In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

Ripoll, Élia; Pluvinet, Raquel; Torrás, Joan; Olivar, Rut; Vidal, August; Franquesa, M.; Cassis, Linda; Cruzado, Josep M.; Bestard, Oriol; Grinyó, Josep M.; Aran, Josep M.; Herrero‐Fresneda, Immaculada

doi:10.1038/gt.2011.39

Cited by 29 publications

(32 citation statements)

References 43 publications

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“…Thus, studying the mechanisms by which this mechanism induces robust tolerance remains an important question for the field, with the aim of developing alternative methods of inhibiting CD154. Recent studies have used an RNAi approach to inhibit CD40 expression (41,42), and a similar approach could be envisaged for CD154 inhibition. Alternatively, non-cross-linking mAbs could be developed to antagonize CD154, much like nonactivating single-chain F V -based reagents have been developed in lieu of cross-linking anti-CD28 mAbs (43), which has resulted in a much more severe side effect profile than that seen in anti-CD154 mAbs in pilot studies in humans (44).…”

Section: Discussionmentioning

confidence: 99%

Antigen-specific induced Foxp3⁺regulatory T cells are generated following CD40/CD154 blockade

Ferrer

Wagener²,

Song³

et al. 2011

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

103

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Blockade of the CD40/CD154 pathway potently attenuates T-cell responses in models of autoimmunity, inflammation, and transplantation. Indeed, CD40 pathway blockade remains one of the most powerful methods of prolonging graft survival in models of transplantation. But despite this effectiveness, the cellular and molecular mechanisms underlying the protective effects of CD40 pathway blockade are incompletely understood. Furthermore, the relative contributions of deletion, anergy, and regulation have not been measured in a model in which donor-reactive CD4 + and CD8 + T-cell responses can be assessed simultaneously. To investigate the impact of CD40/CD154 pathway blockade on graft-specific T-cell responses, a transgenic mouse model was used in which recipients containing ovalbumin-specific CD4 + and CD8 + TCR transgenic T cells were grafted with skin expressing ovalbumin in the presence or absence of anti-CD154 and donor-specific transfusion. The results indicated that CD154 blockade altered the kinetics of donorreactive CD8 + T-cell expansion, delaying differentiation into IFN-γ + TNF + multifunctional cytokine producers. The eventual differentiation of cytokine-producing effectors in tolerant animals coincided with the emergence of an antigen-specific CD4 + CD25 hi Foxp3 + T-cell population, which did not arise from endogenous natural T reg but rather were peripherally generated from naïve Foxp3 − precursors.costimulation blockade B lockade of the CD40/CD154 pathway has long been appreciated as a potent means of inhibiting alloreactive T-cell responses and prolonging graft survival. But despite this pronounced effect on allograft survival in both murine and nonhuman primate models (1-3), clinical trials using anti-CD154 mAbs in transplantation were halted due to thromboembolic complications, likely related to the expression of CD154 on platelets (4, 5). However, recent studies using anti-CD40 mAbs in both murine and nonhuman primate models demonstrated comparable efficacy to CD154 blockade, and thus significant interest in the pathway remains (6-9).Early studies by Parker et al. (3) described the treatment combination of anti-CD154 and donor-specific transfusion (DST) for the induction of immune tolerance in transplantation. Several groups have since demonstrated the potent effects of this combined therapy in the prolongation of islet (3, 10, 11), cardiac (12), skin (10, 13), and kidney (14, 15) allograft survival in murine and nonhuman primate models. Although costimulation blockade has been associated with T-cell anergy (16) or deletion (17, 18), elucidation of the precise independent and synergistic effects of DST and anti-CD154 on the kinetics of donor-reactive CD4 + and CD8 + effector T-cell expansion has been limited because of the inability to identify and track graft-specific T cells in fully allogeneic models.Importantly, studies by Taylor et al. (19) demonstrated that CD4 + CD25 + regulatory T cells (T reg ) are required for tolerance induced via CD40/CD154 pathway blockade in a graft-versushost model....

