Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A

Cippà, Pietro E; Kamarashev, Jivko; Chen, Jin; Kraus, Anna; Segerer, Stephan; Feldmeyer, Laurence; Fehr, Thomas

doi:10.1007/s10495-012-0778-2

Cited by 10 publications

(15 citation statements)

References 36 publications

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“…Tm are less costimulation-dependent than na€ ıve T cells [4]), but also on the antigen-specific precursor frequency (32). The marked skin graft survival prolongation observed in mice treated with ABT-737, MR1 and DST might be related to a reduced precursor frequency due to ABT-737-induced lymphopenia (18) or to the activation of regulatory mechanisms. Importantly, this process was not precluded by adoptive transfer of Tm.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…More precisely, the balance between the proapoptotic Bim and the antiapoptotic Bcl-2 and Bcl-XL controls Tm survival (10)(11)(12)(13), and a direct inhibition of Bcl-2 and Bcl-XL reduced the number of T cells with a memory phenotype in mice (14). 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).…”

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: 99%

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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“…Also, there have been some studies of the influence of CSA on B cells and the humoral response (92)(93)(94). CSA did not suppress Ab production in autoimmune diseases and transplantations (95)(96)(97), suggesting that the target mechanism in T cells is different from that in B cells; CSA targets calcium activation in T cells but may not affect that pathway in B cells (93,(98)(99)(100). However, we speculate that the mechanism by which CSA enhanced Ab production here may be indirect and via induction of Treg cells.…”

Section: Discussionmentioning

confidence: 99%

A Recombinant G Protein Plus Cyclosporine A–Based Respiratory Syncytial Virus Vaccine Elicits Humoral and Regulatory T Cell Responses against Infection without Vaccine-Enhanced Disease

Zhou

Zhong

et al. 2016

The Journal of Immunology

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Respiratory syncytial virus (RSV) infection can cause severe disease in the lower respiratory tract of infants and older people. Vaccination with a formalin-inactivated RSV vaccine (FI-RSV) and subsequent RSV infection has led to mild to severe pneumonia with two deaths among vaccinees. The vaccine-enhanced disease (VED) was recently demonstrated to be due to an elevated level of Th2 cell responses following loss of regulatory T (Treg) cells from the lungs. To induce high levels of neutralizing Abs and minimize pathogenic T cell responses, we developed a novel strategy of immunizing animals with a recombinant RSV G protein together with cyclosporine A. This novel vaccine induced not only a higher level of neutralizing Abs against RSV infection, but, most importantly, also significantly higher levels of Treg cells that suppressed VED in the lung after RSV infection. The induced responses provided protection against RSV challenge with no sign of pneumonia or bronchitis. Treg cell production of IL-10 was one of the key factors to suppress VED. These finding indicate that G protein plus cyclosporine A could be a promising vaccine against RSV infection in children and older people.

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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].…”

mentioning

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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Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A

Cited by 10 publications

References 36 publications

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

A Recombinant G Protein Plus Cyclosporine A–Based Respiratory Syncytial Virus Vaccine Elicits Humoral and Regulatory T Cell Responses against Infection without Vaccine-Enhanced Disease

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

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