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-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.costimulation ͉ IL-17 ͉ rejection ͉ immunosuppression

Interleukin-17 Promotes Early Allograft Inflammation

“…Under these conditions, neutralizing IL-17 facilitates heart allograft survival and attenuates the development of vasculopathy. [21][22][23] In contrast, graft survival in the current study suggests that in the presence of all arms of the alloimmune response, factors other than IL-17 promote T-cell recruitment and facilitate graft rejection, thereby compensating for the absence of IL-17.…”

“…19 In addition, two groups have reported that IL-17-producing cells mediate cardiac allograft rejection in mice unable to mount Th1 alloimmune responses. [21][22][23] The potential significance of IL-17 in transplantation is further underscored by findings that a neutralizing IL-17R-Ig fusion protein reduced intragraft production of IFN␥ and prolonged survival of heart and aorta transplants in rodent models. 24,25 However, the temporal appearance and the role of IL-17 in allograft rejection by wild-type recipients under normal physiological conditions as well as the nature of cooperation between donor-specific CD4 and CD8 T cells producing IL-17 and IFN␥ remain largely undefined.…”

Absence of MyD88 Signaling Induces Donor-Specific Kidney Allograft Tolerance

“…[37][38][39] It has been shown, using mice deficient in the Th1-specific transcription factor T-bet, that Th17 cells can mediate cardiac allograft rejection 40 and are responsible for costimulation blockade-resistant allograft rejection. 41,42 In the current study, we found that WT allografts expressed significantly higher amounts of IL-6 and TGF-b than MyD88 2/2 allografts, and IL-17 mRNA was significantly increased in WTallografts (Supplemental Figure 5) 46 and nTregs, in the presence of IL-6, can themselves differentiate into Th17 cells. 47 In transplantation, the activation of innate immunity through TLR signaling allografts compared with WT allografts and not significantly different to isografts (*P,0.05).…”

T Cell Costimulation Blockade and Organ Transplantation: A Change of Philosophy for Transplant Immunologists?

“…Or has thinking shifted to a paradigm in which novel agents that induce graft acceptance experimentally are developed to replace one of the several immune suppressants that are currently administered to organ transplant recipients, with the hope of reducing patient morbidity after transplantation? Many experimental transplant immunologists still employ the original costimulatory blocking agents reported by Larsen and colleagues to investigate pathways of experimental transplant tolerance, in keeping with the philosophy initiated by Medawar (15)(16)(17)(18)(19). The study by Larsen and colleagues prompted a different philosophy of how to translate experimental immunological studies into use in patients who require chronic immune modulation.…”