Drug Therapy in the Heart Transplant Recipient

Lindenfeld, Jo Ann; Miller, Geraldine G.; Shakar, Simon F.; Zolty, Ronald; Lowes, Brian D.; Wolfel, Eugene E.; Mestroni, Luisa; Page, Robert L.; Kobashigawa, Jon A.

doi:10.1161/01.cir.0000149745.83186.89

Cited by 171 publications

(81 citation statements)

References 33 publications

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“…[1][2][3] The encounter of antigen-presenting cells (APCs) and T lymphocytes in secondary lymphoid organs is essential for the initiation of an alloimmune response [1][2][3] ; therefore, intervening with leukocyte traffic could modulate alloimmunity. Although the currently used immunosuppressive drugs effectively inhibit proliferation of alloreactive T cells, they have several metabolic, infectious, renal, and malignant side effects 4 and have not prevented the development of cardiac allograft arteriosclerosis, the main limitation of long-term survival of heart transplant patients. 5 …”

mentioning

confidence: 99%

Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts

Nykänen

Sandelin²,

Krebs³

et al. 2010

Circulation

135

129

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Background— Lymphatic network and chemokine-mediated signals are essential for leukocyte traffic during the proximal steps of alloimmune response. We aimed to determine the role of lymphatic vessels and their principal growth signaling pathway, vascular endothelial growth factor (VEGF)-C/D/VEGFR-3, during acute and chronic rejection in cardiac allografts. Methods and Results— Analysis of heterotopically transplanted rat cardiac allografts showed that chronic rejection increased VEGF-C + inflammatory cell and hyaluronan receptor-1 (LYVE-1) + lymphatic vessel density. Allograft lymphatic vessels were VEGFR-3 + , contained antigen-presenting cells, and produced dendritic cell chemokine CCL21. Experiments with VEGFR-3/LacZ mice or mice with green fluorescent protein–positive bone marrow cells as cardiac allograft recipients showed that allograft lymphatic vessels originated almost exclusively from donor cells. Intraportal adenoviral VEGFR-3-Ig (Ad.VEGFR-3-Ig/VEGF-C/D-Trap) perfusion was used to inhibit VEGF-C/D/VEGFR-3 signaling. Recipient treatment with Ad.VEGFR-3-Ig prolonged rat cardiac allograft survival. Ad.VEGFR-3-Ig did not affect allograft lymphangiogenesis but was linked to reduced CCL21 production and CD8 + effector cell entry in the allograft. Concomitantly, Ad.VEGFR-3-Ig reduced OX62 + dendritic cell recruitment and increased transcription factor Foxp3 expression in the spleen. In separate experiments, treatment with a neutralizing monoclonal VEGFR-3 antibody reduced arteriosclerosis, the number of activated lymphatic vessels expressing VEGFR-3 and CCL21, and graft-infiltrating CD4 + T cells in chronically rejecting mouse cardiac allografts. Conclusions— These results show that VEGFR-3 participates in immune cell traffic from peripheral tissues to secondary lymphoid organs by regulating allograft lymphatic vessel CCL21 production and suggest VEGFR-3 inhibition as a novel lymphatic vessel–targeted immunomodulatory therapy for cardiac allograft rejection and arteriosclerosis.

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mentioning

confidence: 99%

Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts

Nykänen

Sandelin²,

Krebs³

et al. 2010

Circulation

135

129

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“…Antibodies in the blood of the recipient bind to the vascular endothelium of the transplant and activate complement, which results in neutrophil infiltration, vascular disruption, hemorrhage, fibrin deposition and platelet aggregation [10]. It is rare owing to tests for DSAs [11]. Acute humoral (also called vascular) rejection occurs days to weeks after HT.…”

Section: Acute Antibody-mediated Rejectionmentioning

confidence: 99%

“…The alloantibodies are directed against donor HLA or endothelial cell antigens. It occurs in 6% of patients and its importance stems from its common association with severe ventricular dysfunction, presumably caused by diffuse ischemia secondary to a lack of coronary vasodilatory reserve [11]. Chronic rejection occurs months to years after transplantation and its mechanism is incompletely understood.…”

Section: Acute Antibody-mediated Rejectionmentioning

confidence: 99%

“…In heart transplant recipients AMR is clinically associated with an increased expression of P-selectin and von Willebrand factor on the vascular endothelium [15], which lead to vascular inflammation and extensive aggregates of platelets that occlude the arteries, capillaries and veins [16,17]. This mechanism explains why AMR in heart EMB is usually referred to coronary allograft vasculopathy (CAV) and manifests as diffuse atherosclerosis with myointimal proliferation in the coronary arteries [9,11]. It was estimated that about 50% of heart transplant recipients have angiographically confirmed CAV by 5 years after transplantation, and severe CAV is a major cause of death in patients surviving the first post-transplantation year [18,19].…”

Section: Acute Antibody-mediated Rejectionmentioning

confidence: 99%

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Pathologic diagnosis of antibody-mediated rejection in endomyocardial biopsy after heart transplantation based on renewed International Society for Heart and Lung Transplantation criteria

Szymańska¹,

Grajkowska²,

Pronicki³

2014

pjp

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Heart transplantation is a well-established life-saving treatment for patients presenting with end-stage cardiac failure. Despite improved efficacy of the procedure, allograft rejection continues to be a major cause of mortality and morbidity in cardiact allograft patients. Although acute cellular rejection (ACR) is quite unusual nowadays, acute antibody-mediated rejection (AMR) remains a significant problem. The role of pathologists in detection of AMR is very important, especially in sub-clinical cases. In 1990, histologic hallmarks of AMR were first stated by International Society for Heart and Lung Transplantation (ISHLT) and detailed histopathologic features and immunopathologic criteria were established in 2005. Recently (2013) ISHLT revised nomenclature and classification of AMR. Aim of this paper was to present practical changes coming from new criteria as well as to highlight difficulties concerning AMR assessment in endomyocardial biopsies (EMB).

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“…Information gleaned from reviews in major journals describes three general categories of immunosuppressive agents (Halloran, 2004, Lindenfeld et al, 2004, Gonzalez Posada, 2006, 1970. These include antibodies directed against lymphocytes, steroids, and agents that interfere with metabolism or that have toxic effects on cells.…”

Section: Three Categories Of Drugs Targeting Lymphocytes Have Been Dementioning

confidence: 99%

Immunological Considerations for Inducing Skin Graft Tolerance

Gordon¹

2011

Skin Grafts - Indications, Applications and Current Research

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Drug Therapy in the Heart Transplant Recipient

Cited by 171 publications

References 33 publications

Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts

Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts

Pathologic diagnosis of antibody-mediated rejection in endomyocardial biopsy after heart transplantation based on renewed International Society for Heart and Lung Transplantation criteria

Immunological Considerations for Inducing Skin Graft Tolerance

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