CXCL10/CXCR3 chemokine axis halts T1D onset and progression. Diabetes 62: [2492][2493][2494][2495][2496][2497][2498][2499] 2013 T he mechanisms governing autoreactive T-cell homing to pancreatic islets in type 1 diabetes (T1D) are poorly characterized, which in turn has impeded the rational design of therapies at this crucial intersection. Interest in targeting chemokines was sparked by a study that identified b-cells as a key source of CXCL10 in the viral rat insulin promoter (RIP)lymphocytic choriomeningitis virus (LCMV) diabetes model, which in turn would serve to attract CXCR3expressing T cells (1). In CXCR3-deficient mice, diabetes onset was markedly delayed. It was subsequently reported in the same model that among CXCR3 ligands, which include CXCL9, -10, and -11, only CXCL10 exerted dominant effects on T-cell recruitment .
Islet inflammation and CXCL10 in recent-onset type 1 diabetes
Clinical & Experimental Immunology, 2010
Type 1 diabetes results from a T cell-mediated destruction of insulinproducing pancreatic b cells. Little is known on local factors contributing to migration of T cells to pancreatic tissue. We recently demonstrated evidence of viral infection in b cells in several recent-onset type 1 diabetes patients. Islet inflammation was analysed in a series of new-or recent-onset type 1 diabetic patients and non-diabetic control subjects. Autoimmune T cell reactivity was studied in lymphocytes derived from pancreas-draining lymph nodes of one recent-onset type 1 diabetes patient in partial clinical remission. Insulitic lesions were characterized by presence of b cells, elevated levels of the chemokine CXCL10 and infiltration of lymphocytes expressing the corresponding chemokine receptor CXCR3 in all pancreatic lesions of type 1 diabetes patients, regardless of enterovirus infection of b cells. CXCR3 and CXCL10 were undetectable in pancreata of non-diabetic control subjects. T cells isolated from draining lymph nodes of a recent-onset patient with virally infected b cells and in clinical remission reacted with multiple islet autoantigens and displayed a mixed interferon (IFN)-g/interleukin (IL)-10 cytokine pattern. Our data point to CXCL10 as an important cytokine in distressed islets that may contribute to inflammation leading to insulitis and b cell destruction, regardless of local viral infection. We demonstrate further proand anti-inflammatory islet autoreactivity, indicating that different adaptive and innate immune responses may contribute to insulitis and b cell destruction.c ei_4087 338..343
2000
Type 1 diabetes mellitus is an autoimmune disease characterized by T cell-mediated destruction of the insulin-producing  cells in the islets of Langerhans. From studies in animal models, CD8 ؉ T cells recognizing autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit-related protein, insulin, or glutamic acid decarboxylase (GAD) are believed to play important roles in both the early and late phases of  cell destruction. In this study, we investigated the factors governing the diabetogenic potential of autoreactive CD8 ؉ clones isolated from spleens of NOD mice that had been immunized with GAD65 515-524 or insulin B-chain 15-23 peptides. Although these two clones were identical in most phenotypic and functional aspects, for example cytokine production and killing of autologous  cells, they differed in the expression of IFN-␥-inducible protein-10, which was only produced at high levels by the insulin-specific clone, but not by the GAD65-specific clone, and other autoantigen-specific nonpathogenic CD8 T cell clones. Interestingly, upon i.
Cure of prediabetic mice by viral infections involves lymphocyte recruitment along an IP-10 gradient
Journal of Clinical Investigation, 2004
Viruses can cause but can also prevent autoimmune disease. This dualism has certainly hampered attempts to establish a causal relationship between viral infections and type 1 diabetes (T1D). To develop a better mechanistic understanding of how viruses can influence the development of autoimmune disease, we exposed prediabetic mice to various viral infections. We used the well-established NOD and transgenic RIP-LCMV models of autoimmune diabetes. In both cases, infection with the lymphocytic choriomeningitis virus (LCMV) completely abrogated the diabetic process. Interestingly, such therapeutic viral infections resulted in a rapid recruitment of T lymphocytes from the islet infiltrate to the pancreatic draining lymph node, where increased apoptosis was occurring. In both models this was associated with a selective and extensive expression of the chemokine IP-10 (CXCL10), which predominantly attracts activated T lymphocytes, in the pancreatic draining lymph node, and in RIP-LCMV mice it depended on the viral antigenic load. In RIP-LCMV mice, blockade of TNF-α or IFN-γ in vivo abolished the prevention of T1D. Thus, virally induced proinflammatory cytokines and chemokines can influence the ongoing autoaggressive process beneficially at the preclinical stage, if produced at the correct location, time, and levels.
