Differential T Cell Signaling Pathway Activation by Tacrolimus and Belatacept after Kidney Transplantation: Post Hoc Analysis of a Randomised-Controlled Trial

Kannegieter, Nynke M.; Hesselink, Dennis A.; Dieterich, M.; Graav, Gretchen N. de; Kraaijeveld, Rens; Baan, Carla C.

doi:10.1038/s41598-017-15542-y

Cited by 11 publications

(9 citation statements)

References 49 publications

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“…Memory T cell signalling is still occurring under immunosuppression because these cells are less reliant on co-stimulatory signals 33–36 . For this reason, we can hypothesize about the long lasting persistence of T RM cells within the renal allograft.…”

Section: Discussionmentioning

confidence: 99%

Characterization of donor and recipient CD8+ tissue-resident memory T cells in transplant nephrectomies

Leur

Dieterich

Hesselink

et al. 2019

Sci Rep

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Tissue-resident memory T (T RM ) cells are characterized by their surface expression of CD69 and can be subdivided in CD103+ and CD103− T RM cells. The origin and functional characteristics of T RM cells in the renal allograft are largely unknown. To determine these features we studied T RM cells in transplant nephrectomies. T RM cells with a CD103+ and CD103− phenotype were present in all samples ( n = 13) and were mainly CD8+ T cells. Of note, donor-derived T RM cells were only detectable in renal allografts that failed in the first month after transplantation. Grafts, which failed later, mainly contained recipient derived T RM cells. The gene expression profiles of the recipient derived CD8+ T RM cells were studied in more detail and showed a previously described signature of tissue residence within both CD103+ and CD103− T RM cells. All CD8+ T RM cells had strong effector abilities through the production of IFNγ and TNFα, and harboured high levels of intracellular granzyme B and low levels of perforin. In conclusion, our results demonstrate that donor and recipient T RM cells reside in the rejected renal allograft. Over time, the donor-derived T RM cells are replaced by recipient T RM cells which have features that enables these cells to aggressively respond to the allograft.

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Section: Discussionmentioning

confidence: 99%

Characterization of donor and recipient CD8+ tissue-resident memory T cells in transplant nephrectomies

Leur

Dieterich

Hesselink

et al. 2019

Sci Rep

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“…Tacrolimus effectively inhibits key T cell activation pathways in T cells after kidney transplant [97]. A rat model of IgAN treated with tacrolimus revealed that usage of CNIs leads to an improvement of clinical features, along with reduction of serum concentration of TGF-β1, Th2-type cytokines (IL-4, IL-5), but elevation of Th1-type cytokine IFN-γ, which might have a protective role against the development of IgAN [98].…”

Section: T Cells As a Therapeutic Target Of Traditional And Biologicamentioning

confidence: 99%

T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target

et al. 2018

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Background Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide, is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about their involvement in pathophysiology and treatment of IgAN Methods We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs for T cells’ participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence of drugs used in IgAN therapy on T cell subpopulations. Results We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype. We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1) and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2, Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients. Conclusions T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials with the drugs targeting the reported alterations of the T-cell compartment are highly desirable.

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“…Another reason that may contribute to the increased incidence of AR is that belatacept therapy does not inhibit the T-cell activation pathway downstream of the TCR, in contrast to tacrolimus therapy [106]. In a study of 20 belatacepttreated KTRs, no inhibition of the phosphorylation of three important signaling molecules (p38MAPK, extracellular signal-regulated kinases [ERK] 1 and 2, and AKT8 virus oncogene cellular homolog [Akt]) was noted after treatment with belatacept [106]. Furthermore, the phosphorylation of ERK was increased in belatacept-treated patients on days 4 and 90 in patients with an AR compared with patients without an AR [106].…”

Section: Biomarkers Predicting Belatacept-resistant Rejectionmentioning

confidence: 99%

“…In a study of 20 belatacepttreated KTRs, no inhibition of the phosphorylation of three important signaling molecules (p38MAPK, extracellular signal-regulated kinases [ERK] 1 and 2, and AKT8 virus oncogene cellular homolog [Akt]) was noted after treatment with belatacept [106]. Furthermore, the phosphorylation of ERK was increased in belatacept-treated patients on days 4 and 90 in patients with an AR compared with patients without an AR [106]. Prediction of AR was not possible with a targeted proteomic analysis of pre-rejection serum samples of KTRs treated with belatacept [107].…”

Section: Biomarkers Predicting Belatacept-resistant Rejectionmentioning

confidence: 99%

Costimulation Blockade in Kidney Transplant Recipients

Zwan

Hesselink

Hoogen

et al. 2019

Drugs

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Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.

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Differential T Cell Signaling Pathway Activation by Tacrolimus and Belatacept after Kidney Transplantation: Post Hoc Analysis of a Randomised-Controlled Trial

Cited by 11 publications

References 49 publications

Characterization of donor and recipient CD8+ tissue-resident memory T cells in transplant nephrectomies

Characterization of donor and recipient CD8+ tissue-resident memory T cells in transplant nephrectomies

T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target

Costimulation Blockade in Kidney Transplant Recipients

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