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Low-Dose Interleukin-2 Combined With Rapamycin Led to an Expansion of CD4+CD25+FOXP3+ Regulatory T Cells and Prolonged Human Islet Allograft Survival in Humanized Mice

Journal Article


Abstract


  • © 2020 by the American Diabetes Association. Islet transplantation is an emerging therapy for type 1 diabetes and hypoglycemic unawareness. However, a key challenge for islet transplantation is cellular rejection and the requirement for long-term immunosuppression. In this study, we established a diabetic humanized NOD-scidIL2Rγnull (NSG) mouse model of T-cell-mediated human islet allograft rejection and developed a therapeutic regimen of low-dose recombinant human interleukin-2 (IL-2) combined with low-dose rapamycin to prolong graft survival. NSG mice that had received renal subcapsular human islet allografts and were transfused with 1 × 107 of human spleen mononuclear cells reconstituted human CD45+ cells that were predominantly CD3+ T cells and rejected their grafts with a median survival time of 27 days. IL-2 alone (0.3 × 106 IU/m2 or 1 × 106 IU/m2) or rapamycin alone (0.5-1 mg/kg) for 3 weeks did not prolong survival. However, the combination of rapamycin with IL-2 for 3 weeks significantly prolonged human islet allograft survival. Graft survival was associated with expansion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) and enhanced transforming growth factor-β production by CD4+ T cells. CD8+ T cells showed reduced interferon-γ production and reduced expression of perforin-1. The combination of IL-2 and rapamycin has the potential to inhibit human islet allograft rejection by expanding CD4+FOXP3+ Tregs in vivo and suppressing effector cell function and could be the basis of effective tolerance-based regimens.

Authors


  •   Hu, Min (external author)
  •   Hawthorne, Wayne (external author)
  •   Nicholson, Leigh (external author)
  •   Burns, Heather (external author)
  •   Qian, Yi (external author)
  •   Liuwantara, David (external author)
  •   Jimenez, Elvira (external author)
  •   Chew, Yi (external author)
  •   Williams, Lindy (external author)
  •   Yi, Shounan (external author)
  •   Keung, Karen (external author)
  •   Watson, Debbie
  •   Rogers, Natasha (external author)
  •   Alexander, Stephen (external author)
  •   O'Connell, Philip (external author)

Publication Date


  • 2020

Citation


  • Hu, M., Hawthorne, W., Nicholson, L., Burns, H., Qian, Y., Liuwantara, D., Jimenez, E., Chew, Y., Williams, L., Yi, S., Keung, K., Watson, D., Rogers, N., Alexander, S. & O'Connell, P. (2020). Low-Dose Interleukin-2 Combined With Rapamycin Led to an Expansion of CD4+CD25+FOXP3+ Regulatory T Cells and Prolonged Human Islet Allograft Survival in Humanized Mice. Diabetes, 69 (8), 1735-1748.

Scopus Eid


  • 2-s2.0-85088351097

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/1481

Has Global Citation Frequency


Number Of Pages


  • 13

Start Page


  • 1735

End Page


  • 1748

Volume


  • 69

Issue


  • 8

Place Of Publication


  • United States

Abstract


  • © 2020 by the American Diabetes Association. Islet transplantation is an emerging therapy for type 1 diabetes and hypoglycemic unawareness. However, a key challenge for islet transplantation is cellular rejection and the requirement for long-term immunosuppression. In this study, we established a diabetic humanized NOD-scidIL2Rγnull (NSG) mouse model of T-cell-mediated human islet allograft rejection and developed a therapeutic regimen of low-dose recombinant human interleukin-2 (IL-2) combined with low-dose rapamycin to prolong graft survival. NSG mice that had received renal subcapsular human islet allografts and were transfused with 1 × 107 of human spleen mononuclear cells reconstituted human CD45+ cells that were predominantly CD3+ T cells and rejected their grafts with a median survival time of 27 days. IL-2 alone (0.3 × 106 IU/m2 or 1 × 106 IU/m2) or rapamycin alone (0.5-1 mg/kg) for 3 weeks did not prolong survival. However, the combination of rapamycin with IL-2 for 3 weeks significantly prolonged human islet allograft survival. Graft survival was associated with expansion of CD4+CD25+FOXP3+ regulatory T cells (Tregs) and enhanced transforming growth factor-β production by CD4+ T cells. CD8+ T cells showed reduced interferon-γ production and reduced expression of perforin-1. The combination of IL-2 and rapamycin has the potential to inhibit human islet allograft rejection by expanding CD4+FOXP3+ Tregs in vivo and suppressing effector cell function and could be the basis of effective tolerance-based regimens.

Authors


  •   Hu, Min (external author)
  •   Hawthorne, Wayne (external author)
  •   Nicholson, Leigh (external author)
  •   Burns, Heather (external author)
  •   Qian, Yi (external author)
  •   Liuwantara, David (external author)
  •   Jimenez, Elvira (external author)
  •   Chew, Yi (external author)
  •   Williams, Lindy (external author)
  •   Yi, Shounan (external author)
  •   Keung, Karen (external author)
  •   Watson, Debbie
  •   Rogers, Natasha (external author)
  •   Alexander, Stephen (external author)
  •   O'Connell, Philip (external author)

Publication Date


  • 2020

Citation


  • Hu, M., Hawthorne, W., Nicholson, L., Burns, H., Qian, Y., Liuwantara, D., Jimenez, E., Chew, Y., Williams, L., Yi, S., Keung, K., Watson, D., Rogers, N., Alexander, S. & O'Connell, P. (2020). Low-Dose Interleukin-2 Combined With Rapamycin Led to an Expansion of CD4+CD25+FOXP3+ Regulatory T Cells and Prolonged Human Islet Allograft Survival in Humanized Mice. Diabetes, 69 (8), 1735-1748.

Scopus Eid


  • 2-s2.0-85088351097

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers1/1481

Has Global Citation Frequency


Number Of Pages


  • 13

Start Page


  • 1735

End Page


  • 1748

Volume


  • 69

Issue


  • 8

Place Of Publication


  • United States