Costimulation blockade and Tregs in solid organ transplantation

Abstract

Regulatory T cells (Tregs) play a critical role in maintaining self-tolerance and in containing allo-immune responses in the context of transplantation. Recent advances yielded the approval of the first pharmaceutical costimulation blockers (abatacept and belatacept), with more of them in the pipeline. These costimulation blockers inhibit effector cells with high clinical efficacy to control disease activity, but might inadvertently also affect Tregs. Treg homeostasis is controlled by a complex network of costimulatory and coinhibitory signals, including CD28, the main target of abatacept/belatacept, and CTLA4, PD-1 and ICOS. This review shall give an overview on what effects the therapeutic manipulation of costimulation has on Treg function in transplantation.

Single-Cell Heterogeneity Restorative Chimeric Engineering Nanoparticles for Alleviating Antibody-Mediated Allograft Injury

“…Surprisingly, the immune checkpoint-related gene (CTLA4) in T cells with rejection was stably expressed in T cells with rejection, and there was no statistical difference compared with the isograft group and the DSA trapper group. Thus, these findings supported that the alloimmune microenvironment upregulated the antibody-dependent cell-mediated cytotoxicity (ADCC) effect, promoted antigen presentation, and immune cell homing activities, thus leading to the transplantation rejection and the graft loss . The gene set enrichment analysis (GSEA) confirmed the changes that using DSA trappers significantly downregulated the cytotoxicity-related genes in CD8 + T cells and the Th1-polarized genes in CD4 + T helper cells, while the expression set of immunoregulatory genes was increased compared to the allograft, as shown in Figure G.…”

“…Thus, these findings supported that the alloimmune microenvironment upregulated the antibody-dependent cell-mediated cytotoxicity (ADCC) effect, promoted antigen presentation, and immune cell homing activities, thus leading to the transplantation rejection and the graft loss. 49 The gene set enrichment analysis (GSEA) confirmed the changes that using DSA trappers significantly downregulated the cytotoxicityrelated genes in CD8 + T cells and the Th1-polarized genes in CD4 + T helper cells, while the expression set of immunoregulatory genes was increased compared to the allograft, as shown in Figure 5G. Furthermore, it was supported that the DSA trappers reversed the highly biased cytotoxicity and promoted the proliferative profiles of Treg in alloimmunity, directly providing an obligate immune-tolerant niche for single-cell heterogeneity restoration (Figure 5H,I).…”

IL-6 inhibition prevents costimulation blockade-resistant allograft rejection in T cell-depleted recipients by promoting intragraft immune regulation in mice

“…In our model, IL-6 blockade resulted in only a modest increase in systemic Treg levels, which were already elevated after ATG induction. Nonetheless, we identified distinct phenotypical changes in Tregs of αIL-6 treated recipients that may correspond to a more suppressive Treg phenotype 78 .…”

Eras of designer Tregs: Harnessing synthetic biology for immune suppression

“…Treg engineering may also overcome the negative effects of costimulatory blockade, which can be used in transplantation to dampen allograft rejection by abrogating T-cell stimulation and inducing anergy. 158,159 A commonly targeted pathway is the CD80/86-CD28 pathway, which is inhibited using therapies such as CTLA-4-Ig (e.g. Belatacept and Abatacept).…”