Use of rapamycin in the induction of tolerogenic dendritic cells.
Rapamycin (RAPA), a macrocyclic triene antibiotic pro-drug, is a clinically-utilized 'tolerance-sparing' immunosuppressant that inhibits the activity of T, B, and NK cells. Furthermore, maturation-resistance and tolerogenic properties of dendritic cells (DC) can be supported and preserved by conditioning with RAPA. Propagation of murine bone marrow (BM)-derived myeloid DC (mDC) in clinically relevant concentrations of RAPA (RAPA-DC) generates phenotypically immature DC with low levels of MHC and significantly reduced co-stimulatory molecules (especially CD86), even when exposed to inflammatory stimuli. RAPA-DC are weak stimulators of T cells and induce hyporesponsiveness and apoptosis in allo-reactive T cells. An interesting observation has been that RAPA-DC retain the ability to stimulate and enrich the regulatory T cells (Treg). Presumably as a result of these properties, alloantigen (alloAg)-pulsed recipient-derived DC are effective in subverting anti-allograft immune responses in rodent transplant models, making them an attractive subject for further investigation of their tolerance-promoting potential.
Fischer
Ryan
R
Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Turnquist
Heth R
HR
Taner
Timuçin
T
Thomson
Angus W
AW
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002633:Chemotaxis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D007166:Immunosuppressive Agents; D020123:Sirolimus