Interferon-beta trans-signaling in transplant

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

Project Summary Transplantation is the ideal treatment for end-stage organ failure, but graft survival is suboptimal, with an average half-life of ~10-15 years for most organs. Ischemia-reperfusion injury (IRI), which is proportional to the organ's cold ischemia storage (CIS) time, contributes to delayed graft function and constitutes a major risk factor for early allograft loss. IRI activates the production of a network of interactive pro-inflammatory cytokines, including (IL-6), that promote donor-reactive effector (Teff) and memory (Tmem) T cells and reduce regulatory T cells (Treg). Understanding the physiological mechanisms that counteract this inflammation has the potential to identify new therapeutic targets in transplant. During this proposal's first cycle, we predicted, using an in silico computational model, an unanticipated Treg-enhancing effect of the pro-inflammatory cytokine interferon-beta (IFN), a type I interferon. We tested this prediction experimentally and demonstrated that, in stark contradiction with its pro-inflammatory physiological role IRI in transplant, exogenous interferon-beta (IFN) synergizes with CTLA-4 Ig to prolong allograft survival by directly acting on T cells to enhance Treg induction through the increase of Foxp3 acetylation. Herein we propose to build upon these findings and study a previously-unrecognized mode of type I IFN signaling (trans- signaling) involving a soluble isoform of the interferon receptor 2 subunit (sIFNAR2), which we contend is required for the immunosuppressive effects of IFN in transplant. We have obtained solid preliminary data supporting the hypothesis that (i) sIFNAR2 is produced in response to IRI-induced pro-inflammatory cytokines, including IL-6, (ii) sIFNAR2 builds up and over time shifts the IFN response on T cells from inflammatory to immunosuppressive, and (iii) this is achieved mechanistically through IFN/sIFNAR2 trans-signaling which increases Treg induction and decreases Teff proliferation. We also contend that early exogenous administration of sIFNAR2 together with IFN post-transplant can counteract the Treg-depleting effect of pro-inflammatory cytokines produced in IRI to prolong allograft survival. We will test this hypothesis using an integrated computational and experimental approach, which accelerates research and minimizes the number of experiments in animals through the following specific aims. We will demonstrate that IFN/sIFNAR2 trans- signaling is required for IFN to increase Treg and decrease Teff responses in vivo in the context of transplant (Aim 1), we will elucidate the molecular mechanisms responsible for IFN/sIFNAR2 trans-signaling effects on T cell responses and innate antiviral responses (Aim 2), and we will establish the role of sIFNAR2 in controlling the pro-inflammatory/immunosuppressive balance in T cell responses during ischemia-reperfusion injury (IRI) in murine transplant models (Aim 3).