title: Biopatterned CTLA4/Fc Matrices Facilitate Local Immunomodulation, Engraftment, and Glucose Homeostasis After Pancreatic Islet Transplantation.
abstract: Pancreatic islet transplantation (PIT) represents a potential therapy to circumvent the need for exogenous insulin in type 1 diabetes. However, PIT remains limited by lack of donor islets and the need for long-term multidrug immunosuppression to prevent alloimmune islet rejection. Our goal was to evaluate a local immunoregulatory strategy that sustains islet allograft survival and restores glucose homeostasis in the absence of systemic immunosuppression. Nanogram quantities of murine CTLA4/Fc fusion protein were controllably delivered within human acellular dermal matrix scaffolds using an inkjet-based biopatterning technology and cotransplanted with allogeneic islets under the renal capsule to create an immunoregulatory microenvironment around the islet allograft. We achieved long-term engraftment of small loads of allogeneic islet cells with 40% of MHC-mismatched mouse recipients maintaining sustained normoglycemia following pancreatic β-cell ablation by streptozotocin. Biopatterned CTLA4/Fc local therapy was associated with expansion of Foxp3+regulatory T cells and shifts in cytokine production and gene expression from proinflammatory to regulatory profiles, thus substantially benefiting islet allografts survival and function. This study is a new paradigm for targeted therapies in PIT that demonstrates the favorable effects of immune alterations in the transplant milieu and suggests a unique strategy for minimizing systemic immunosuppression and promoting islet allograft survival.
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Gorantla
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.|Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA.
authors.forename: Phil G
authors.initials: PG
authors.lastname: Campbell
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Komatsu
authors.affiliation: McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.|Robotics Institute, Carnegie Mellon University, Pittsburgh, PA.
authors.forename: Lee E
authors.initials: LE
authors.lastname: Weiss
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA solarimg@upmc.edu xzheng6688@163.com.|Transplantation Medical Center, Zhongnan Hospital, Wuhan University, Wuhan, China.
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.affiliation: Department of Plastic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA solarimg@upmc.edu xzheng6688@163.com.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Mario G
authors.initials: MG
authors.lastname: Solari
mesh_terms: D000069594:Abatacept / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006085:Graft Survival / Q000276:immunology / Q000502:physiology; D006706:Homeostasis / Q000276:immunology / Q000502:physiology; D056747:Immunomodulation / Q000276:immunology / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism
chemical_list: D016207:Cytokines; D000069594:Abatacept; D005947:Glucose