The Journal of Immunology, 2005
Type 1 diabetes mellitus is an autoimmune disease characterized by T cell-mediated destruction of the insulin-producing  cells in the islets of Langerhans. From studies in animal models, CD8 ؉ T cells recognizing autoantigens such as islet-specific glucose-6-phosphatase catalytic subunit-related protein, insulin, or glutamic acid decarboxylase (GAD) are believed to play important roles in both the early and late phases of  cell destruction. In this study, we investigated the factors governing the diabetogenic potential of autoreactive CD8 ؉ clones isolated from spleens of NOD mice that had been immunized with GAD65 515-524 or insulin B-chain 15-23 peptides. Although these two clones were identical in most phenotypic and functional aspects, for example cytokine production and killing of autologous  cells, they differed in the expression of IFN-␥-inducible protein-10, which was only produced at high levels by the insulin-specific clone, but not by the GAD65-specific clone, and other autoantigen-specific nonpathogenic CD8 T cell clones. Interestingly, upon i.p. injection into neonatal mice, only the insulin B-chain 15-23-reactive CD8 ؉ T clone accelerated diabetes in all recipients after 4 wk, although both insulin-and GAD-reactive clones homed to pancreas and pancreatic lymph nodes with similar kinetics. Diabetes was associated with increased pancreatic T cell infiltration and, in particular, recruitment of macrophages. Thus, secretion of IFN-␥-inducible protein-10 by autoaggressive CD8 ؉ lymphocytes might determine their diabetogenic capacity by affecting recruitment of cells to the insulitic lesion.
2014
Autoimmune type 1 diabetes (T1D) development results from the interaction between pancreatic b-cells, and the innate and the adaptive immune systems culminating with the destruction of the insulin-secreting b-cells by autoreactive T cells. This diabetogenic course starts during the first postnatal weeks by the infiltration of the pancreatic islets by innate immune cells and particularly neutrophils. Here, we aim to determine the cellular and molecular mechanism leading to the recruitment of this neutrophils in the pancreatic islets of non-obese diabetic (NOD) mice. Here, we show that neutrophil recruitment in the pancreatic islets is controlled by inflammatory macrophages and b-cells themselves. Macrophages and b-cells produce the chemokines CXCL1 and CXCL2, recruiting CXCR2-expressing neutrophils from the blood to the pancreatic islets. We further show that pancreatic macrophages secrete IL-1b-inducing CXCR2 ligand production by the b-cells. Finally, the blockade of neutrophil recruitment at early ages using CXCR2 antagonist dampens the diabetogenic T-cell response and the later development of autoimmune diabetes, supporting the therapeutic potential of this approach.
Clinical & Experimental Immunology, 2007
Chemokines and their receptors are part of polarized T helper 1 (Th1)-and Th2-mediated immune responses which control trafficking of immunogenic cells to sites of inflammation. The chemokine stromal cell-derived factor-1 CXCL-12 (SDF-1) and its ligand the CXCR4 chemokine receptor are important regulatory elements. CXCR4 is expressed on the surface of CD4 + T cells, dendritic cells and B lymphocytes. Levels of CXCR4 mRNA were increased in pancreatic lymph nodes (PLNs) of 4-week-old non-obese diabetic (NOD) mice in comparison to Balb/C mice. However, a significant reduction of CXCR4 was noticed at 12 weeks both at the mRNA and protein levels while expression increased in the inflamed islets. The percentage of SDF-1 attracted splenocytes in a transwell chemotaxis assay was significantly increased in NOD versus Balb/c mice. SDF-1 attracted T cells completely abolished the capacity of diabetogenic T cells to transfer diabetes in the recipients of an adoptive cell co-transfer. When T splenocytes from NOD females treated with AMD3100, a specific CXCR4 antagonist, were mixed with diabetogenic T cells during adoptive cell co-transfer experiments, prevalence of diabetes in the recipients rose from 33% to 75% (P < 0•001). This effect was associated with an increase of interferon (IFN)-g mRNA and a reduction of interleukin (IL)-4 mRNA levels both in PLNs and isolated islets. AMD3100 also reduced IL-4 and IL-10 production of plate-bound anti-CD3 and anti-CD28-stimulated splenocytes. Immunofluorescence studies indicated that AMD3100 reduced the number of CXCR4 + and SDF-1 positive cells in the inflamed islets. We can conclude that the CXCL-12/CXCR4 pathway has protective effects against autoimmune diabetes.
CXCL10 DNA Vaccination Prevents Spontaneous Diabetes through Enhanced Cell Proliferation in NOD Mice
The Journal of Immunology, 2005
CXCL10, a chemokine for Th1 cells, is involved in the pathogenesis of various Th1-dominant autoimmune diseases. Type 1 diabetes is considered to be a Th1-dominant autoimmune disease, and a suppressive effect of CXCL10 neutralization on diabetes development has been reported in a cyclophosphamide-induced accelerated diabetes model through induction of  cell proliferation. However, intervention in a diabetes model might bring about opposite effects, depending on the timing, amount, or method of treatment. In the present study, we examined the effect of CXCL10 neutralization in a "spontaneous diabetes" model of NOD mice, using CXCL10 DNA vaccination (pCAGGS-CXCL10). pCAGGS-CXCL10 treatment in young NOD mice induced the production of anti-CXCL10 Ab in vivo and suppressed the incidence of spontaneous diabetes, although this treatment did not inhibit insulitis or alter the immunological response. pCAGGS-CXCL10 treatment enhanced the proliferation of pancreatic  cells, resulting in an increase of  cell mass in this spontaneous diabetes model as well. Therefore, CXCL10 neutralization is suggested to be useful for maintaining  cell mass at any stage of autoimmune diabetes. The Journal of Immunology, 2005, 175: 8401-8408. Abbreviations used in this paper: CY, cyclophosphamide; pLN, pancreatic lymph node; GAD, glutamic acid decarboxylase; PDX-1, pancreatic duodenal homeobox-1.