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Immunological Shielding by Induced Recruitment of Regulatory T-Lymphocytes Delays Rejection of Islets Transplanted in Muscle
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
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2015 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 24, no 2, 263-276 p.Article in journal (Refereed) Published
Abstract [en]

The only clinically available curative treatment of type 1 diabetes mellitus is replacement of the pancreatic islets by allogeneic transplantation, which requires immunosuppressive therapies. Regimens used today are associated with serious adverse effects and impaired islet engraftment and function. The aim of the current study was to induce local immune privilege by accumulating immune-suppressive regulatory T-lymphocytes (Tregs) at the site of intramuscular islet transplantation to reduce the need of irnmunosuppressive therapy during engraftment. Islets were cotransplanted with a plasmid encoding the chemokine CCL22 into the muscle of MHC-mismatched mice, after which pCCL22 expression and leukocyte recruitment were studied in parallel with graft functionality. Myocyte pCCL22 expression and secretion resulted in local accumulation of Tregs. When islets were cotransplanted with pCCL22, significantly fewer effector T-lymphocytes were observed in close proximity to the islets, leading to delayed graft rejection. As a result, diabetic recipients cotransplanted with islets and pCCL22 intramuscularly became normoglycemic for 10 consecutive days, while grafts cotransplanted with control plasmid were rejected immediately, leaving recipients severely hyperglycemic. Here we propose a simple method to initially shield MHC-mismatched islets by the recruitment of endogenous Tregs during engraftment in order to improve early islet survival. Using this approach, the very high doses of systemic immunosuppression used initially following transplantation can thereby be avoided.

Place, publisher, year, edition, pages
2015. Vol. 24, no 2, 263-276 p.
Keyword [en]
Diabetes; Immunosuppression; C-C motif ligand 22 (CCL22); DNA plasmid; Muscle; Intramuscular transplantation
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-299680DOI: 10.3727/096368914X678535ISI: 000351251400011PubMedID: 24480306OAI: oai:DiVA.org:uu-299680DiVA: diva2:949890
Funder
Swedish Research Council, K2012-99x; 65X-12219-15-6; 5570x-15043Swedish Diabetes AssociationSwedish Child Diabetes FoundationNovo NordiskRagnar Söderbergs stiftelseKnut and Alice Wallenberg FoundationNIH (National Institute of Health), 2U01A1065192-06
Available from: 2016-07-25 Created: 2016-07-25 Last updated: 2016-07-28Bibliographically approved

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Vågesjö, EvelinaChristoffersson, GustafWaldén, Tomas BCarlsson, Per-OlaEssand, MagnusKorsgren, OllePhillipson, Mia
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Integrative PhysiologyDepartment of Medical Cell BiologyTransplantation and regenerative medicineDepartment of Immunology, Genetics and Pathology
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Cell Transplantation
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