TGF-β affinity-bound to a macroporous alginate scaffold generates local and peripheral immunotolerant responses and improves allocell transplantation

Shira Orr, Itai Strominger, Ekatrina Eremenko, Ekaterine Vinogradov, Emil Ruvinov, Alon Monsonego, Smadar Cohen

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Enhancing vascularization of cell-transplantation devices is necessary for maintaining cell viability and integration within the host, but it also increases the risk of allograft rejection. Here, we investigated the feasibility of generating an immunoregulatory environment in a highly vascularized macroporous alginate scaffold by affinity-binding of the transforming growth factor-β (TGF-β) in a manner mimicking its binding to heparan sulfate. Using this device to transplant allofibroblasts under the kidney capsule resulted in the induction of local and peripheral TGF-β-dependent immunotolerance, characterized by higher frequency of immature dendritic cells and regulatory T cells within the device and by markedly reduced allofibroblast-specific T-cell response in the spleen, thereby increasing the viability of the transplanted cells. Culturing whole splenocytes in the TGF-β-bound scaffold indicated that the regulatory function of TGF-β is IL-10-dependent. We thus demonstrate a novel platform for transplantation devices, designed to promote an immunoregulatory microenvironment suitable for cell transplantation and autoimmune regulation. Statement of Significance Allogeneic cell graft transplantation is a potentially optimal treatment for many clinical deficiencies. It is yet challenging to overcome chronic rejection without compromising host immunity to pathogens. We present the features and function of a cell transplantation device designed based on the principle of affinity binding of angiogenic and immunoregulatory factors to extracellular matrix in aim to achieve sustained release of these factors. We show that presentation of these factors in such manner generates the infrastructure for device vascularization and induces profound local allocell-specific tolerance, which then evokes peripheral T-cell tolerance. The tolerance is antigen specific, does not cause immune deficits and may thus serve to improve allocell survival as well as a platform to mitigate pathogenic autoimmunity.

Original languageEnglish
Pages (from-to)196-209
Number of pages14
JournalActa Biomaterialia
Volume45
DOIs
StatePublished - 1 Nov 2016

Keywords

  • Alginate sulfate
  • Cell transplantation
  • Control release
  • Immune regulation
  • TGF-β
  • Vascularization

ASJC Scopus subject areas

  • Biotechnology
  • Biomaterials
  • Biochemistry
  • Biomedical Engineering
  • Molecular Biology

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