TLR agonists abrogate co-stimulation blockade-induced mixed chimerism and transplantation tolerance.
We investigated the mechanisms by which Toll-like receptor (TLR) agonists affect the induction of mixed chimerism and skin allograft survival in mice treated with co-stimulation blockade (CB). We report that TLR agonists prevent the generation of mixed chimerism by breaking tolerance in the alloreactive CD4(+) and CD8(+) T cell compartments, and that type I interferon (IFN) is important in this process. Understanding how environmental perturbations affect CB-induced transplantation tolerance may lead to more effective regimens that can be used as an approach for the treatment of type I diabetes, for which the transplantation of pancreatic islets is a promising therapy.
Miller
David M
DM
Department of Medicine, Division of Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Thornley
Thomas
T
Pearson
Todd
T
Yamazaki
Masahiro
M
Brehm
Michael A
MA
Rossini
Aldo A
AA
Greiner
Dale L
DL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D046528:Chimerism / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D016038:Skin Transplantation / Q000276:immunology / Q000662:veterinary; D051196:Toll-Like Receptor 3 / Q000819:agonists; D051197:Toll-Like Receptor 4 / Q000819:agonists; D051193:Toll-Like Receptors / Q000819:agonists*; D023001:Transplantation Tolerance / Q000187:drug effects*
C508032:Ifnar1 protein, mouse; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D053633:Receptor, Interferon alpha-beta; D011070:Poly I-C