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

M. M. El Khatib, T. Sakuma, J. M. Tonne, M. S. Mohamed, S. J. Holditch, B. Lu, Yogish C Kudva, Yasuhiro H Ikeda

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)430-438
Number of pages9
JournalGene Therapy
Volume22
Issue number5
DOIs
StatePublished - May 9 2015

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CTLA-4 Antigen
Type 1 Diabetes Mellitus
Interleukin-10
Inbred NOD Mouse
Major Histocompatibility Complex
Hyperglycemia
B7 Antigens
Polyproteins
Tissue Transplantation
Dependovirus
Cytoprotection
Antigen Presentation
Organ Transplantation
Autoimmunity
Immunosuppression
Transplantation
Ligands
Transplants
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

El Khatib, M. M., Sakuma, T., Tonne, J. M., Mohamed, M. S., Holditch, S. J., Lu, B., ... Ikeda, Y. H. (2015). β-cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. Gene Therapy, 22(5), 430-438. https://doi.org/10.1038/gt.2015.18

β-cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. / El Khatib, M. M.; Sakuma, T.; Tonne, J. M.; Mohamed, M. S.; Holditch, S. J.; Lu, B.; Kudva, Yogish C; Ikeda, Yasuhiro H.

In: Gene Therapy, Vol. 22, No. 5, 09.05.2015, p. 430-438.

Research output: Contribution to journalArticle

El Khatib, M. M. ; Sakuma, T. ; Tonne, J. M. ; Mohamed, M. S. ; Holditch, S. J. ; Lu, B. ; Kudva, Yogish C ; Ikeda, Yasuhiro H. / β-cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection. In: Gene Therapy. 2015 ; Vol. 22, No. 5. pp. 430-438.
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