Differential Expression of CC Chemokines and the CCR5 Receptor in the Pancreas Is Associated with Progression to Type I Diabetes

Abstract

We investigated the biological role of CC chemokines in the Th1-mediated pathogenesis of spontaneous type I diabetes in nonobese diabetic (NOD) mice. Whereas an elevated ratio of macrophage inflammatory protein-1α (MIP-1α):MIP-1β in the pancreas correlated with destructive insulitis and progression to diabetes in NOD mice, a decreased intrapancreatic MIP-1α:MIP-1β ratio was observed in nonobese diabetes-resistant (NOR) mice. IL-4 treatment, which prevents diabetes in NOD mice by polarizing intraislet Th2 responses, decreased CCR5 expression in islets and potentiated a high ratio of MIP-1β and monocyte chemotactic protein-1 (MCP-1): MIP-1α in the pancreas. Furthermore, NOD.MIP-1α−/− mice exhibited reduced destructive insulitis and were protected from diabetes. Neutralization of MIP-1α with specific Abs following transfer of diabetogenic T cells delayed the onset of diabetes in NOD.Scid recipients. These studies illustrate that the temporal expression of certain CC chemokines, particularly MIP-1α, and the CCR5 chemokine receptor in the pancreas is associated with the development of insulitis and spontaneous type I diabetes.

Relation of circulating concentrations of chemokine receptor CCR5 ligands to C-peptide, proinsulin and HbA1c and disease progression in type 1 diabetes

“…Due to the considerable overlap of measurements at the different time points these cytokine measurements do not qualify as diagnostic markers on an individual basis. However, they may offer insights on the role of chemokines in type 1 diabetes and our findings such as associations with remission or metabolic parameters are in line with observations made in animal experiments in vivo [4,23,24].…”

Homing of human autoreactive T cells into pancreatic tissue of NOD-scid mice

“…Cloned human autoreactive T cells express CXCR3, a chemokine receptor associated with T cell infiltration in insulitis The expression of various chemokine receptors associated with type 1 diabetes (CCR5, CXCR3 [19][20][21]), with various sites of inflammation (CCR1, CCR4 and CXCR6) or with homing to T cell zones in lymphoid organs (CCR7 [22], CXCR4 [23]) was analysed on the two islet-specific autoreactive T cell clones (1C6 and PM1#11) as well as on the hsp60-specific T cell clone (Fig. 2).…”

“…The contribution of CCR5 to the pathogenesis of autoimmune diabetes in NOD mice was indirectly demonstrated by reduced insulitis and protection from diabetes in NOD. MIP-1α −/− mice, the chemokine that binds to CCR5 [19]. A contribution of CXCR3 as well as CCR4 in autoimmune diabetes or pancreatic infiltration has also been documented [20,40,41].…”

Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non‐obese diabetic mice

“…In NOD mice, g -cell expression of CCL2 (monocyte chemotactic protein-1, MCP-1) leads to insulitis, with a predominance of macrophages but no diabetes [6]. In another study, CCL3 (macrophage inflammatory protein-1 § , MIP-1 § ) -/-NOD mice showed reduced incidence of pre-diabetic symptoms at 10 weeks of age [7]. CCR4-expressing T cells were recently shown to participate in insulitis and diabetes development in NOD mice [8], whereas lack of the CXCR3 chemokine receptor delayed the onset of induced diabetes in a transgenic NOD mouse model [9].…”

“…CCR4-expressing T cells were recently shown to participate in insulitis and diabetes development in NOD mice [8], whereas lack of the CXCR3 chemokine receptor delayed the onset of induced diabetes in a transgenic NOD mouse model [9]. down-regulated following IL-4 treatment [7,9]. In the present study, we observed an increase in CCR5-expressing T and B cells in NOD mice, and correlated the expression of this chemokine receptor in T cells with an activated/effector cell phenotype.…”