Tolerance in Organ Transplantation

Transplantation is often the best option to treat organ end stage failure. Transplanted patients need to take long-term immunosuppressive drugs to inhibit rejection and maintain their graft. But those therapies have numerous important side effects such as cancer induction and opportunistic infections. Thus, the development of novel therapies to induce specific rather than general immunosuppression and therefore, tipping the balance between effector and regulatory functions to inhibit transplant rejection is a major goal in the field. One major approach is the blockade of costimulatory signals to abort effector T-cell activation following TCR engagement and to promote regulatory T cells. Here we summarized the research to date that details immune mechanisms involved in tolerance in organ transplantation and strategies toward tolerance

Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/− Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice

Both CD4+ and CD8+ Tregs play a critical role in the control of immune responses and immune tolerance; however, our understanding of CD8+ Tregs is limited while they are particularly promising for therapeutic application. We report here existence of highly suppressive human CD8+CD45RClow/− Tregs expressing Foxp3 and producing IFNγ, IL-10, IL-34, and TGFβ to mediate their suppressive activity. We demonstrate that total CD8+CD45RClow/− Tregs can be efficiently expanded in the presence of anti-CD3/28 mAbs, high-dose IL-2 and IL-15 and that such expanded Tregs efficiently delay GVHD and human skin transplantation rejection in immune humanized mice. Robustly expanded CD8+ Tregs displayed a specific gene signature, upregulated cytokines and expansion in the presence of rapamycin greatly improved proliferation and suppression. We show that CD8+CD45RClow/− Tregs are equivalent to canonical CD4+CD25highCD127low/− Tregs for suppression of allogeneic immune responses in vitro. Altogether, our results open new perspectives to tolerogenic strategies in human solid organ transplantation and GVHD

Transient antibody targeting of CD45RC induces transplant tolerance and potent antigen-specific regulatory T cells

International audienceRat and human CD4(+) and CD8(+) Tregs expressing low levels of CD45RC have strong immunoregulatory properties. We describe here that human CD45 isoforms are nonredundant and identify distinct subsets of cells. We show that CD45RC is not expressed by CD4(+) and CD8(+) Foxp3(+) Tregs, while CD45RA/RB/RO are. Transient administration of a monoclonal antibody (mAb) targeting CD45RC in a rat cardiac allotransplantation model induced transplant tolerance associated with inhibition of allogeneic humoral responses but maintained primary and memory responses against cognate antigens. Anti-CD45RC mAb induced rapid death of CD45RC(high) T cells through intrinsic cell signaling but preserved and potentiated CD4(+) and CD8(+) CD45RC(low/-) Tregs, which are able to adoptively transfer donor-specific tolerance to grafted recipients. Anti-CD45RC treatment results in distinct transcriptional signature of CD4(+) and CD8(+) CD45RC(low/-) Tregs. Finally, we demonstrate that anti-human CD45RC treatment inhibited graft-versus-host disease (GVHD) in immune-humanized NSG mice. Thus, short-term anti-CD45RC is a potent therapeutic candidate to induce transplantation tolerance in human

Expanded human CD8+CD45RClowFoxp3+ Tregs secreting IFNγ, IL-10, IL-34 and TGFβinhibit human transplant rejection

International audienceTregs play a critical role in the control of immune responses and tolerance induction; however our understanding of CD8+ Tregs is limited while they are particularly promising for therapeutic application. We previously reported that CD8+CD45RC[low] Tregs use IFNγ and IL-34 to suppress donor responses in a rat model of allotransplantation (Guillonneau et al, JCI, 2007 ; Bezieetal, JCI, 2015). Here, we aim to characterize human CD8+ Tregs to assess their potential for cell therapy in transplantation in comparison to CD4+CD25[high]CD127- Tregs

Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/-Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice

International audienceBoth CD4+and CD8+Tregs play a critical role in the control of immune responses and immune tolerance; however, our understanding of CD8+Tregs is limited while they are particularly promising for therapeutic application. We report here existence of highly suppressive human CD8+CD45RClow/-Tregs expressing Foxp3 and producing IFNγ, IL-10, IL-34, and TGFβ to mediate their suppressive activity. We demonstrate that total CD8+CD45RClow/-Tregs can be efficiently expanded in the presence of anti-CD3/28 mAbs, high-dose IL-2 and IL-15 and that such expanded Tregs efficiently delay GVHD and human skin transplantation rejection in immune humanized mice. Robustly expanded CD8+Tregs displayed a specific gene signature, upregulated cytokines and expansion in the presence of rapamycin greatly improved proliferation and suppression. We show that CD8+CD45RClow/-Tregs are equivalent to canonical CD4+CD25highCD127low/-Tregs for suppression of allogeneic immune responsesin vitro. Altogether, our results open new perspectives to tolerogenic strategies in human solid organ transplantation and GVHD

Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/\textminus Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice

International audienc

Expansion of natural CD8+Tregs for cell therapy

International audienceTregs play a critical role in the control of immune responses and tolerance induction; however our understanding of CD8+ Tregs is limited while they are particularly promising for therapeutic application. We previously reported that CD8+CD45RC[low] Tregs use IFNγ and IL-34 to suppress donor responses in a rat model of allotransplantation (Guillonneau et al, JCI, 2007; Bezie et al, JCI, 2015). Here, we aim to characterize human CD8+ Tregs to assess their potential for cell therapy in transplantation

Ex Vivo Expanded Human Non-Cytotoxic CD8+CD45RClow/\textminus Tregs Efficiently Delay Skin Graft Rejection and GVHD in Humanized Mice

International audienc