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Updated: Apr 22, 2026
Accelerated Type 1 Diabetes Induction in Mice by Adoptive Transfer of Diabetogenic CD4+ T Cells
Published on: May 6, 2013
CXCR1/2 inhibition blocks and reverses type 1 diabetes in mice
Antonio Citro1, Andrea Valle2, Elisa Cantarelli2
1San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy Department of Surgery, University of Pavia, Pavia, Italy.
Abstract:
Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, noncompetitive allosteric inhibitors, were used to pharmacologically blockade CXCR1/2. Transient blockade of said receptors was effective in preventing inflammation-mediated damage in MLD-STZ and in preventing and reversing diabetes in NOD mice. Blockade of CXCR1/2 was associated with inhibition of insulitis and modification of leukocytes distribution in blood, spleen, bone marrow, and lymph nodes. Among leukocytes, CXCR2(+) myeloid cells were the most decreased subpopulations. Together these results identify CXCR1/2 chemokine receptors as "master regulators" of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving residual β-cells holds the potential to make a significant change in the approach to management of human T1D.
Insights
Inhibiting CXCR1/2 chemokine receptors prevents pancreatic islet damage in type 1 diabetes (T1D) models. This targeted approach shows potential for preserving beta-cells and managing T1D.
Area of Science:
- Immunology
- Endocrinology
- Pharmacology
Background:
- Chemokines and their receptors are implicated in type 1 diabetes (T1D) pathogenesis.
- A specific chemokine/receptor target for T1D therapeutics remains elusive.
- Pancreatic islet inflammation and autoimmune damage are key features of T1D.
Purpose of the Study:
- To investigate the therapeutic potential of inhibiting CXCR1/2 chemokine receptors in T1D.
- To evaluate the efficacy of CXCR1/2 inhibition in preventing and reversing diabetes-associated pancreatic damage.
- To identify CXCR1/2 as a potential master regulator in T1D pathogenesis.
Main Methods:
- Utilized multiple low-dose streptozotocin (MLD-STZ) injections and the NOD mouse model.
- Employed noncompetitive allosteric inhibitors (Reparixin, Ladarixin) to block CXCR1/2.
- Analyzed insulitis, leukocyte distribution in various tissues, and beta-cell preservation.
Main Results:
- Transient blockade of CXCR1/2 prevented inflammation-mediated damage in MLD-STZ models.
- CXCR1/2 inhibition prevented and reversed diabetes in NOD mice.
- Blockade reduced insulitis and altered leukocyte distribution, particularly decreasing CXCR2(+) myeloid cells.
Conclusions:
- CXCR1/2 chemokine receptors are identified as master regulators in T1D pathogenesis.
- Targeting CXCR1/2 offers a promising strategy for preserving residual beta-cells in T1D.
- This approach holds potential for a significant shift in human T1D management.
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