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β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection

Gene Therapy volume 22, pages 430–438 (2015)Cite this article

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Abstract

Protection of β cells from autoimmune destruction potentially cures type 1 diabetes mellitus (T1D). During antigen presentation, interactions between cytotoxic T-lymphocyte antigen-4 (CTLA4) and B7 molecules, or programmed death 1 (PD1) and its ligand PDL1, negatively regulate immune responses in a non-redundant manner. Here we employed β-cell-targeted adeno-associated virus serotype 8 (AAV8)-based vectors to overexpress an artificial PDL1-CTLA4Ig polyprotein or interleukin 10 (IL10). β-Cell-targeted expression of PDL1-CTLA4Ig or IL10 preserved β-cell mass and protected NOD mice from T1D development. When NOD mice were treated with vectors at early onset of hyperglycemia, PDL1-CTLA4Ig or IL10 alone failed to normalize the early onset of hyperglycemia. When drug-induced diabetic mice received major histocompatibility complex (MHC)-matched allo-islets, with or without pretreatment of the PDL1-CTLA4Ig-expressing vector, PDL1-CTLA4Ig-expressing islets were protected from rejection for at least 120 days. Similarly, transplantation of PDL1-CTLA4Ig-expressing MHC-matched islets into mice with established T1D resulted in protection of allo-islets from acute rejection, although islet grafts were eventually rejected. Thus the present study demonstrates the potent immuno-suppressive effects of β-cell-targeted PDL1-CTLA4Ig overexpression against T1D development and allo-islet rejection. The gene-based simultaneous inhibition of PD1 and CTLA4 pathways provides a unique strategy for immunosuppression-free tissue/organ transplantation, especially in the setting of no established autoimmunity.

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Acknowledgements

This work was supported by the Mayo Foundation, Eisenberg Stem Cell Trust, Minnesota Partnership Grant (to YI), Mayo Center for Regenerative Medicine (to YI and TS) and National Institutes of Health (HL098502 to YI).

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Authors and Affiliations

  1. Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA

    M M El Khatib, T Sakuma, J M Tonne, M S Mohamed, S J Holditch, B Lu & Y Ikeda

  2. Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA

    Y C Kudva

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  1. M M El Khatib
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  2. T Sakuma
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  3. J M Tonne
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  4. M S Mohamed
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  7. Y C Kudva
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  8. Y Ikeda
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Correspondence to Y Ikeda.

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El Khatib, M., Sakuma, T., Tonne, J. et al. β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. Gene Ther 22, 430–438 (2015). https://doi.org/10.1038/gt.2015.18

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