High-Level Endothelial Expression of Human Cd59 Prolongs Heart Function in an Ex Vivo Model of Xenograft Rejection

Cowan, Peter J.; Somerville, Christine A.; Shinkel, Trixie A.; Katerelos, Marina; Aminian, A; Romanella, Margarita; Tange, M. J.; Pearse, Martin J.; d’Apice, Anthony J.F.

doi:10.1097/00007890-199803270-00010

Cited by 27 publications

(12 citation statements)

References 24 publications

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Section: Resultsmentioning

confidence: 99%

“…We generated human CD59 (hCD59) transgenic mice that selectively express the transgene in erythrocyte ( ThCD59 RBC ) or in endothelium and some hematopoietic cells such as platelets (Supplemental Figure I), neutrophils, and monocytes ( ThCD59 END ) as previously described 25, 26 . In these transgenic strains, over-expression of hCD59 is effective in providing additional protection against mouse complement 25, 26 . To study the role of CD59 and complement in atherosclerosis in the context of a favorable pro-atherogenic environment, mCd59ab −/− and Apoe −/− mice were crossed to generate mCd59ab −/− / Apoe −/− , and ThCD59 END+/− and Apoe −/− mice to generate ThCD59 END+/− /Apoe −/− mice (Supplemental Figure II, A-C online).…”

Section: Resultsmentioning

confidence: 99%

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Complement Regulator CD59 Protects Against Atherosclerosis by Restricting the Formation of Complement Membrane Attack Complex

Shahsafaei

et al. 2009

Circulation Research

109

123

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Complement is a central effector system within the immune system and is implicated in a range of inflammatory disorders. CD59 is a key regulator of complement membrane attack complex (MAC) assembly. The atherogenic role of terminal complement has long been suspected, but is still unclear. Here, we demonstrate that among mice deficient in apolipoprotein E (Apoe), the additional loss of murine CD59 (mCd59ab−/−/Apoe−/−) accelerated advanced atherosclerosis featuring occlusive coronary atherosclerosis, vulnerable plaque, and premature death, and that these effect could be attenuated by over-expression of human CD59 in the endothelium. Complement inhibition using a neutralizing anti-mouse C5 antibody attenuated atherosclerosis in mCd59ab−/−/Apoe−/− mice. Furthermore, MAC mediated endothelial damage and promoted foam cell formation. These combined results highlight the atherogenic role of MAC and the athero-protective role of CD59, and suggest that inhibition of MAC formation may provide a therapeutic approach for the treatment of atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Complement Regulator CD59 Protects Against Atherosclerosis by Restricting the Formation of Complement Membrane Attack Complex

Shahsafaei

et al. 2009

Circulation Research

109

123

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“…However, the importance of preformed xenoreactive antibodies to non-Gal antigens remains to be determined. Previous studies have suggested that if the response of anti-Gal antibodies was eliminated, that grafts expressing high levels of complement regulatory proteins survived longer than wild-type pig organs (38) (39) (40) (41) (42). Since the major target or targets of non-Gal antibodies has not been determined, immunoadsorbtion of the xenoreactive antibodies seems impractical at this time.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of CD59: Potential Mechanism of Accommodation in a Large Animal Model

Griesemer

Okumi²,

Shimizu³

et al. 2009

Transplantation

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Background Survival of ABO-mismatched kidneys with stable renal function despite the persistence of anti-ABO antibodies is called accommodation. The mechanism of accommodation is unclear, but may involve complement regulatory proteins such as CD59. The development of alpha-1,3-Galactosyltransferase knock-out (GalT-KO) swine that produce anti-Gal antibodies provides a large animal model capable of determining the role of complement regulatory proteins in accommodation. Methods ELISA and antibody FACS were used to examine the rate of anti-Gal antibody expression as a function of age. MHC-matched kidneys were transplanted from Gal-positive MGH miniature swine to MGH GalT-KO swine with systemic immunosuppression. One recipient underwent adsorbtion of anti-Gal antibodies prior to transplantation. Graft survival, antibody and complement deposition patterns and CD59 expression were determined. Results Three animals rejected Gal-positive kidneys via humoral mechanisms. One animal with low titers of anti-Gal Ab displayed spontaneous accommodation and the animal that was treated with Ab adsorbtion also displayed accommodation. Rejected grafts had deposition of IgM, IgG, C3 and C5b-9 with low expression of CD59, while accommodated grafts had low deposition of C5b-9 and high expression of CD59. Re-transplantation of one accommodated graft to a naïve GalT-KO animal confirmed that changes in the graft were responsible for the lack of C5b-9 deposition. Conclusion GalT-KO miniature swine produce anti-Gal antibodies and titers increase with age. These anti-Gal antibodies can cause rejection of MHC matched kidneys unless accommodation occurs. CD59 upregulation appears to be involved in the mechanism of accommodation by preventing the formation of the MAC on the accommodated graft.

