Molecular Signature of Antibody-Mediated Chronic Vasculopathy in Heart Allografts in a Novel Mouse Model

Tsuda, Hidetoshi; Dvorina, Nina; Keslar, Karen; Nevarez‐Mejia, Jessica; Valenzuela, Nicole M.; Reed, Elaine F.; Fairchild, Robert L.; Baldwin, William M.

doi:10.1016/j.ajpath.2022.04.003

Cited by 9 publications

(6 citation statements)

References 44 publications

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“…With regard to vasculopathies associated with cardiac transplant, work by Norum et al revealed a correlation between the Notch ligand Dll1 and cardiac allograft vasculopathy (198). The importance of Notch signaling in allograft vasculopathy is further supported by transcriptional analysis of allograft arteries showing an elevated expression of Dll4 is associated with both high titers of donor-specific antibodies and the occurrence of vasculopathy (137). Notch signaling is also reported in the context of endothelialto mesenchymal transition.…”

Section: The Relationship Between Inflammation Antibodies and Endothe...mentioning

confidence: 98%

“…The Fairchild and Baldwin labs reported development of a new mouse model of CAV in which CCR5 −/− CD8 −/− B6 recipients of MHC mismatched heart or kidney allografts develop high titers of donor specific MHC antibody and inflammation ( 135 , 136 ). They found that when recipients are treated with CD4 depletion to slow DSA development and prevent T cell mediated rejection, grafts go on to develop fibrosis and CAV ( 137 ). This recapitulates the human disease, induced by chronic injury with HLA DSA, and represents a new tool with which to study the mechanisms of transplant vasculopathy.…”

Section: Chronic Antibody-mediated Rejection and Transplant Vasculopathymentioning

confidence: 99%

“…Immune complexes from patients with systemic sclerosis upregulate also TGFβ and collagen production by endothelium ( 171 ), and in situ complement activation was associated with phosphorylated SMAD2/3 in dialysis-associated occlusive arteriopathy ( 172 ), suggesting a conserved mechanism of antibody/complement-mediated injury and EndMT. In a new MHC antibody-driven CAV mouse model, COL1A1 and DLL4 , both implicated in EndMT, were significantly changed in more severe CAV with higher titers of DSA ( 137 ). In vitro , stimulation of human glomerular endothelium with anti-HLA class I antibodies for 48 h upregulated secretion of TGFβ ( 173 ).…”

Section: Chronic Antibody-mediated Rejection and Transplant Vasculopathymentioning

confidence: 99%

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New insights into maladaptive vascular responses to donor specific HLA antibodies in organ transplantation

et al. 2023

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Transplant vasculopathy (TV) causes thickening of donor blood vessels in transplanted organs, and is a significant cause of graft loss and mortality in allograft recipients. It is known that patients with repeated acute rejection and/or donor specific antibodies are predisposed to TV. Nevertheless, the exact molecular mechanisms by which alloimmune injury culminates in this disease have not been fully delineated. As a result of this incomplete knowledge, there is currently a lack of effective therapies for this disease. The immediate intracellular signaling and the acute effects elicited by anti-donor HLA antibodies are well-described and continuing to be revealed in deeper detail. Further, advances in rejection diagnostics, including intragraft gene expression, provide clues to the inflammatory changes within allografts. However, mechanisms linking these events with long-term outcomes, particularly the maladaptive vascular remodeling seen in transplant vasculopathy, are still being delineated. New evidence demonstrates alterations in non-coding RNA profiles and the occurrence of endothelial to mesenchymal transition (EndMT) during acute antibody-mediated graft injury. EndMT is also readily apparent in numerous settings of non-transplant intimal hyperplasia, and lessons can be learned from advances in those fields. This review will provide an update on these recent developments and remaining questions in our understanding of HLA antibody-induced vascular damage, framed within a broader consideration of manifestations and implications across transplanted organ types.

