Spontaneous Resolution of Acute Rejection and Tolerance Induction With IL-2 Fusion Protein in Vascularized Composite Allotransplantation

Abstract

y These authors contributed equally to this study.Vascularized composite allotransplantation (VCA) has emerged as a treatment option for treating nonlife-threatening conditions. Therefore, in order to make VCA a safe reconstruction option, there is a need to minimize immunosuppression, develop tolerance-inducing strategies and elucidate the mechanisms of VCA rejection and tolerance. In this study we explored the effects of hIL-2/Fc (a long-lasting human IL-2 fusion protein), in combination with antilymphocyte serum (ALS) and short-term cyclosporine A (CsA), on graft survival, regulatory T cell (Treg) proliferation and tolerance induction in a rat hind-limb transplant model. We demonstrate that hIL-2/Fc therapy tips the immune balance, increasing Treg proliferation and suppressing effector T cells, and permits VCA tolerance as demonstrated by long-term allograft survival and donor-antigen acceptance. Moreover, we observe two distinct types of acute rejection (AR), progressive and reversible, within hIL-2/Fc plus ALS and CsA treated recipients. Our study shows differential gene expression profiles of FoxP3 versus GzmB, Prf1 or interferon-g in these two types of AR, with reversible rejection demonstrating higher Treg to Teff gene expression. This correlation of gene expression profile at the first clinical sign of AR with VCA outcomes can provide the basis for further inquiry into the mechanistic aspects of VCA rejection and future drug targets.

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

“…These effects are synergistic when the combined tacrolimus and IL-2 treatment is initiated at the time of transplantation and are also apparent when IL-2 is administered at a later time point to transplant recipients on prolonged tacrolimus therapy. A synergistic effect of IL-2 and CNIs in combination with donor-specific transfusion or anti-lymphocyte serum had been described previously in a murine MHC-mismatched islet model and in a rat hind-limb transplant model, respectively (30,31). Our current work provides a clear mechanistic explanation for these previously reported findings.…”

Potent antitumour activity of interleukin-2-Fc fusion proteins requires Fc-mediated depletion of regulatory T-cells

“…Indeed, a large proportion of new biologic drugs contain antibody Fc regions due to the commercial requirement for half-life extension23, further highlighting the relevance of this format for drug development applications. As such, a number of IL-2-Fc-fusion proteins with therapeutic potential for induction of transplantation tolerance19242526 and prevention of autoimmunity2728 have been reported. Furthermore, recent studies highlight the synergistic nature of combination therapy strategies consisting of antitumour antigen antibodies and IL-2-IgG fusions in models of malignancy2930.…”

Composite tissue allotransplantation: opportunities and challenges

“…Notably, responsiveness toward third-party antigens remained intact, indicating a functional immune response. 111 Subsequently, measuring FoxP3, GymB, IFN-γ, and Prf1 allowed a prediction of rejection episodes under hIL-2/Fc, ALS, and CsA treatment, enabling the reduction of immunosuppression. 111 Injections of donor-derived allogeneic mesenchymal stromal cells after irradiation therapy causing a state of chimerism in recipients have been shown to improve allograft survival of a pig hindlimb.…”

“…111 Subsequently, measuring FoxP3, GymB, IFN-γ, and Prf1 allowed a prediction of rejection episodes under hIL-2/Fc, ALS, and CsA treatment, enabling the reduction of immunosuppression. 111 Injections of donor-derived allogeneic mesenchymal stromal cells after irradiation therapy causing a state of chimerism in recipients have been shown to improve allograft survival of a pig hindlimb. 112 In a pig hemifacial model, prolonged allograft survival upon repetitive high-dose application of bone marrowderived mesenchymal stem cells (MSCs) has been reported.…”