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CD11a/ICAM‐1 blockade combined with IL‐2 targeting therapy causes a paradoxical acceleration of type 1 diabetes
Author(s) -
Brenu Ekua W,
Bartley Timothy J,
Wright Casey M,
HamiltonWilliams Emma E
Publication year - 2017
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2017.49
Subject(s) - effector , islet , cd8 , nod mice , combination therapy , immunology , cell therapy , medicine , blockade , interleukin 2 , t cell , endocrinology , antigen , biology , diabetes mellitus , microbiology and biotechnology , cytokine , immune system , receptor , stem cell
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.