Low gravity rotational culture and the integration of immunomodulatory stem cells reduce human islet allo-reactivity

Khalid M. Qureshi, Jou Lee, Michelle B. Paget, Clifford J. Bailey, S. John Curnow, Hilary E. Murray*, Richard Downing

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)90-98
Number of pages9
JournalClinical Transplantation
Volume29
Issue number1
Early online date5 Dec 2014
DOIs
Publication statusPublished - Jan 2015

Bibliographical note

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Keywords

  • Allo-reactivity
  • amniotic epithelial cells
  • immunomodulation
  • islet transplantation
  • rotational cell culture
  • T cell

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