Prolonged Survival of Mouse Skin Allografts in Recipients Treated With Donor Splenocytes and Antibody to Cd40 Ligand1

Markees, Thomas G.; Phillips, Nancy E.; Noelle, Randolph J.; Shultz, Leonard D.; Mordes, John P.; Greiner, Dale L.; Rossini, Aldo A.

doi:10.1097/00007890-199707270-00026

Cited by 159 publications

(134 citation statements)

References 50 publications

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“…We tested the possibility to overcome this obstacle by Bcl-2/Bcl-XL inhibition in a model including DST, costimulation blockade with anti-CD154 (MR1) and skin transplantation (27). To selectively investigate the effect on Tm while excluding the effect of preexisting donor-reactive antibodies, an adoptive transfer approach was chosen ( Figure 4A).…”

Section: Bcl-2/bcl-xl Inhibition Restores Sensitivity To Costimulatiomentioning

confidence: 99%

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: Bcl-2/bcl-xl Inhibition Restores Sensitivity To Costimulatiomentioning

confidence: 99%

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Cippà

Gabriel

Kraus

et al. 2014

American Journal of Transplantation

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“…CD40 binding to CD40L is known to be an important costimulatory signal for the activation of naïve T cells, and antigen recognition by naïve T cells in the absence of costimulation has been shown to actively induce a tolerant state (12)(13)(14). In contrast to naïve T cells, however, antigen-experi-enced T cells have lower costimulatory requirements for activation, and may become activated in the total absence of costimulation, particularly if the T-cell receptor MHC-peptide interaction is of high affinity (21,22,35,36).…”

Section: Memory T Cells Abrogate Prolonged Graft Survivalmentioning

confidence: 99%

“…Costimulatory blockade with anti-CD40 ligand antibody (aCD40L) plus donor specific transfusion (DST) is one approach that is extremely effective in rodents and shows promise in larger animals (12)(13)(14)(15)(16). Present evidence suggests that this intervention may delete alloantigen-reactive CD8π T cells and may induce anergy and/or regulatory immunity of donor-reactive CD4π T cells (17,18).…”

Section: Introductionmentioning

confidence: 99%

Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

Valujskikh

Pantenburg

Heeger

2002

American Journal of Transplantation

228

214

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“…Anti-CD154 (CD40 ligand) treatment has been shown to be an effective way of preventing transplant rejection in animal models (8)(9)(10)(11). It has been proposed that such treatment impairs the maturation of host antigen-presenting cells, generates tolerogenic dendritic cells, promotes T cell anergy (12) and deletion (13), and induces regulatory T cells (14,15).…”

mentioning

confidence: 99%

Peripheral deletion of mature alloreactive B cells induced by costimulation blockade

Shen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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(4). In animal models, the major evidence comes from studies using the MT mice. These mice have a targeted mutation at the transmembrane domain of B cell receptor -chain and have defects in B cells and antibody secretion (5), as well as a reduction in T cell and dendritic cell numbers (6). In a mouse cardiac transplant model in which B10.A (H-2 a ) hearts are transplanted into H-2 b MT mouse, acute rejection is prevented. Passive transfer of complement-activating alloantibodies restores acute rejection, suggesting that antibodies can facilitate the development of acute allograft rejection (7).Anti-CD154 (CD40 ligand) treatment has been shown to be an effective way of preventing transplant rejection in animal models (8-11). It has been proposed that such treatment impairs the maturation of host antigen-presenting cells, generates tolerogenic dendritic cells, promotes T cell anergy (12) and deletion (13), and induces regulatory T cells (14, 15). Graft survival can be further enhanced by donor-specific transfusion (DST) (16), and in the presence of anti-CD154, the infused DST is presented by host antigen-presenting cells in a tolerogenic manner, resulting in T cell anergy and regulation (17). Blocking CD154-CD40 interaction also prevents the T-dependent humoral responses (18). As a result, alloantibody production is inhibited (19), which can also be important for the long-term survival of allografts. However, the detailed mechanism of how alloreactive B cells are regulated by such costimulation-targeted therapies is not clear.To characterize the fate of alloreactive B cells after tolerance induction by anti-CD154-based therapy, we took advantage of a B cell receptor transgenic mouse, . This mouse inherits the transgenes that encode the heavy and light chain of a B cell receptor that recognizes the mouse class I MHC molecule H-2K b . B cells expressing the transgene can develop normally on the BALB/c background but are efficiently regulated by receptor editing on the C57BL/6 background (21). When the K b antigen is only expressed by the liver hepatocytes, the 3-83 B cells are deleted in the periphery (22). We used 3-83Igi mice on the BALB/c background as recipients of transplanted C57BL/6 hearts. We then induced tolerance with anti-CD154 and DST. The alloreactive 3-83 B cells are easily detected by an anti-idiotype (Id) antibody (23), allowing us to visualize changes in these B cells after tolerance induction. The results of our study showed that alloreactive B cells were specifically deleted in the periphery at the mature stage.

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Prolonged Survival of Mouse Skin Allografts in Recipients Treated With Donor Splenocytes and Antibody to Cd40 Ligand1

Cited by 159 publications

References 50 publications

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Primed Allospecific T Cells Prevent the Effects of Costimulatory Blockade on Prolonged Cardiac Allograft Survival in Mice

Peripheral deletion of mature alloreactive B cells induced by costimulation blockade

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