Absence of donor CD40 protects renal allograft epithelium and preserves renal function

Kraus, Anna; Cippà, Pietro E; Gaspert, Ariana; Chen, Jin; Edenhofer, Ilka; Wüthrich, R.; Lindenmeyer, Maja T.; Segerer, Stephan; Fehr, Thomas

doi:10.1111/tri.12070

Cited by 6 publications

(5 citation statements)

References 38 publications

(37 reference statements)

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“…Previous work in renal disease and renal transplant models has implicated activation of the CD40/CD40L signaling cascade as a key mediator of inflammation and fibrosis within the kidney (27, 28). Specifically, stimulation of the CD40 receptor causes T-cell activation and increased expression of numerous pro-inflammatory mediators including IL-6, IL-8, RANTES, and MCP-1 (10, 27).…”

Section: Discussionmentioning

confidence: 99%

Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure

Kumarasamy

Folt

Wuescher

et al. 2017

Kidney International

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High blood pressure is a common cause of chronic kidney disease. Since CD40, a member of the tumor necrosis factor receptor family, has been linked to the progression of kidney disease in ischemic nephropathy, we studied the role of Cd40 in the development of hypertensive renal disease. The Cd40 gene was mutated in the Dahl S genetically hypertensive rat with renal disease by targeted-gene disruption using zinc-finger nuclease technology. These rats were then given low (0.3%) and high (2%) salt diets and compared. The resultant Cd40 mutants had significantly reduced levels of both urinary protein excretion (41.8 ± 3.1 mg/24hours vs. 103.7 ± 4.3 mg/24hours) and plasma creatinine (0.36 ± 0.05 mg/dL vs. 1.15 ± 0.19 mg/dL), with significantly higher creatinine clearance compared to the control S rats (3.04 ± 0.48 ml/minute vs. 0.93 ± 0.15 ml/minute) indicating renoprotection was conferred by mutation of the Cd40 locus. Furthermore, the Cd40 mutants had a significant attenuation in renal fibrosis, which persisted on the high salt diet. However, there was no difference in systolic blood pressure between the control and Cd40 mutant rats. Thus, these data serve as the first evidence for a direct link between Cd40 and hypertensive nephropathy. Hence, renal fibrosis is one of the underlying mechanisms by which Cd40 plays a crucial role in the development of hypertensive renal disease.

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Section: Discussionmentioning

confidence: 99%

Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure

Kumarasamy

Folt

Wuescher

et al. 2017

Kidney International

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“…Antigen recognition via the T cell receptor is not sufficient for a complete T cell activation. A collection of costimulatory and coinhibitory signals modulates the complex interaction between T cells and antigen presenting cells (APCs) in the process of T cell priming and between T cells and target cells in the effector phase of the immune response [ 1 , 2 ]. Because of the fundamental role of T cell costimulation in the activation of donor reactive T cells after transplantation, costimulation blockade has become a promising target for the development of more specific and less toxic strategies to prevent rejection and induce tolerance [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation

et al. 2016

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DNAX accessory protein-1 (DNAM-1, CD226) is a co-stimulatory and adhesion molecule expressed mainly by natural killer cells and T cells. DNAM-1 and its two ligands CD112 and CD155 are important in graft-versus-host disease, but their role in solid organ transplantation is largely unknown. We investigated the relevance of this pathway in a mouse kidney transplantation model. CD112 and CD155 are constitutively expressed on renal tubular cells and strongly upregulated in acutely rejected renal allografts. In vitro DNAM-1 blockade during allogeneic priming reduced the allospecific T cell response but not the allospecific cytotoxicity against renal tubular epithelial cells. Accordingly, absence of DNAM-1 in recipient mice or absence of CD112 or CD155 in the kidney allograft did not significantly influence renal function and severity of rejection after transplantation, but led to a higher incidence of infarcts in CD112 and CD155 deficient kidney allografts. Thus, DNAM-1 blockade is not effective in preventing transplant rejection. Despite of being highly expressed, CD112 and CD155 do not appear to play a major immunogenic role in kidney transplantation. Considering the high incidence of renal infarcts in CD112 and CD155 deficient grafts, blocking these molecules might be detrimental.

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“…It remains controversial whether CD154 transmits a cell-intrinsic signal to T cells (11)(12)(13), which would be of relevance for the development of antibodies interfering with the CD40:CD154 pathway. Recently, it was shown that the absence of CD40 signaling leads to protection of tubular epithelium from apoptosis and thereby preserved kidney allograft function (14).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin and CTLA4Ig Synergize to Induce Stable Mixed Chimerism Without the Need for CD40 Blockade

Pilat

Klaus

Schwarz

et al. 2015

American Journal of Transplantation

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y Both authors contributed equally.The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40: CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely whereas fully mismatched grafts are rejected, suggesting that non-MHC antigens cause graft rejection and split tolerance.

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Absence of donor CD40 protects renal allograft epithelium and preserves renal function

Cited by 6 publications

References 38 publications

Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure

Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure

The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation

Rapamycin and CTLA4Ig Synergize to Induce Stable Mixed Chimerism Without the Need for CD40 Blockade

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