Introduction and Objective: T1D & T2D Dysglycemia impairs intrinsic Mesenchymal Stromal Cells’ (MSCs) protective & regenerative functions including those of pancreatic Islet-intrinsic MSCs. This accelerates b-Cell loss. Replacing MSCs at high numbers within Neo-Islets (NIs) corrects the dysfunction. The MSC component in NIs exerts trophic, anti-inflammatory, auto- and allo-immune modulatory actions (survival, angiogenic, anti-fibrotic). We investigated immune modulatory mechanisms that provide durable glycemic control in allogeneic (allo) NI treated diabetic NOD mice vs. ineffective allo islets.Methods: Diabetic female NOD mice (~12 wks, Blood Glucose [BG] > 350 mg/dL) were treated i.p. in 3 Groups (Grp; n=6 each). 1: allo (C57/Bl6) NIs; 2: allo, C57/Bl6 islets; 3: vehicle. Prior to therapies (all grps), BG levels were controlled with insulin pellets. Monitoring in each group: BG levels (tail vein); body weights; survival. At 11 weeks, omental NI engraftment, insulin & C-Peptide expression (IHC); autoreactive T cell & Treg in spleens and omenta; IgG levels against allo NIs & islets (FACS); renal fibrosis.Results: NI therapy normalized blood glucose levels in Grp 1, improved renal function and body weights. Grps 2 and 3 became hyperglycemic & several died. NIs engrafted in omenta, expressed insulin & C-Peptide & induced angiogenesis. T helper cells in spleens and omenta from Grp 1 mice were signif. decreased vs islet treated mice. Treg numbers were signif. increased in both organs. Grp 2 sera showed significant increase in anti-islet IgG; Grp 1 sera showed none. Kidney trichrome stains from Grp 1 showed minimal interstitial fibrosis vs Grp 2.Conclusion: Allo NI therapy of NOD mice achieves durable euglycemia and renoprotection. Identical 3 yr observations are found in in allo-NI treated diabetic dogs. Human clinical studies are planned.
C.M. Westenfelder: Board Member; Current; SymbioCellTech, LLC. A. Gooch: Board Member; Current; SymbioCellTech, LLC. Employee; Current; SymbioCellTech, LLC.
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