title: Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells.
abstract: 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-co-stimulatory 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.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Xueli
authors.initials: X
authors.lastname: Yuan
authors.forename: M Javeed
authors.initials: MJ
authors.lastname: Ansari
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Addio
authors.forename: Jesus
authors.initials: J
authors.lastname: Paez-Cortez
authors.forename: Isabella
authors.initials: I
authors.lastname: Schmitt
authors.forename: Michela
authors.initials: M
authors.lastname: Donnarumma
authors.forename: Olaf
authors.initials: O
authors.lastname: Boenisch
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Zhao
authors.forename: Joyce
authors.initials: J
authors.lastname: Popoola
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clarkson
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: John
authors.initials: J
authors.lastname: Iacomini
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Glimcher
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D016027:Heart Transplantation / Q000379:methods; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous; D000098815:T-bet Transcription Factor
chemical_list: D000911:Antibodies, Monoclonal; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17; D008565:Membrane Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor