The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-costimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation.
|Titolo:||Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells|
|Parole Chiave:||Costimulation; IL-17; Immunosuppression; Rejection; Acute Disease; Animals; Antibodies, Monoclonal; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Fluorescent Antibody Technique; Graft Rejection; Heart Transplantation; Hepatitis A Virus Cellular Receptor 1; Interleukin-17; Kaplan-Meier Estimate; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; T-Box Domain Proteins; Transplantation Tolerance; Transplantation, Homologous; Multidisciplinary|
|Settore Scientifico Disciplinare:||Settore MED/13 - Endocrinologia|
|Data di pubblicazione:||2009|
|Digital Object Identifier (DOI):||10.1073/pnas.0812538106|
|Appare nelle tipologie:||01 - Articolo su periodico|