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Section: The Relationship Between Inflammation Antibodies and Endothe...mentioning

confidence: 98%

Section: Chronic Antibody-mediated Rejection and Transplant Vasculopathymentioning

confidence: 99%

Section: Chronic Antibody-mediated Rejection and Transplant Vasculopathymentioning

confidence: 99%

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New insights into maladaptive vascular responses to donor specific HLA antibodies in organ transplantation

et al. 2023

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“… 3 , 19 Macrophages are also found within the neointima and adventitia of CAV-affected lesions in both rejected human cardiac allografts and mouse models of chronic AMR. 20 , 21 Despite the high prevalence of macrophages in rejecting allografts, mechanisms of their polarization, pheno-type, and function remain elusive. In general, M1 macrophages have been linked to acute rejection as they secrete proinflammatory cytokines, generate pathogenic reactive oxygen species, and express costimulatory molecules (eg, CD80/CD86) which can amplify T cell–mediated activation.…”

Section: Introductionmentioning

confidence: 99%

Human leukocyte antigen class I antibody-activated endothelium promotes CD206+ M2 macrophage polarization and MMP9 secretion through TLR4 signaling and P-selectin in a model of antibody-mediated rejection and allograft vasculopathy

Nevarez-Mejia,

Jin,

Pickering

et al. 2024

American Journal of Transplantation

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“…In addition, cardiac allograft vasculopathy (CAV), which contributes significantly to the mortality of HTx patients, is mediated by immunopathological mechanisms leading to remodeling of the allograft vasculature. After HTx, CAV is induced by injury of the endothelial cell (EC) layer and stimulation of smooth cell proliferation due to ischemia-reperfusion injury or allogeneic immune responses ( 4 , 5 ). Hence, HLA mismatches between donor and recipient remain a major cause of premature organ dysfunction and reduced allograft survival ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

Heart immunoengineering by lentiviral vector-mediated genetic modification during normothermic ex vivo perfusion

Schmalkuche,

Rother,

Burgmann

et al. 2024

Front. Immunol.

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Heart transplantation is associated with major hurdles, including the limited number of available organs for transplantation, the risk of rejection due to genetic discrepancies, and the burden of immunosuppression. In this study, we demonstrated the feasibility of permanent genetic engineering of the heart during ex vivo perfusion. Lentiviral vectors encoding for short hairpin RNAs targeting beta2-microglobulin (shβ2m) and class II transactivator (shCIITA) were delivered to the graft during two hours of normothermic EVHP. Highly efficient genetic engineering was indicated by stable reporter gene expression in endothelial cells and cardiomyocytes. Remarkably, swine leucocyte antigen (SLA) class I and SLA class II expression levels were decreased by 66% and 76%, respectively, in the vascular endothelium. Evaluation of lactate, troponin T, and LDH levels in the perfusate and histological analysis showed no additional cell injury or tissue damage caused by lentiviral vectors. Moreover, cytokine secretion profiles (IL-6, IL-8, and TNF-α) of non-transduced and lentiviral vector-transduced hearts were comparable. This study demonstrated the ex vivo generation of genetically engineered hearts without compromising tissue integrity. Downregulation of SLA expression may contribute to reduce the immunogenicity of the heart and support graft survival after allogeneic or xenogeneic transplantation.

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Molecular Signature of Antibody-Mediated Chronic Vasculopathy in Heart Allografts in a Novel Mouse Model

Cited by 9 publications

References 44 publications

New insights into maladaptive vascular responses to donor specific HLA antibodies in organ transplantation

New insights into maladaptive vascular responses to donor specific HLA antibodies in organ transplantation

Human leukocyte antigen class I antibody-activated endothelium promotes CD206+ M2 macrophage polarization and MMP9 secretion through TLR4 signaling and P-selectin in a model of antibody-mediated rejection and allograft vasculopathy

Heart immunoengineering by lentiviral vector-mediated genetic modification during normothermic ex vivo perfusion

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