title: Role of CCL2/MCP-1 in islet transplantation.
abstract: High levels of donor-derived CCL2 have been associated with poor islet allograft outcome in patients with type 1 diabetes. The aim of our work was to determine whether CCL2 secreted by the islet has independent proinflammatory effects that influence engraftment and graft acceptance. Both in mice and humans CCL2 is significantly positively associated with other cytokines/chemokines, in particular with the highly released "proinflammatory" IL-6 and CXCL8 or CXCL1. Transplantation of CCL2-/- islets into syngenic recipients did not improve the transplant function. Transplantation of islets into CCL2-/- syngenic recipients led to a significant improvement of transplant function and partial abrogation of local hepatic inflammation. When evaluated in human islets CCL2 release was strongly related to the immediate local inflammatory response in the liver and impacted short-term human islet function dependently by the induced inflammatory response and independently by the immunosuppressive therapy. The data showed that islet CCL2 release is a sign of "inflamed" islets without having a direct role in graft failure. On the other hand, a causal effect for developing detrimental proinflammatory conditions after transplant was proved for recipient CCL2. Strategies to selectively decrease recipient, but not donor, CCL2 release may increase the success of islet transplantation.
authors.affiliation: Beta Cell Biology Unit, Diabetes Research Institute, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Melzi
authors.forename: Alessia
authors.initials: A
authors.lastname: Mercalli
authors.forename: Valeria
authors.initials: V
authors.lastname: Sordi
authors.forename: Elisa
authors.initials: E
authors.lastname: Cantarelli
authors.forename: Rita
authors.initials: R
authors.lastname: Nano
authors.forename: Paola
authors.initials: P
authors.lastname: Maffi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sitia
authors.forename: Luca G
authors.initials: LG
authors.lastname: Guidotti
authors.forename: Antonio
authors.initials: A
authors.lastname: Secchi
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
mesh_terms: D000328:Adult; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000502:physiology*; D054360:Chemokine CXCL1 / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000209:etiology; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged
chemical_list: D018932:Chemokine CCL2; D054360:Chemokine CXCL1; D015850:Interleukin-6; D016209:Interleukin-8