Prevention, but not cure, of autoimmune diabetes in a NOD.scid transfer model by FTY720 despite effective modulation of blood T cells

Abstract

FTY720 modulates lymphocyte trafficking through blood (peripheral blood lymphocyte, PBL) and peripheral lymph nodes (PLN). Treatment with FTY720 causes retention of most blood lymphocytes in PLN. Long-term treatment can slow and/or prevent Type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse model. B and T cells are both affected by FTY720 binding to sphingosine-1-phosphate receptor 1 (S1P₁). However, little has been done to elucidate which T-cell subsets are differentially affected by FTY720 under healthy conditions, and how this affects disease pathogenesis in T1D. In healthy C57BL/6J (B6) mice, total CD4⁺ and CD8⁺ T-cell subsets were diminished by FTY720, but recently activated and memory subsets were spared and constituted significantly higher percentage of remaining T cells in blood. FTY720 also lowered PBL counts in NOD mice, but less severely than in B6 mice. This is consistent with a different ratio of naïve, activated, and memory cells in NOD mice compared to those in B6 mice, as well as alterations in S1P₁ and sphingosine-1-phosphate (S1P) levels in PBLs and blood of NOD mice, respectively. To address the functional consequences of PBL T-cell depletion, we studied the effects of FTY720 on disease progression in a timed adoptive transfer model of T1D. Continuous treatment with FTY720 eliminated T1D, if treatment was started before splenocyte transfer. FTY20 treatment started after disease onset slowed disease progression. The inability to fully suppress memory and effector T-cell circulation may explain why FTY720 is only partially effective in the NOD adoptive transfer model of T1D.

Keywords::

• Type 1 diabetes
• T cells
• immunomodulation
• FTY720
• adoptive transfer

Acknowledgments

The authors would like to thank Volker Brinkmann (Novartis) for the gift of FTY720, the technical assistance of Dr Kevin R. Lynch (S1P measurements) and Edward Bahng (sample preparation for flow cytometry). Additionally, we would like to thank the Research Histology Core at the University of Virginia for their help in embedding, sectioning, and staining the pancreas tissues, as well as to the Pathology Core at Eastern Virginia Medical School for additional sectioning of pancreas tissues. Dr Morris was supported in part by grants from JDRF (3-2004-551) and the NIH (NIH R01 DK55240).

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.