Pancreatic nerve electrostimulation inhibits recent-onset autoimmune diabetes

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Abstract

Vagus nerve stimulation can ameliorate autoimmune diseases such as rheumatoid arthritis by modulation of the immune system. Its efficacy for the treatment of type 1 diabetes has not been explored, in part because the nerves projecting to the pancreatic lymph nodes (pLNs) in mice are unmapped. Here, we map the nerve projecting to the pancreas and pLNs in mice and use a minimally invasive surgical procedure to implant micro-cuff electrodes onto the nerve. Pancreatic nerve electrical stimulation (PNES) resulted in β-adrenergic receptor-mediated-accumulation of B and T cells in pLNs and reduced production of pro-inflammatory cytokines following lipopolysaccharide stimulation. Autoreactive T cells showed reduced proliferation in pLNs of mice receiving PNES as compared to sham controls. In a spontaneous mouse model of autoimmune diabetes, PNES inhibited disease progression in diabetic mice.

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Fig. 1: Pancreatic nerve electrophysiological and functional characterization.
Fig. 2: Impact of PNES on immune cell number, cytokine production and T cell proliferation in pLNs.
Fig. 3: Impact of PNES on glycemia and insulitis in NOD mice.

Data availability

Datasets that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. 1.

    Padro, C. J. & Sanders, V. M. Neuroendocrine regulation of inflammation. Semin. Immunol. 26, 357–368 (2014).

  2. 2.

    Koopman, F. A. et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 113, 8284–8289 (2016).

  3. 3.

    Bonaz, B. et al. Chronic vagus nerve stimulation in Crohn’s disease: a 6-month follow-up pilot study. Neurogastroenterol. Motil. 28, 948–953 (2016).

  4. 4.

    Herold, K. C. Restoring immune balance in type 1 diabetes. Lancet Diabetes Endocrinol. 1, 261–263 (2013).

  5. 5.

    Coppieters, K. & von Herrath, M. The development of immunotherapy strategies for the treatment of type 1 diabetes. Front. Med. 5, 283 (2018).

  6. 6.

    Duclaux, R., Mei, N. & Ranieri, F. Conduction velocity along the afferent vagal dendrites: a new type of fibre. J. Physiol. 260, 487–495 (1976).

  7. 7.

    Nakai, A., Hayano, Y., Furuta, F., Noda, M. & Suzuki, K. Control of lymphocyte egress from lymph nodes through β2-adrenergic receptors. J. Exp. Med. 211, 2583–2598 (2014).

  8. 8.

    Faustman, D. L. et al. TNF, TNF inducers, and TNFR2 agonists: a new path to type 1 diabetes treatment. Diabetes Metab. Res. Rev. https://doi.org/10.1002/dmrr.2941 (2018).

  9. 9.

    Mandrup-Poulsen, T. Interleukin-1 antagonists and other cytokine blockade strategies for type 1 diabetes. Rev. Diabet. Stud. RDS 9, 338–347 (2012).

  10. 10.

    Chen, Y.-L. et al. Correlation between serum interleukin-6 level and type 1 diabetes mellitus: a systematic review and meta-analysis. Cytokine 94, 14–20 (2017).

  11. 11.

    Kurts, C., Heath, W. R., Kosaka, H., Miller, J. F. & Carbone, F. R. The peripheral deletion of autoreactive CD8+ T cells induced by cross-presentation of self-antigens involves signaling through CD95 (Fas, Apo-1). J. Exp. Med. 188, 415–420 (1998).

  12. 12.

    Amrani, A. et al. Perforin-independent beta-cell destruction by diabetogenic CD8(+) T lymphocytes in transgenic nonobese diabetic mice. J. Clin. Invest. 103, 1201–1209 (1999).

  13. 13.

    Christianson, S. W., Shultz, L. D. & Leiter, E. H. Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 42, 44–55 (1993).

  14. 14.

    Hervé, J. et al. β2-Adrenoreceptor agonist inhibits antigen cross-presentation by dendritic cells. J. Immunol. 190, 3163–3171 (2013).

  15. 15.

    Hogquist, K. A. et al. T cell receptor antagonist peptides induce positive selection. Cell 76, 17–27 (1994).

  16. 16.

    Kurts, C., Miller, J. F., Subramaniam, R. M., Carbone, F. R. & Heath, W. R. Major histocompatibility complex class I-restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction. J. Exp. Med. 188, 409–414 (1998).

  17. 17.

    Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).

  18. 18.

    Savitt, J. M., Jang, S. S., Mu, W., Dawson, V. L. & Dawson, T. M. Bcl-x is required for proper development of the mouse substantia nigra. J. Neurosci. 25, 6721–6728 (2005).

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Acknowledgements

This work was funded by a collaborative research grant from GlaxoSmithKline Bioelectronics R&D to P.B. This work was also supported by the LABEX SIGNALIFE (no. ANR-11-LABX-0028-01) and the FHU Oncoage.

Author information

P.B. conceived the study. M.G., T.S. and P.B. designed experiments. M.G., F.C., T.S., A.G., C.P., E.M., D.D., R.B., S.A., S.H-A., S.J.L. and P.B. performed experiments. M.G., F.C., T.S., A.G., A.S., N.G. and P.B. interpreted the data. S.J.L. helped to identify the location of the pancreatic nerve in mice. J.-L.D. provided one of the external stimulators used in this study. P.B. wrote the manuscript and N.G. edited the manuscript. All the authors read and approved the final manuscript.

Correspondence to Philippe Blancou.

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Guyot, M., Simon, T., Ceppo, F. et al. Pancreatic nerve electrostimulation inhibits recent-onset autoimmune diabetes. Nat Biotechnol 37, 1446–1451 (2019) doi:10.1038/s41587-019-0295-8

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