Targeting apoptosis to induce stable mixed hematopoietic chimerism and long-term allograft survival without myelosuppressive conditioning in mice

Cippà, Pietro E; Gabriel, Sarah S.; Jin, Can; Bardwell, Philip D.; Bushell, Andrew; Guimezanes, Annick; Kraus, Anna; Wekerle, Thomas; Wüthrich, Rudolf P.; Fehr, Thomas

doi:10.1182/blood-2012-09-453944

Cited by 24 publications

(34 citation statements)

References 49 publications

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“…Bcl-2/Bcl-XL inhibitors such as ABT-737 represent a new class of immunomodulatory drugs with a particular relevance in the field of transplantation (14). ABT-737 inhibited allogeneic immune responses in na€ ıve mice (19) and promoted the induction of mixed chimerism and tolerance in combination with costimulation blockade (20). The present study demonstrates that the same approach is effective to control memory recall responses in virtue of the proapoptotic effect of ABT-737 on Tm.…”

Section: Discussionmentioning

confidence: 69%

“…The establishment of a clinical protocol to induce mixed chimerism based on costimulation blockade would represent a major advance in the field, but is currently precluded at least in part because of the barrier provided by Tm (1). A short induction therapy to reduce Tm by using Bcl-2 inhibitors might therefore represent the optimal solution to this central problem, particularly because of the beneficial effect of ABT-737 on mixed chimerism induction in combination with cyclosporine A (18,20).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we hypothesized that a pharmacological modulation of the intrinsic apoptosis pathway using recently developed proapoptotic small molecule Bcl-2 inhibitors, such as ABT-737 and ABT-263 (navitoclax), might represent a promising opportunity to control Tm responses (15)(16)(17)(18). The application of this approach in transplantation medicine seems particularly promising, since Bcl-2 inhibitors suppressed allogeneic immune responses and promoted the induction of donorspecific tolerance in combination with costimulation blockade (19,20). The BM3.3 mouse, which expresses on all CD8 T cells a transgenic T cell receptor (TCR) selective for a naturally processed octapeptide bound to the allogeneic MHC class I molecule H-2K b , was kindly provided by A.-M. Schmitt-Verhulst (21,22).…”

Section: Introductionmentioning

confidence: 99%

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Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Cippà

Gabriel

Kraus

et al. 2014

American Journal of Transplantation

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y Both authors contributed equally.Memory T cells (Tm) represent a major barrier for immunosuppression and tolerance induction after solid organ transplantation. Taking into consideration the critical role of the intrinsic apoptosis pathway in the generation and maintenance of Tm, we developed a new concept to deplete alloreactive Tm by targeting Bcl-2 proteins. The small-molecule Bcl-2/Bcl-XL inhibitor ABT-737 efficiently induced apoptosis in alloreactive Tm in vitro and in vivo and prolonged skin graft survival in sensitized recipients. A short course of ABT-737 induction therapy prevented Tm-mediated resistance in a donor-specific transfusion model and allowed mixed chimerism induction across Tm barriers. Since Bcl-2 inhibitors yielded encouraging safety results in cancer trials, this novel approach might represent a substantial advance to prevent allograft rejection and induce tolerance in sensitized recipients.

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Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Cippà

Gabriel

Kraus

et al. 2014

American Journal of Transplantation

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“…In a mixed chimerism-based model using costimulatory blockade, constitutive Bcl-xL expression impaired the early deletion of donor-reactive T cells and prevented the induction of donor-specific tolerance [34], whereas FasL was dispensable for CD4 cell tolerance [36]. A Bcl-2/Bcl-xL inhibitor (ABT-737), combined with co-stimulatory blockade and donor bone marrow cells, induces complete peripheral deletion of alloreactive T cells, allowing mixed chimerism induction without cytoreductive conditioning [37]. Furthermore, Bim, a key player in the intrinsic apoptosis pathway, is required for induction of mixed chimerism without lymphoablation [37].…”

Section: Ii) Tolerance Mechanisms Associated With Transient Mixed Chimentioning

confidence: 99%

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Zuber

Sykes

2017

Trends in Immunology

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Immune responses to allografts represent a major barrier in organ transplantation. Immune tolerance to avoid chronic immunosuppression is a critical goal in the field, recently achieved in the clinic by combining bone marrow transplantation with kidney transplantation following non-myeloablative conditioning. At high levels of chimerism, such protocols can permit central deletional tolerance, yet with a significant risk of graft-versus-host disease (GVHD). In contrast, transient chimerism-based tolerance is devoid of GVHD risk and appears to initially depend on regulatory T cells followed by a gradual, presumably peripheral, clonal deletion of donor-reactive T cells. Here, we review recent mechanistic insights into tolerance and the development of more robust and safer protocols for tolerance induction that will be guided by innovative immune monitoring tools.

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“…1) The second method for eliminating cytoreduction relies on proapoptotic drug therapy. The group of Thomas Fehr applied ABT-737, an inhibitor of the antiapoptotic Bcl-2 family, together with low-dose cyclosporine A and anti-CD40L, to induce mixed chimerism and donor-specific tolerance in mice [43,44]. While activated T cells in these mice were shown to become resistant to ABT-737 through a process involving calcineurin-NFAT dependent upregulation of A1, cyclosporine A reverses this effect [45].…”

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confidence: 99%

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

et al. 2015

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Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans.Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells. Keywords: Clonal deletion Mixed chimerism Nonmyeloablative conditioning Transplantation tolerance Treg cells IntroductionLong-term outcome after organ transplantation has improved little in the past few decades and remains suboptimal [1]. Grafts are still lost to immunological damage that is not prevented by current immunosuppressive drug regimens [2], which in addition cause severe adverse effects, including increased risks of malignancy and infection. Therefore, immunological tolerance -i.e., a state of specific nonresponsiveness to donor antigens -remains the "Holy Grail" in clinical organ transplantation. Among the Correspondence: Dr. Thomas Wekerle e-mail: Thomas.Wekerle@meduniwien.ac.at numerous strategies that have been tested over time, chimerismbased tolerance induction appears particularly promising [3,4]. This concept is based on the cotransplantation of donor hematopoietic stem cells (HSCs) (contained in bone marrow (BM) or mobilized peripheral blood stem cells (mPBSCs)) into the organ transplant recipient who has been sufficiently preconditioned, either with radiation or cytotoxic drugs, to permit HSC engraftment. If engraftment is achieved, multilineage chimerism ensues, which is termed "mixed" chimerism if donor representation is clearly detectable (by flow cytometry, for instance) but is less than 100% (which would constitute "full" chimerism) and can be achieved with less extensive recipient conditioning.In 1945 Ray Owen described a naturally occur...

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Targeting apoptosis to induce stable mixed hematopoietic chimerism and long-term allograft survival without myelosuppressive conditioning in mice

Cited by 24 publications

References 49 publications

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Mechanisms of Mixed Chimerism-Based Transplant Tolerance

Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism

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