Membrane Attack Complex Contributes to Destruction of Vascular Integrity in Acute Lung Allograft Rejection

Nakashima, Shinji; Qian, Zhiping; Rahimi, Salma; Wąsowska, Barbara; Baldwin, William M.

doi:10.4049/jimmunol.169.8.4620

Cited by 70 publications

(54 citation statements)

References 66 publications

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“…OKT-3 activates complement (96) and can also cause an accumulation of neutrophils in pulmonary capillaries that might be confused with "capillaritis" (97). Indeed, reports from several groups using microarrays in a rodent model indicate that antibody and complement genes are upregulated in the transplanted lung (45,98,99). These data are similar to prior reports from other investigators (45,98).…”

Section: Humoral Immunitysupporting

confidence: 81%

Lung Transplantation: Opportunities for Research and Clinical Advancement

Wilkes¹

2006

Am J Respir Crit Care Med

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Lung transplantation is the only definitive therapy for many forms of end-stage lung diseases. However, the success of lung transplantation is limited by many factors: (1 ) Too few lungs available for transplantation due to limited donors or injury to the donor lung; (2 ) current methods of preservation of excised lungs do not allow extended periods of time between procurement and implantation; (3 ) acute graft failure is more common with lungs than other solid organs, thus contributing to poorer short-term survival after lung transplant compared with that for recipients of other organs; (4 ) lung transplant recipients are particularly vulnerable to pulmonary infections; and (5 ) chronic allograft dysfunction, manifest by bronchiolitis obliterans syndrome, is frequent and limits long-term survival. Scientific advances may provide significant improvements in the outcome of lung transplantation. The National Heart, Lung, and Blood Institute convened a working group of investigators on June 14-15, 2004, in Bethesda, Maryland, to identify opportunities for scientific advancement in lung transplantation, including basic and clinical research. This workshop provides a framework to identify critical issues related to clinical lung transplantation, and to delineate important areas for productive scientific investigation. Keywords: allograft dysfunction; infection; ischemia-reperfusion injury; lung transplantation; obliterative bronchiolitis; rejectionThe transplantation of organs offers the promise of life-saving and life-enhancing therapy for a variety of ailments. Lung transplantation (LTx) has become an acceptable therapy to palliate patients with a variety of end-stage lung diseases. However, lung transplantation has not turned out to be a panacea for chronic lung disease because of significant limitations in the entire transplant process (Figure 1). First, there are not nearly enough suitable donor lungs to meet the needs of all patients with end-stage lung disease. As a result, more patients die waiting for transplants than from mortality associated with a lung transplant. Second, early graft survival after LTx is worse than for other types of organs transplanted (1). Finally, late survival after successful LTx is hampered by the development of chronic allograft dysfunction and by the life-limiting complications associated with conventional immunosuppressive medications. Two factors impede progress to address these problems: (1 ) lung transplant centers lack the infrastructure to facilitate prospective, multicenter clinical studies of sufficient power to address clinical questions and (2 ) there are too few investigators studying the biology of lung transplantation.The NHLBI convened a workshop on June 14-15, 2004, to better understand these complex problems and to identify strategies to address these and prioritize them. The topics addressed by participants were wide-ranging. They included the following: lung use rates from conventional brain-dead organ donors; safe limits for donor lung function; consideration o...

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Section: Humoral Immunitysupporting

confidence: 81%

Lung Transplantation: Opportunities for Research and Clinical Advancement

Wilkes¹

2006

Am J Respir Crit Care Med

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“…CXCL1 binding to CXCR2 on tissue-infiltrating neutrophils induces degranulation and the release of a myriad of proteases and oxidants that mediate graft endothelium and parenchymal tissue damage (30,31). As has been shown in many studies, Ab-mediated activation of complement and formation of the membrane attack complex is also a major cause of graft endothelium damage (28,(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients

Nozaki

Amano

Bickerstaff

et al. 2007

The Journal of Immunology

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Rejected MHC-mismatched cardiac allografts in CCR5−/− recipients have low T cell infiltration, but intense deposition of C3d in the large vessels and capillaries of the graft, characteristics of Ab-mediated rejection. The roles of donor-specific Ab and CD4 and CD8 T cell responses in the rejection of complete MHC-mismatched heart grafts by CCR5−/− recipients were directly investigated. Wild-type C57BL/6 and B6.CCR5−/− (H-2b) recipients of A/J (H-2a) cardiac allografts had equivalent numbers of donor-reactive CD4 T cells producing IFN-γ, whereas CD4 T cells producing IL-4 were increased in CCR5−/− recipients. Numbers of donor-reactive CD8 T cells producing IFN-γ were reduced 60% in CCR5−/− recipients. Day 8 posttransplant serum titers of donor-specific Ab were 15- to 25-fold higher in CCR5−/− allograft recipients, and transfer of this serum provoked cardiac allograft rejection in RAG-1−/− recipients within 14 days, whereas transfer of either serum from wild-type recipients or immune serum from CCR5-deficient recipients diluted to titers observed in wild-type recipients did not mediate this rejection. Wild-type C57BL/6 and B6.CCR5−/− recipients rejected A/J cardiac grafts by day 11, whereas rejection was delayed (day 12–60, mean 21 days) in μMT−/−/CCR5−/− recipients. These results indicate that the donor-specific Ab produced in CCR5−/− heart allograft recipients is sufficient to directly mediate graft rejection, and the absence of recipient CCR5 expression has differential effects on the priming of alloreactive CD4 and CD8 T cells.

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“…18,30,31 Furthermore, elevated urinary excretion of C5a has been correlated to renal allograft rejection. 32 C5a is not only a potent neutrophil and macrophage chemoattractant but also recognized as a pleiotropic molecule modulating the activity of many cell types with a broad range of biologic functions via its receptor.…”

Section: Discussionmentioning

confidence: 99%

Complement 5a Receptor Inhibition Improves Renal Allograft Survival

Gueler¹,

Rong²,

Gwinner³

et al. 2008

Journal of the American Society of Nephrology

105

116

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Complement activation plays a key role in mediating apoptosis, inflammation, and transplant rejection. In this study, the role of the complement 5a receptor (C5aR) was examined in human renal allografts and in an allogenic mouse model of renal transplant rejection. In human kidney transplants with acute rejection, C5aR expression was increased in renal tissue and in cells infiltrating the tubulointerstitium. Similar findings were observed in mice. When recipient mice were treated once daily with a C5aR antagonist before transplantation, long-term renal allograft survival was markedly improved compared with vehicle-treatment (75 versus 0%), and apoptosis was reduced. Furthermore, treatment with a C5aR antagonist significantly attenuated monocyte/macrophage infiltration, perhaps a result of reduced levels of monocyte chemoattractant protein 1 and the intercellular adhesion molecule 1. In vitro, C5aR antagonism inhibited intercellular adhesion molecule 1 upregulation in primary mouse aortic endothelial cells and reduced adhesion of peripheral blood mononuclear cells. Furthermore, C5aR blockade markedly reduced alloreactive T cell priming. These results demonstrate that C5aR plays an important role in mediating acute kidney allograft rejection, suggesting that pharmaceutical targeting of C5aR may have potential in transplantation medicine.

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Membrane Attack Complex Contributes to Destruction of Vascular Integrity in Acute Lung Allograft Rejection

Cited by 70 publications

References 66 publications

Lung Transplantation: Opportunities for Research and Clinical Advancement

Lung Transplantation: Opportunities for Research and Clinical Advancement

Antibody-Mediated Rejection of Cardiac Allografts in CCR5-Deficient Recipients

Complement 5a Receptor Inhibition Improves Renal Allograft Survival

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