Renal inflamm-aging provokes intra-graft inflammation following experimental kidney transplantation

He, An; Sarwar, Attia; Thole, Linda Marie Laura; Siegle, Janine; Sattler, Arne; Ashraf, Muhammad Imtiaz; Proß, Vanessa; Stahl, Carolin; Dornieden, Theresa; Bergmann, Yasmin; Ritschl, Paul Viktor; Ebner, Susanne; Hublitz, Karolin Wiebke; Stamatiades, Efstathios G.; Bülow, Roman David; Kotsch, Katja

doi:10.1111/ajt.17154

Cited by 11 publications

(5 citation statements)

References 66 publications

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“…Other pathways were related to cellular processes activated by inflammation and their response to ABT263. The Allograft rejection pathway is affected by navitoclax in the case of organ transplant procedures through pre-treatment that significantly improves 28 days post kidney transplantation [43] . Navitoclax being a BCL2 protein inhibitor involves pathways such as Calcium signaling [44] , Nucleocytoplasmic transport [45] , and RNA polymerase [46] .…”

Section: Resultsmentioning

confidence: 99%

Evaluation of zero counts to better understand the discrepancies between bulk and single-cell RNA-Seq platforms

Zyla,

Papiez,

Zhao

et al. 2023

Computational and Structural Biotechnology Journal

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Section: Resultsmentioning

confidence: 99%

Evaluation of zero counts to better understand the discrepancies between bulk and single-cell RNA-Seq platforms

Zyla,

Papiez,

Zhao

et al. 2023

Computational and Structural Biotechnology Journal

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“…Less is known regarding the function of GZK, although it appears to also exhibit cytolytic and immunomodulatory potential ( Bouwman et al, 2021 ) and recently has been described as a key marker of CD8 + T-cells and macrophages enriched in inflamed tissues ( Turner et al, 2019 ; Jonsson et al, 2022 ). Importantly, the expression of both GZB and GZK have been shown to increase with age ( Mogilenko et al, 2021 ; Zöphel et al, 2022 ), which for GZB, has been postulated as a driver of pathological inflammation (i.e., inflammaging) in older adults ( Turner et al, 2021 ; He et al, 2022 ). However, little is known of the factors other than chronological aging that lead to increased GZB or GZK expression in older adults, and whether GZB/GZK expression impacts the efficacy of preventative measures against infection such as vaccination.…”

Section: Discussionmentioning

confidence: 99%

NK- and T-cell granzyme B and K expression correlates with age, CMV infection and influenza vaccine-induced antibody titres in older adults

Picard¹,

Andrew²,

Haynes³

et al. 2023

Front. Aging

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Granzymes are a family of serine-proteases that act as critical mediators in the cytolytic and immunomodulatory activities of immune cells such as CD8+ T-cells and natural killer (NK) cells. Previous work indicates that both granzyme B (GZB) and K (GZK) are increased with age in CD8+ T-cells, and in the case of GZB, contribute to dysfunctional immune processes observed in older adults. Here, we sought to determine how GZB and GZK expression in NK-cells, and CD4+, CD8+, and gamma-delta T-cells, quantified in terms of positive cell frequency and mean fluorescence intensity (MFI), differed with age, age-related health-traits and the antibody response to high-dose influenza vaccine. We found that the frequency and MFI of GZB-expressing NK-cells, and CD8+ and Vδ1+ T-cells, and GZK-expressing CD8+ T-cells was significantly higher in older (66–97 years old; n = 75) vs. younger (24–37 years old; n = 10) adults by up to 5-fold. There were no significant associations of GZB/GZK expression with sex, frailty or plasma levels of TNF or IL-6 in older adults, but those who were seropositive for cytomegalovirus (CMV) exhibited significantly higher frequencies of GZB+ NK-cells, and CD4+, CD8+ and Vδ1+ T-cells, and GZK+ CD8+ T-cells (Cohen’s d = .5–1.5). Pre-vaccination frequencies of GZB+ NK-cells were positively correlated with vaccine antibody responses against A/H3N2 (d = .17), while the frequencies of GZK+ NK and CD8+ T-cells were inversely associated with A/H1N1 (d = −0.18 to −0.20). Interestingly, GZK+ NK-cell frequency was inversely correlated with pre-vaccination A/H1N1 antibody titres, as well as those measured over the previous 4 years, further supporting a role for this subset in influencing vaccine antibody-responses. These findings further our understanding of how granzyme expression in different lymphoid cell-types may change with age, while suggesting that they influence vaccine responsiveness in older adults.

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“…The accumulation of senescent T cells in old organs has furthermore been linked to a proinflammatory response within the graft while promoting distinct recipient alloimmune responses in mice. 72 Applying senolytics (ABT-263) that deplete senescent cells dampened organ inflammation and restrained Th1-driven alloimmune responses. 72 Moreover, single-cell RNA and antigen receptor sequencing in various murine organs revealed a subpopulation of age-associated granzyme K (GZMK) expressing CD8 + memory T cells that had been distinct from classic T effector memory cells.…”

Section: The Impact Of T-cell Aging On Organ Functionmentioning

confidence: 99%

“…72 Applying senolytics (ABT-263) that deplete senescent cells dampened organ inflammation and restrained Th1-driven alloimmune responses. 72 Moreover, single-cell RNA and antigen receptor sequencing in various murine organs revealed a subpopulation of age-associated granzyme K (GZMK) expressing CD8 + memory T cells that had been distinct from classic T effector memory cells. Strikingly, these cells have been shown to produce enhanced SASP amounts including the release of IL-6, chemokine (C-C motif) ligand 5, chemokine (C-C motif) ligand 2, and chemokine (C-X-C motif) ligand 1 from nonsenescent stroma cells through secretion of GZMK in various tissues.…”

Section: The Impact Of T-cell Aging On Organ Functionmentioning

confidence: 99%

The Impact of T-cell Aging on Alloimmunity and Inflammaging

et al. 2023

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Aging affects immunity broadly through changes caused by immunosenescence, clinically resulting in augmented susceptibility to infections, autoimmunity, and cancer. The most striking alterations associated with immunosenescence have been observed in the T-cell compartment with a significant shift toward a terminally differentiated memory phenotype taking on features of innate immune cells. At the same time, cellular senescence impairs T-cell activation, proliferation, and effector functions, compromising the effectiveness of immunity. In clinical transplantation, T-cell immunosenescence has been the main driver of less frequent acute rejections in older transplant recipients. This patient population, at the same time, suffers more frequently from the side effects of immunosuppressive therapy including higher rates of infections, malignancies, and chronic allograft failure. T-cell senescence has also been identified as an instigator of age-specific organ dysfunction through a process that has been coined “inflammaging,” accelerating organ injury and potentially contributing to the limited lifetime of organ transplants. Here, we provide a summary of the latest evidence on molecular characteristics of T-cell senescence affecting alloimmunity and organ quality while dissecting the consequences of unspecific organ injury and immunosuppression on T-cell senescence. Rather than conceptualizing immunosenescence as a broad and general “weaker” alloimmune response, it appears critical to understand both mechanisms and clinical effects in detail as a basis to refine treatment.

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Renal inflamm-aging provokes intra-graft inflammation following experimental kidney transplantation

Cited by 11 publications

References 66 publications

Evaluation of zero counts to better understand the discrepancies between bulk and single-cell RNA-Seq platforms

Evaluation of zero counts to better understand the discrepancies between bulk and single-cell RNA-Seq platforms

NK- and T-cell granzyme B and K expression correlates with age, CMV infection and influenza vaccine-induced antibody titres in older adults

The Impact of T-cell Aging on Alloimmunity and Inflammaging

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