title: TGF-β affinity-bound to a macroporous alginate scaffold generates local and peripheral immunotolerant responses and improves allocell transplantation.
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.
  
  
  
  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.
authors: Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Shira
authors: S
authors: Orr
authors: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute of Biotechnology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Itai
authors: I
authors: Strominger
authors: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute of Biotechnology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Ekatrina
authors: E
authors: Eremenko
authors: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute of Biotechnology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Ekaterine
authors: E
authors: Vinogradov
authors: Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Emil
authors: E
authors: Ruvinov
authors: The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, and The National Institute of Biotechnology, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: ortshira@gmail.com.
authors: Alon
authors: A
authors: Monsonego
authors: Avram and Stella Goldstein-Goren Department of Biotechnology Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel; The Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors: Smadar
authors: S
authors: Cohen
mesh_terms: D000464:Alginates / Q000737:chemistry*; D000818:Animals; D060833:Cellular Microenvironment / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D007108:Immune Tolerance / Q000187:drug effects*; D056747:Immunomodulation / Q000187:drug effects; D016753:Interleukin-10 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000187:drug effects; D016062:Porosity; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D054457:Tissue Scaffolds / Q000737:chemistry*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: D000464:Alginates; D006603:Hexuronic Acids; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D020723:Glucuronic Acid
keywords: Alginate sulfate; Cell transplantation; Control release; Immune regulation; TGF-β; Vascularization