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“…The hCD59 in hCD59 ICAM-2+/− mice is selectively expressed in endothelial cells, macrophages, and platelets19. In these transgenic strains, over-expression of hCD59 is effective in providing additional protection against mouse complement18, 19. We crossed each of the two strains with ApoE −/− mice (B6 background, Jackson Laboratory) to produce mCd59ab −/− /ApoE −/− and hCD59 ICAM-2+/− /ApoE −/− mice, respectively.…”

Section: Methodsmentioning

confidence: 99%

Complement Regulator CD59 Protects Against Angiotensin II–Induced Abdominal Aortic Aneurysms in Mice

Chen

Shahsafaei

et al. 2010

Circulation

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Background-Complement system, an innate immunity, has been well documented to play a critical role in many inflammatory diseases. However, the role of complement in the pathogenesis of abdominal aortic aneurysm, which is considered an immune and inflammatory disease, remains obscure. Methods and Results-Here, we evaluated the pathogenic roles of complement membrane attack complex and CD59, a key regulator that inhibits the membrane attack complex, in the development of abdominal aortic aneurysm. We demonstrated that in the angiotensin II-induced abdominal aortic aneurysm model, deficiency of the membrane attack complex regulator CD59 in ApoE-null mice (mCd59ab Ϫ/Ϫ /ApoE Ϫ/Ϫ ) accelerated the disease development, whereas transgenic overexpression of human CD59 (hCD59 ICAM-2ϩ/Ϫ /ApoE Ϫ/Ϫ ) in this model attenuated the progression of abdominal aortic aneurysm. The severity of aneurysm among these 3 groups positively correlates with C9 deposition, and/or the activities of MMP2 and MMP9, and/or the levels of phosphorylated c-Jun, c-Fos, IKK-␣/␤, and p65. Furthermore, we demonstrated that the membrane attack complex directly induced gene expression of matrix metalloproteinase-2 and -9 in vitro, which required activation of the activator protein-1 and nuclear factor-B signaling pathways. A bdominal aortic aneurysm (AAA) is characterized by chronic aortic wall inflammation and destructive connective tissue remodeling, including depletion of aortic elastin and fragmentation of medial elastic fibers. AAA is a leading cause of sudden death in aging (Ͼ55 years) men. 1 Rupture of AAA accounts for 4% of all deaths in people Ͼ65 years of age. Risk factors for AAA include age, male gender, atherosclerosis, hypertension, and genetic predisposition, although atherosclerosis is considered to be a main cause of AAA. 2 Enzymatic degradation of elastic lamellae and extracellular matrix proteins are underlying characteristics of AAA. 3 It is well established that abnormally increased protease activity in aortic tissue plays a critical role in the pathogenesis of aortic dissection and aneurysm. Matrix metalloproteinases (MMPs) such as MMP2 and MMP9 are the predominant proteinases in AAA wall. 2 In animal models, the development of aneurysms can be suppressed by pharmacological inhibition (ie, by tetracycline derivatives) of MMP2 and MMP9 or by genetic alterations that eliminate the expression of either proteinase. 4 Elastolytic cysteine proteases, including cathepsins, also play a critical role in the development of aneurysm. 5 AAA is also considered an immune and inflammatory disease, and macrophages, lymphocytes, and mast cells participate in its development. 1 However, the role of complement, a main effector of immunity and inflammation, remains unclear. Conclusion-Together Clinical Perspective on p 1346The complement system consists of Ϸ30 soluble and membrane-bound proteins and is activated by different sequential activation cascades (the classic, alternative, and lectin pathways) either on the pathogens or in plasma. These pat...

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High-Level Endothelial Expression of Human Cd59 Prolongs Heart Function in an Ex Vivo Model of Xenograft Rejection

Abstract: High-level endothelial-specific expression of CD59 was effective in prolonging the function of mouse hearts perfused with 20% human plasma, whereas low-level, broader expression did not provide protection from 6% plasma.

Cited by 27 publications

References 24 publications

Complement Regulator CD59 Protects Against Atherosclerosis by Restricting the Formation of Complement Membrane Attack Complex

Complement Regulator CD59 Protects Against Atherosclerosis by Restricting the Formation of Complement Membrane Attack Complex

Upregulation of CD59: Potential Mechanism of Accommodation in a Large Animal Model

Complement Regulator CD59 Protects Against Angiotensin II–Induced Abdominal Aortic Aneurysms in Mice

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