Bone marrow-derived AXL tyrosine kinase promotes mitogenic crosstalk and cardiac allograft vasculopathy

Glinton, Kristofor; DeBerge, Matthew; Fisher, Emily; Schroth, Samantha; Sinha, Arjun; Wang, Jiao Jing; Wasserstrom, J. Andrew; Ansari, M. Javeed; Zhang, Zheng Jenny; Feinstein, Matthew J.; Leventhal, Joseph R.; Forbess, Joseph M.; Lomasney, Jon W.; Luo, Xunrong; Thorp, Edward B.

doi:10.1016/j.healun.2021.03.006

Cited by 6 publications

(5 citation statements)

References 43 publications

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“…Critically, our results show that transient pharmacological AXL inhibition can provide similar benefits to permanent Axl genetic KO ( 13 ). In the early posttransplant phase, an inflammatory milieu is potentiated by intragraft Mϕs that release proinflammatory cytokines as well as process and present alloantigens to adaptive immune cells ( 19 , 31 , 34 ).…”

Section: Discussionmentioning

confidence: 53%

“…Previously, in a heart transplant model, we showed that intragraft myeloid cell AXL can facilitate donor-specific T cell and vascular smooth muscle cell proliferation, which in turn promotes cardiac allograft rejection and vasculopathy ( 13 ). However, the precise mechanism by which AXL promotes donor-specific T cell proliferation is not known.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival

Jordan,

Tunbridge,

Husain

et al. 2024

JCI Insight

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival

Jordan,

Tunbridge,

Husain

et al. 2024

JCI Insight

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“…However, it has been shown that adoptive transfer of 10 4 –10 5 isogenic TCR transgenic T cells is able to modify the endogenous immune response ( 53 ). Additionally, murine models of transplantation where donor organs differ in only three amino acids in the β-chain of MHC class II molecules will result in chronic allograft rejection in the absence of immunosuppression ( 54 , 55 ). It is therefore not unreasonable to hypothesize that minor differences between donor and recipient B6 mice who received the live isogenic cell infusion were sufficient to induce transcriptional differences within the analyzed DC populations but not strong enough to be recognized by host immune cells for subsequent removal.…”

Section: Discussionmentioning

confidence: 99%

Alloantigen Infusion Activates the Transcriptome of Type 2 Conventional Dendritic Cells

Schroth,

Jones,

Thorp

2023

ImmunoHorizons

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Recent studies have revealed novel molecular mechanisms by which innate monocytic cells acutely recognize and respond to alloantigen with significance to allograft rejection and tolerance. What remains unclear is the single-cell heterogeneity of the innate alloresponse, particularly the contribution of dendritic cell (DC) subsets. To investigate the response of these cells to exposure of alloantigen, C57BL/6J mice were administered live allogenic BALB/cJ splenic murine cells versus isogenic cells. In parallel, we infused apoptotic allogenic and isogenic cells, which have been reported to modulate immunity. Forty-eight hours after injection, recipient spleens were harvested, enriched for DCs, and subjected to single-cell mRNA sequencing. Injection of live cells induced a greater transcriptional change across DC subsets compared with apoptotic cells. In the setting of live cell infusion, type 2 conventional DCs (cDC2s) were most transcriptionally responsive with a Ccr2+ cDC2 subcluster uniquely responding to the presence of alloantigen compared with the isogenic control. In vitro experimentation confirmed unique activation of CCR2+ cDC2s following alloantigen exposure. Candidate receptors of allorecognition in other innate populations were interrogated and A type paired Ig-like receptors were found to be increased in the cDC2 population following alloexposure. These results illuminate previously unclear distinctions between therapeutic infusions of live versus apoptotic allogenic cells and suggest a role for cDC2s in innate allorecognition. More critically, these studies allow for future interrogation of the transcriptional response of immune cells in the setting of alloantigen exposure in vivo, encouraging assessment of novel pathways and previously unexamined receptors in this setting.

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“…Aside from advances in imaging, there has been a concurrent search for biomarkers associated with CAV for early detection and as potential treatment targets. These include osteopontin, a pro-inflammatory cytokine that correlates with severe CAV [39]; endothelin-1, a vasoconstrictor peptide associated with accelerated CAV development [40]; and various microRNAs [41][42][43], among others [44][45][46][47][48]. These markers still require prospective validation to assess their utility in CAV detection, as well as continued evaluation as possible treatment targets.…”

Section: Cardiac Allograft Vasculopathy Detectionmentioning

confidence: 99%

Noninvasive methods to reduce cardiac complications postheart transplant

Zhou

Wolfson

Vaidya

2021

Current Opinion in Organ Transplantation

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Purpose of reviewLong-term success of heart transplantation is limited by allograft rejection and cardiac allograft vasculopathy (CAV). Classic management has relied on frequent invasive testing to screen for early features of rejection and CAV to allow for early treatment. In this review, we discuss new developments in the screening and prevention of allograft rejection and CAV. Recent findingsNewer noninvasive screening techniques show excellent sensitivity and specificity for the detection of clinically significant rejection. New biomarkers and treatment targets continue to be identified and await further studies regarding their utility in preventing allograft vasculopathy. SummaryNoninvasive imaging and biomarker testing continue to show promise as alternatives to invasive testing for allograft rejection. Continued validation of their effectiveness may lead to new surveillance protocols with reduced frequency of invasive testing. Furthermore, these noninvasive methods will allow for more personalized strategies to reduce the complications of long-term immunosuppression whereas continuing the decline in the overall rate of allograft rejection.

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Bone marrow-derived AXL tyrosine kinase promotes mitogenic crosstalk and cardiac allograft vasculopathy

Cited by 6 publications

References 43 publications

AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival

AXL inhibition suppresses early allograft monocyte-to-macrophage differentiation and prolongs allograft survival

Alloantigen Infusion Activates the Transcriptome of Type 2 Conventional Dendritic Cells

Noninvasive methods to reduce cardiac complications postheart transplant

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