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

Tolerance induction by targeting the CD45RC molecule : mechanisms and potential in human transplantation

L'immunosuppression générale est utilisée pour traiter les patients transplantés ou greffés avec des cellules souches. Ils ont des effets secondaires graves et sont peu efficaces à long terme. li faut donc développer de nouvelles stratégies thérapeutiques, plus ciblées, pour limiter ces effets secondaires et améliorer la qualité de vie des patients. Le niveau d'expression de la molécule CD45RC permet de distinguer, les cellules CD45RChigh associées au rejet de greffe et à la GVHD, et les cellules CD45RClow qui ont des fonctions régulatrices importantes et inhibent ces maladies. Nous avons étudié le potentiel thérapeutique d'un anti--CD45RC mAb injecté à court terme dans des modèles de greffe et de GVHD. Dans le modèle de greffe cardiaque chez le rat, l'anticorps prévient le rejet de greffe dans 60 à 80% des cas. Dans les modèles de GVHD chez le rat et la souris NSG, l'anti-CD45RC mAb associé à la rapamycine permet de prévenir la GVHD dans 50% des rats el la totalité des souris. Nous avons montré que cet anticorps induit la déplétion transitoire des L Ts CD45RChigh par apoptose. Le nombre de LTs CD45RClow est augmenté au cours du traitement el leur potentiel suppresseur est accru à long terme in vitro et in vivo. En effet le transfert adoptif des cellules, de rats tolérants leur greffon à long terme, à de nouveaux rats greffés cardiaque (même configuration génétique}. prévient le rejet de greffe. Nous avons également montré que les réponses immunitaires naïves et mémoires ne sont pas affectées. Le traitement court avec un anti-CD45RC mAb a donc un potentiel thérapeutique important dans la prévention du rejet de greffe et de la GVHD.General immunosuppressants serve lo treat solid organ or CSH transplanted patients. But they have many side effects and their efficacy is limited at long term. So its necessary lo develop new therapeutic strategies, more specific, to limit these side effects and lo improve patient quality life. The leval of expression of CD45RC distinguishes Iwo different cells types. Cells expressing CD45RChigh are associated with allograft rejection and GVHD, while cells that dont express CD45RC haveregulatory properties and inhibit these diseases. We studied the therapeutic potential of anti-CD45RC mAb as a short treatment in allograft and GVHD models. ln the heart allograft rat model, the antibody prevents rejection in 60 to 80% of the case. ln the GVHD model (rat of NSG mice), association of anti-CD45RC mAb and rapamycin prevents 50% of GVHD in the rat and all in NSG mice. We showed that the antibody induces a transitory depletion of CD45RChigh T cells throughapopolosis, while the number of CD45RClow T cells is increased and their regulatory properties are improved in vitro and in vivo. Indeed, adoptive transfer of tolerant rat lo new irradiated heart grafted rat prevents allograft rejection. We also describe that naive and memory immune responses are not impaired by the treatment Short course treatment with anti--CD45RC mAb hes a great potential lo prevent allograft rejection and GVHD

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

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