No prolongation of skin allograft survival by immunoproteasome inhibition in mice

Abstract

The immunoproteasome, a distinct class of proteasomes, which is inducible under inflammatory conditions and constitutively expressed in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on major histocompatibility complex (MHC) class I molecules. Moreover, inhibition of the immunoproteasome subunit LMP7 ameliorates clinical symptoms of autoimmune diseases in vivo and was shown to suppress the development of T helper cell (Th) 1 and Th17 cells and to promote regulatory T-cell (Treg) generation independently of its function in antigen processing. Since Th1 and Th17 cells are detrimental and Treg cells are critical for transplant acceptance, we investigated the influence of the LMP7-selective inhibitor ONX 0914 in a mixed lymphocyte reaction (MLR) in vitro as well as on allograft rejection in a MHC-disparate (C57BL/6 to BALB/c) and a multiple minor histocompatibility antigen (miHA)-disparate (B10.Br to C3H) model of skin transplantation in vivo. Although we observed reduced allo-specific IL-17 production of T cells in vitro, we found that selective inhibition of LMP7 had neither an influence on allograft survival in an MHC-mismatch model nor in a multiple minor mismatch skin transplantation model. We conclude that inhibition of the immunoproteasome is not effective in prolonging skin allograft survival in skin allotransplantation.

Immunoproteasome inhibition prevents chronic antibody-mediated allograft rejection in renal transplantation

“…We have tested recently whether ONX 0914 can be employed to interfere with acute T cell-mediated rejection of allotransplanted skin in mice, but no prolongation of graft survival was achieved, not even in combination with cyclosporine A. 32 Also in an MLR performed with allogeneic C57BL/6 and BALB/c mice, ONX 0914 was unable to interfere with T cell proliferation, in contrast to cyclosporine A. Therefore, we think that the suppression of chronic renal allografts shown in this study relies on the inhibition of plasma cells rather than T cells.…”

The Significant Role of PA28αβ in CD8+ T Cell-Mediated Graft Rejection Contrasts with Its Negligible Impact on the Generation of MHC-I Ligands

“…Skin transplantation experiments were performed as previously described [ 49 ]. Briefly, the skin of the tails of sacrificed donor mice was transplanted onto the back of recipient mice.…”

On the role of the immunoproteasome in transplant rejection

“…LMP7 inhibition was shown to suppress the differentiation of the proinflammatory T helper subtypes Th1 and Th17 in vitro Kalim et al 2012;Muchamuel et al 2009; and in vivo (Basler et al 2014;. Therefore, the effect of immunoproteasome inhibition was investigated in skin allograft transplantation using the LMP7selective inhibitor ONX 0914 (Mundt et al 2017). In vitro, in a mixed-lymphocyte-reaction (MLR), ONX 0914 reduced allospecific IL-17 production in T cells.…”

“…Alterations can only be observed for CTLs specific for LMP7-dependent class I peptides. Thus, the influence of immunoproteasome inhibition on Th cell differentiation appears to be not strong enough to influence skin allograft rejection which is dominated by CTLs in the used skin allograft models (Mundt et al 2017). Hence, immunoproteasome inhibition does not appear to be a suitable approach to treat acute T cell-mediated skin allograft rejection.…”