Preserving Treg Function: Beyond mTOR Inhibitors

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When the antifungal compound rapamycin was discovered in 1972 within bacteria isolated from soil samples acquired on the South Pacific island of Rapa Nui, its future use in preventing transplant rejection could not have been predicted. As advancing research unearthed the evolutionarily conserved signal transduction pathway mTOR (mechanistic target of rapamycin),1 an understanding of the role of rapamycin in abrogating T-cell activation developed. There has since been much interest in detailing the potential of this class of immunosuppressant in modulating or enhancing regulatory T (Treg) cell function.2,3 An additional interest has been the anticancer potential of mTOR inhibitors, although these effects are not entirely clear or consistent.4-7 During the late 1980s and early 1990s, another receptor-signaling pathway, exclusive to resting Treg cells and activated T cells bearing the OX40 (CD134) receptor was also discovered.8 OX40 is enriched at sites of autoimmune inflammation9,10 and is found on the surface of circulating lymphocytes in systemic autoimmune diseases. Once ligated, OX40 signaling promotes the development of a cytokine-producing effector T (Teff) cells and prolongs the survival of memory T (Tmem) cells. Blockade or deficiency of OX40 has been shown to effectively attenuate autoimmune pathology.11,12 In vivo studies have demonstrated that OX40 ligand (OX40L) blockade can abrogate autoimmunity,11 potentially representing a more effective target than its receptor.13 In transplantation, blockade of OX40 effectively targets both CD4+ and CD8+ T cells to prevent rejection.14
Leslie Kean’s group has contributed extensively to the field of transplant tolerance, with a specific focus on the summative benefits of combinatorial therapies targeting T cell costimulatory and coinhibitory pathways. Having previously published promising results in their nonhuman primate (NHP) transplant model,15-21 the group is currently involved in clinical trials assessing the efficacy of CTLA4-Ig therapy to prevent severe graft versus host disease (GVHD); moreover, current trials include an anti-CD28 Fab22 for the treatment of rheumatoid arthritis. There is certainly a strong argument for using combinatorial therapies to manipulate lymphocyte signaling pathways to simultaneously tilt the immune balance toward allograft tolerance in both Treg cell and Teff cell compartments.22
In their recent study published in Science Translational Medicine,23 the authors aimed to identify an immunoprophylactic therapy that can synergize with the protolerogenic capabilities of sirolimus and in doing so highlighted the ability of OX40-OX40L blockade to control Tmem and Teff function while preserving the homeostasis and function of Treg. Using an NHP model of GVHD, they demonstrated increased expression of OX40L on lymph node-derived myeloid dendritic cells after allotransplantation in the absence of immunoprophylaxis. Moreover, they observed the OX40-encoding transcript TNFRSF4 in T cells after allotransplantation when using sirolimus. Based on those observations, they assessed the effects of OX40-OX40L blockade using a monoclonal anti-OX40L antibody (KY1005) with or without sirolimus in their high-risk NHP allogeneic GVHD model. KY1005 monotherapy reduced the rates of proliferating T cells and OX40+ CD4+ conventional T cells (predominantly central memory [TCM]) without impacting the proportion of Treg while modestly extended recipient survival (+11.5 days compared with untreated controls). Anti-OX40L treatment also reduced CD4+ T-cell expression of IL-17A, the hallmark cytokine of the Th17 profile typically associated with breakthrough acute GVHD (aGVHD).
Additionally, all recipients demonstrated effective donor engraftment with robust T-cell chimerism. Allospecific T-cell activation was controlled with significantly reduced CD4+ and CD8+ proliferation, decreased proportions (however, not numbers) of CD4+ TCM cells, and enhanced reconstitution of Treg and naive CD4+ T cells. Recipients that received the combinatorial treatment had distinct immunological transcriptome profiles, suggesting a unique synergistic effect of the combined therapies.
This study impressively demonstrates how the simultaneous blockade of synergistic inflammatory pathways can enhance efficacy.
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