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
Date
2020
Authors
Hu, M.
Hawthorne, W.J.
Nicholson, L.
Burns, H.
Qian, Y.W.
Liuwantara, D.
Jimenez Vera, E.
Chew, Y.V.
Williams, L.
Yi, S.
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Journal article
Citation
Diabetes, 2020; 69(8):1735-1748
Statement of Responsibility
Min Hu, Wayne J. Hawthorne, Leigh Nicholson, Heather Burns, Yi Wen Qian, David Liuwantara, Elvira Jimenez Vera, Yi Vee Chew, Lindy Williams, Shounan Yi, Karen Keung, Debbie Watson, Natasha Rogers, Stephen I. Alexander, and Philip J. O'Connell
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Abstract
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.
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© 2020 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals .org/content/license.