Low gravity rotational culture and the integration of immunomodulatory stem cells reduce human islet allo‐reactivity |
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| Authors: | Khalid M. Qureshi Jou Lee Michelle B. Paget Clifford J. Bailey S. John Curnow Hilary E. Murray Richard Downing |
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| Affiliation: | 1. The Islet Research Laboratory, Worcester Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK;2. Diabetes Research, Aston Pharmacy School, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham, UK;3. Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, UK |
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| Abstract: | Modification of human islets prior to transplantation may improve long‐term clinical outcome in terms of diabetes management, by supporting graft function and reducing the potential for allo‐rejection. Intragraft incorporation of stem cells secreting beta (β)‐cell trophic and immunomodulatory factors represents a credible approach, but requires suitable culture methods to facilitate islet alteration without compromising integrity. This study employed a three‐dimensional rotational cell culture system (RCCS) to achieve modification, preserve function, and ultimately influence immune cell responsiveness to human islets. Islets underwent intentional dispersal and rotational culture‐assisted aggregation with amniotic epithelial cells (AEC) exhibiting intrinsic immunomodulatory potential. Reassembled islet constructs were assessed for functional integrity, and their ability to induce an allo‐response in discrete T‐cell subsets determined using mixed islet:lymphocyte reaction assays. RCCS supported the formation of islet:AEC aggregates with improved insulin secretory capacity compared to unmodified islets. Further, the allo‐response of peripheral blood mononuclear cell (PBMC) and purified CD4+ and CD8+ T‐cell subsets to AEC‐bearing grafts was significantly (p < 0.05) attenuated. Rotational culture enables pre‐transplant islet modification involving their integration with immunomodulatory stem cells capable of subduing the allo‐reactivity of T cells relevant to islet rejection. The approach may play a role in achieving acute and long‐term graft survival in islet transplantation. |
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| Keywords: | allo‐reactivity amniotic epithelial cells immunomodulation islet transplantation rotational cell culture T cell |
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