Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Kitchens, William H.; Chase, Catharine M.; Uehara, Shuichiro; Cornell, Liam; Colvin, Robert B.; Russell, Paul; Madsen, Joren C.

doi:10.1111/j.1600-6143.2007.01997.x

Cited by 106 publications

(87 citation statements)

References 48 publications

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“…Experimental strategies of monocyte/M depletion are limited and strategies involving the administration of antibodies, carrageenan, or liposomal clodronate have previously been used (7,28,29). In this study, we used CD11b-DTR mice that have previously been used to demonstrate a key role for resident and infiltrating M in peritonitis (15), pleurisy (14), nephrotoxic glomerulonephritis (9), and hepatic injury/ fibrosis (24).…”

Section: Discussionmentioning

confidence: 97%

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Depletion of Cells of Monocyte Lineage Prevents Loss of Renal Microvasculature in Murine Kidney Transplantation

Adair

Ferenbach

et al. 2008

Transplantation

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Section: Discussionmentioning

confidence: 97%

“…Macrophages (M) are central to many innate immune responses to injury and some evidence suggests that M can promote acute allograft rejection (6) and the chronic vasculopathy of murine cardiac allografts (7). Furthermore, the presence of M infiltration is of prognostic importance in human renal transplantation (8).…”

mentioning

confidence: 99%

Depletion of Cells of Monocyte Lineage Prevents Loss of Renal Microvasculature in Murine Kidney Transplantation

Adair

Ferenbach

et al. 2008

Transplantation

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“…Although allograft vessels are likely to be sterile and devoid of PAMPs (unless infected by CMV, see above), they may be injured and release PAMPs that can activate macrophages to produce mitogens for SMCs. Depletion of macrophages can reduce CAV in mouse models, but the adaptive immune system is intact in these models and activated T cells can serve to direct the macrophage response 38 . It seems likely that NK cells and macrophages also play a role in human CAV as such cells are present in the lesions in patterns similar to what has been seen in mouse models 39 , but there are no data in humans to support a role for these cells independent of adaptive immunity.…”

Section: Innate Immunitymentioning

confidence: 99%

Interacting Mechanisms in the Pathogenesis of Cardiac Allograft Vasculopathy

Pober

Jane‐wit

Qin

et al. 2014

ATVB

100

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Cardiac allograft vasculopathy is the major cause of late graft loss in heart transplant recipients. Histological studies of characteristic end stage lesions reveal arterial changes consisting of a diffuse, confluent and concentric intimal expansion containing graft-derived cells expressing smooth muscle markers, extracellular matrix, penetrating microvessels and a host mononuclear cell infiltrate concentrated subjacent to an intact graft-derived luminal endothelial cell lining with little evidence of acute injury. This intimal expansion combined with inadequate compensatory outward remodeling produces severe generalized stenosis extending throughout the epicardial and intramyocardial arterial tree that causes ischemic graft failure. CAV lesions affect at least 50% of transplant recipients and are both progressive and refractory to treatment, resulting in about 5% graft loss per year through the first ten years post-transplant. Lesions typically stop at the suture line, implicating alloimmunity as the primary driver, but pathogenesis may be multifactorial. Here we will discuss six potential contributors to lesion formation: (1) conventional risk factors for atherosclerosis; (2) pre- or peri-transplant injuries; (3) infection; (4) innate immunity; (5) T cell-mediated immunity; and (6) B cell-mediated immunity through production of donor-specific antibody. Finally, we will consider how these various mechanisms may interact with each other.

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“…Also, minor antigenmismatched heart transplants in mice do not elicit donor-reactive antibodies, yet the mice develop significant CAV, suggesting that other mediators of chronic rejection exist (7). Although some studies have shown that NK cells, T cells, macrophages, IFN-γ, and TNFR contribute to CAV (9)(10)(11)(12)(13), the concomitant potential effects of antibodies and/or B cells were not excluded in these studies. In addition to producing antibodies, B cells influence T cell responses by mechanisms such as antigen presentation, cytokine production, costimulation, and organization of splenic lymphoid architecture required for productive immunity (14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

B cells mediate chronic allograft rejection independently of antibody production

Zeng¹,

Ng²,

Singh³

et al. 2014

J. Clin. Invest.

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Chronic rejection is the primary cause of long-term failure of transplanted organs and is often viewed as an antibody-dependent process. Chronic rejection, however, is also observed in mice and humans with no detectable circulating alloantibodies, suggesting that antibody-independent pathways may also contribute to pathogenesis of transplant rejection. Here, we have provided direct evidence that chronic rejection of vascularized heart allografts occurs in the complete absence of antibodies, but requires the presence of B cells. Mice that were deficient for antibodies but not B cells experienced the same chronic allograft vasculopathy (CAV), which is a pathognomonic feature of chronic rejection, as WT mice; however, mice that were deficient for both B cells and antibodies were protected from CAV. B cells contributed to CAV by supporting splenic lymphoid architecture, T cell cytokine production, and infiltration of T cells into graft vessels. In chimeric mice, in which B cells were present but could not present antigen, both T cell responses and CAV were markedly reduced. These findings establish that chronic rejection can occur in the complete absence of antibodies and that B cells contribute to this process by supporting T cell responses through antigen presentation and maintenance of lymphoid architecture.

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Macrophage Depletion Suppresses Cardiac Allograft Vasculopathy in Mice

Abstract: Cardiac allograft vasculopathy (CAV) is

Cited by 106 publications

References 48 publications

Depletion of Cells of Monocyte Lineage Prevents Loss of Renal Microvasculature in Murine Kidney Transplantation

Depletion of Cells of Monocyte Lineage Prevents Loss of Renal Microvasculature in Murine Kidney Transplantation

Interacting Mechanisms in the Pathogenesis of Cardiac Allograft Vasculopathy

B cells mediate chronic allograft rejection independently of antibody production

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