Preventing Post-Transplant Diabetes Mellitus Via Orchestration of the IL-33/ST2 Axis in Pancreatic Islets

Abstract

Post-transplant diabetes mellitus (PTDM) occurs after allogeneic hematopoietic cell transplantation (HCT) in over 50% of HCT recipients and will increase 3-fold their risk of death. Further, levels of soluble Stimulation-2 (ST2) are predictive of PTDM in adults and children. However, molecular pathology of PTDM remains poorly understood, and therapeutic strategies for PTDM are limited. PTDM is initiated by hyperinsulinemia and hyperglycemia, and the alarmin IL-33 has been found to contribute to the secretion of insulin in islets by activating innate lymphoid cells type 2 (ILC2s) via Stimulation2 (ST2), the IL-33 receptor (<i>Dalmas E. et al, Immunity 2017</i>). This ST2/IL-33 regulatory axis is also critical for regulating inflammation and the balance between cytopathic T effector cells (Teffs) and regulatory cells (CD4⁺FOXP3⁺ Tregs and ILC2s). Therefore, we explored the role of ST2/IL-33 in pancreatic islets post-HCT. First, neither fasting blood glucose nor glucose tolerance (time and area under the curve) was significantly different between syngeneic and allogeneic wild-type (WT) or ST2^−/− recipients of minor mismatch HCT (B6→C3H.SW) (Fig. 1A, 1B). Total infiltrating CD90.2⁺ T cells in the pancreas were increased in the allogeneic groups but not different between WT or ST2^−/− recipients (Fig. 1C). However, pancreatic IFNγ⁺ T cells were significantly decreased while total Tregs in ST2^−/− recipient were increased (Fig. 1D, 1E). Second, using ST2 blockade with a neutralizing antibody from day -1 to day 9, 100 μg every over day for 6 doses), we showed significant improvement of survival in the treated group as compared to the isotype group (Fig. 2A), consistent with an increase in plasma IL-33 (Fig. 2B) as well as decreased plasma TNFα and IFNγ (Fig. 2C, 2D). Lastly, increased β-cell proliferation before immune cell invasion prevents progression of type 1 diabetes (<i>Ercument. et al, Nature Metabolism 2019</i>), and we found increase T cell infiltration. Thus, we specifically sought to analyze the ratio of β-cells/α-cells and both Teffs and regulatory cells in the pancreatic islets in anti-ST2 antibody treated vs. isotype groups. We found that the average ratio of β-cells/α-cells was decreased in the treated group in comparison to the isotype group (Fig. 3A). In addition, both frequencies of Tregs and ILC2s significantly increased while frequency of CD8⁺ Teffs decreased in the treated group as compared to the isotype group (Fig. 3B, 3C, 3D). We conclude that the effects of PTDM on glucose tolerance in the acute preclinical HCT model are not immediate while the effects on β-cells and immune cells are. Our data also suggest that PTDM display both type 1 and 2 diabetes phenotypes. Importantly, blockade of the IL-33/ST2 axis protected islet endocrine cells by regulating Teffs/ regulatory Tcells and ILC2s balance, and may provide an attractive approach for PTDM prevention.