Abstract
Type 1 diabetes (T1D) is mainly precipitated by the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans by autoaggressive T cells. The etiology of the disease is still not clear, but besides genetic predisposition the exposure to environmental triggers seems to play a major role. Virus infection of islets has been demonstrated in biopsies of T1D patients, but there is still no firm proof that such an infection indeed results in islet-specific autoimmunity. However, virus infection results in a local inflammation with expression of inflammatory factors, such as cytokines and chemokines that attract and activate immune cells, including potential autoreactive T cells. Many chemokines have been found to be elevated in the serum and expressed by islet cells of T1D patients. In mouse models, it has been demonstrated that β-cells express chemokines involved in the initial recruitment of immune cells to the islets. The bulk load of chemokines is however released by the infiltrating immune cells that also express multiple chemokine receptors. The result is a mutual attraction of antigen-presenting cells and effector immune cells in the local islet microenvironment. Although there is a considerable redundancy within the chemokine ligand-receptor network, a few chemokines, such as CXCL10, seem to play a key role in the T1D pathogenesis. Studies with neutralizing antibodies and investigations in chemokine-deficient mice demonstrated that interfering with certain chemokine ligand-receptor axes might also ameliorate human T1D. However, one important aspect of such a treatment is the time of administration. Blockade of the recruitment of immune cells to the site of autoimmune destruction might not be effective when the disease process is already ongoing. By that time, autoaggressive cells have already arrived in the islet microenvironment and a blockade of migration might even hold them in place leading to accelerated destruction. Thus, an anti-chemokine therapy makes most sense in situations where the cells have not yet migrated to the islets. Such situations include treatment of patients at risk already carrying islet-antigen autoantibodies but are not yet diabetic, islet transplantation recipients, and patients that have undergone a T cell reset as occurring after anti-CD3 antibody treatment.
Highlights
The CXCL10/CXCR3 chemokine axis is of particular interest, since patients with Type 1 diabetes (T1D) display enhanced serum levels of CXCL10, both CXCL10 as well as CXCR3 have been found in pancreas tissue sections from T1D patients, and neutralization studies in mouse models demonstrated a reduction of T1D incidence and severity
Even if treatment would start in individuals at risk that have already generated autoantibodies against two or more islet autoantigens a migration blockade might be behind schedule since insulitis has very likely already started
In two independent mouse models, a well-timed combination therapy of anti-CD3 antibody administration followed by an additional blockade of the CXCL10-CXCR3 axis prevented the re-infiltration of the islets by regenerating T cells and thereby induced a persistent remission in the majority of treated mice
Summary
Cellular infiltrations into inflamed tissues as occurring in acute or chronic infections as well as autoimmune diseases are orchestrated by chemokines. This observation was confirmed by Uno et al who performed double-immunofluorescence staining of pancreas sections of five recent-onset T1D patients They clearly identified b-cells as a main source of CXCL10 and Tcells as the main cell type expressing CXCR3 in the islet microenvironment [47]. An anti-CXCL10 antibody treatment of already diabetic RIPLCMV mice starting at day 13 after LCMV-infection resulted only in a slight, non-significant reduction by about 25% [56] One reason for this lack of efficacy is that at the start of the therapy the autoaggressive T cells have already assembled in the islet microenvironment and have started to progressively destroy b-cells. Chemokine neutralization might be better suited as part of a combination therapy
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