CD11a/ICAM‐1 blockade combined with IL‐2 targeting therapy causes a paradoxical acceleration of type 1 diabetes
| Autor: | Emma E. Hamilton-Williams, Casey M. Wright, Ekua W Brenu, Timothy J Bartley |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Cytotoxicity
Immunologic 0301 basic medicine Interleukin 2 Combination therapy medicine.medical_treatment Immunology Biology Lymphocyte Activation T-Lymphocytes Regulatory Mice 03 medical and health sciences Interleukin 21 0302 clinical medicine Mice Inbred NOD T-Lymphocyte Subsets Insulin-Secreting Cells Blocking antibody medicine Animals Humans Immunology and Allergy CD11a Antigen Antibodies Blocking Cell Proliferation Effector Antibodies Monoclonal Interleukin Cell Biology Immunotherapy Intercellular Adhesion Molecule-1 Killer Cells Natural Diabetes Mellitus Type 1 030104 developmental biology 030220 oncology & carcinogenesis Interleukin-2 CD8 medicine.drug |
| Zdroj: | Immunology & Cell Biology. 95:803-813 |
| ISSN: | 1440-1711 0818-9641 |
| DOI: | 10.1038/icb.2017.49 |
| Popis: | Enhancement of regulatory T-cell (Treg) function is the goal of many immunotherapies aimed at treating type 1 diabetes (T1D). The use of interleukin (IL)-2 is hindered by its effects on other populations such as effector T cells and NK cells. Combination therapies aimed at suppressing effector T cells while using IL-2 to expand Tregs could be beneficial and have been trialed in T1D patients. We have investigated a combination therapy using IL-2 and αCD11a blocking antibody to simultaneously expand Tregs and suppress the activation and migration of autoreactive T cells. When non-obese diabetic mice were treated with low-dose IL-2/anti-IL-2 complexes (IL-2c) and αCD11a, significant Treg expansion occurred in both the spleen and pancreas. Activation and IFNγ production by islet-specific T cells was robustly suppressed in the periphery following IL-2c/αCD11a treatment. Surprisingly, combination therapy accelerated diabetes onset compared with control treatments. Analysis of IL-2 responsive populations found that combination therapy increased the activation of CD8+ T cells and natural killer (NK) cells specifically within the pancreas despite concomitant Treg expansion. Blocking effector T-cell migration with the inhibitor FTY720 together with IL-2c treatment also resulted in intra-pancreatic expansion of effector cell populations. Thus, inhibiting effector T-cell migration into the islets unleashes islet-resident pathogenic effectors in the presence of low doses of exogenous IL-2. |
| Databáze: | OpenAIRE |
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