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Section: Discussionmentioning

confidence: 99%

Antigen-specific induced Foxp3⁺regulatory T cells are generated following CD40/CD154 blockade

Ferrer

Wagener²,

Song³

et al. 2011

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

103

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“…15,16,17,18,19,20 Additionally, recent work has demonstrated that patients at risk of recurrent FSGS have high plasma titers of CD40 autoantibodies which produce renal injury in mice. 21 These studies suggest that CD40 inhibition would have therapeutic value in the treatment of glomerulonephritis and related renal diseases.…”

Section: Introductionmentioning

confidence: 99%

CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin-induced Nephropathy and Kidney Inflammation

Donner

Yeh

Hung

et al. 2015

Molecular Therapy - Nucleic Acids

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Preclinical and clinical data suggest CD40 activation contributes to renal inflammation and injury. We sought to test whether upregulation of CD40 in the kidney is a causative factor of renal pathology and if reduction of renal CD40 expression, using antisense oligonucleotides (ASOs) targeting CD40, would be beneficial in mouse models of glomerular injury and unilateral ureter obstruction. Administration of a Generation 2.5 CD40 ASO reduced CD40 mRNA and protein levels 75–90% in the kidney. CD40 ASO treatment mitigated functional, transcriptional, and pathological endpoints of doxorubicin-induced nephropathy. Experiments using an activating CD40 antibody revealed CD40 is primed in kidneys following doxorubicin injury or unilateral ureter obstruction and CD40 ASO treatment blunted CD40-dependent renal inflammation. Suborgan fractionation and imaging studies demonstrated CD40 in glomeruli before and after doxorubicin administration that becomes highly enriched within interstitial and glomerular foci following CD40 activation. Such foci were also sites of ASO distribution and activity and may be predominately comprised from myeloid cells as bone marrow CD40 deficiency sharply attenuated CD40 antibody responses. These studies suggest an important role of interstitial renal and/or glomerular CD40 to augment kidney injury and inflammation and demonstrate that ASO treatment could be an effective therapy in such disorders.

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“…88-90 Targeting CD40 can also be achieved with small interfering RNA directed toward CD40 mRNA. 91,92 Finally, gene transfer of CD40Ig fusion proteins is also being explored, with contrasting results. 93,94 …”

Section: Cd40-cd40l Pathwaymentioning

confidence: 99%

Costimulation Blockade in Kidney Transplantation

2016

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In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4. Belatacept has been demonstrated to be as efficient as cyclosporine-based immunosuppression and is associated with significantly better renal function, that is, no nephrotoxicity. However, in the immediate posttransplant period, significantly more mild/moderate episodes of acute rejection have been reported, favored by the fact that cytotoxic T lymphocyte-associated protein pathway has an inhibitory effect on the alloimmune response; thereby its inhibition is detrimental in this regard. This has led to the development of antibodies that target CD28. The most advanced is FR104, it has shown promise in nonhuman primate models of autoimmune diseases and allotransplantation. In addition, research into blocking the CD40-CD154 pathway is underway. A phase II study testing ASK1240, that is, anti-CD40 antibody has been completed, and the results are pending.

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In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

Cited by 29 publications

References 43 publications

Antigen-specific induced Foxp3⁺regulatory T cells are generated following CD40/CD154 blockade

Antigen-specific induced Foxp3⁺regulatory T cells are generated following CD40/CD154 blockade

CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin-induced Nephropathy and Kidney Inflammation

Costimulation Blockade in Kidney Transplantation

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In vivo therapeutic efficacy of intra-renal CD40 silencing in a model of humoral acute rejection

Cited by 29 publications

References 43 publications

Antigen-specific induced Foxp3+regulatory T cells are generated following CD40/CD154 blockade

Antigen-specific induced Foxp3+regulatory T cells are generated following CD40/CD154 blockade

CD40 Generation 2.5 Antisense Oligonucleotide Treatment Attenuates Doxorubicin-induced Nephropathy and Kidney Inflammation

Costimulation Blockade in Kidney Transplantation

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Product

Resources

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Antigen-specific induced Foxp3⁺regulatory T cells are generated following CD40/CD154 blockade

Antigen-specific induced Foxp3⁺regulatory T cells are generated following CD40/CD154 blockade