Immunological shielding by induced recruitment of regulatory T lymphocytes delays rejection of islets transplanted to muscle
2015 (English)In: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 24, no 2, 263-276 p.Article in journal (Refereed) Published
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 immunosuppressive therapy during engraftment. Islets were co-transplanted with a plasmid encoding the chemokine CCL22 into 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 co-transplanted with pCCL22, significantly fewer effector T lymphocytes wereobserved in close proximity to the islets, leading to delayed graft rejection.As a result, diabeticrecipients co-transplanted with islets and pCCL22 intramuscularly became normoglycemic for ten consecutive days, while grafts co-transplanted with control plasmid muscle 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.
Immunology in the medical area
IdentifiersURN: urn:nbn:se:uu:diva-239507DOI: 10.3727/096368914X678535ISI: 000351251400011PubMedID: 24480306OAI: oai:DiVA.org:uu-239507DiVA: diva2:774765