Atorvastatin Down-Regulates the Primate Cellular Response to Porcine Aortic Endothelial Cells In Vitro

Ezzelarab, Mohamed; Welchons, Daniel; Torres, Corine; Hara, Hidetaka; Long, Cassandra; Yeh, Peter C.; Ayares, David; Cooper, David K. C.

doi:10.1097/tp.0b013e3181821cad

Cited by 24 publications

(21 citation statements)

References 13 publications

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“…Anti-inflammatory agents prevent TF expression and thrombosis (63). For example, we have shown that statins inhibit upregulation of TF expression on pig endothelial cells in response to primate xenoreactive antibodies (64) and regulate human and baboon T cell proliferation against pig endothelial cells (65). …”

Section: Discussionmentioning

confidence: 99%

Systemic inflammation in xenograft recipients precedes activation of coagulation

Ezzelarab

Ekser

Azimzadeh

et al. 2014

Xenotransplantation

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115

173

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Background Dysregulation of coagulation is considered a major barrier against successful pig organ xenotransplantation in nonhuman primates. Inflammation is known to promote activation of coagulation. The role of pro-inflammatory factors as well as the relationship between inflammation and activation of coagulation in xenograft recipients is poorly understood. Methods Baboons received kidney (n=3), heart (n=4) or artery patch (n=8) xenografts from α1,3-galactosyltransferase gene-knockout (GTKO) pigs or GTKO pigs additionally transgenic for human complement regulatory protein CD46 (GTKO/CD46). Immunosuppression (IS) was based on either CTLA4-Ig or anti-CD154 costimulation blockade. Three artery patch recipients did not receive IS. Pro-inflammatory cytokines, chemokines and coagulation parameters were evaluated in the circulation after transplantation. In artery patch recipients, monocytes and dendritic cells (DC) were monitored in peripheral blood. Expression of tissue factor (TF) and CD40 on monocytes and DC were assessed by flow cytometry. C-reactive protein (C-RP) levels in the blood and C-RP deposition in xenografts as well as native organs were evaluated. Baboon and pig C-RP mRNA in heart and kidney xenografts were evaluated. Results In heart and kidney xenograft recipients, the levels of INFγ, TNF-α, IL-12 and IL-8 were not significantly higher after transplantation. However, MCP-1 and IL-6 levels were significantly higher after transplantation, particularly in kidney recipients. Elevated C-RP levels preceded activation of coagulation in heart and kidney recipients, where high levels of C-RP were maintained until the time of euthanasia in both heart and kidney recipients. In artery patch recipients, INFγ, TNF-α, IL-12, IL-8 and MCP-1 were elevated with no IS, while IL-6 was not. With IS, INFγ, TNF-α, IL-12, IL-8 and MCP-1 were reduced, but IL-6 was elevated. Elevated IL-6 levels were observed as early as 2 weeks in artery patch recipients. While IS was associated with reduced thrombin activation, fibrinogen and C-RP levels were increased when IS was given. There was a significant positive-correlation between C-RP, IL-6, and fibrinogen levels. Additionally, absolute numbers of monocytes were significantly increased when IS was given, but not without IS. This was associated with increased CD40 and TF expression on CD14+ monocytes and lineageneg CD11c+ DC, with increased differentiation of the pro-inflammatory CD14+ CD11c+ monocyte population. At the time of euthanasia, C-RP deposition in kidney and heart xenografts, C-RP positive cells in artery patch xenograft and native lungs were detected. Finally, high levels of both pig and baboon C-RP mRNA were detected in heart and kidney xenografts. Conclusions Inflammatory responses precede activation of coagulation after organ xenotransplantation. Early upregulation of C-RP and IL-6 levels may amplify activation of coagulation through upregulation of TF on innate immune cells. Prevention of systemic inflammation in xenograft recipients (SIXR) may be required ...

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Section: Discussionmentioning

confidence: 99%

Systemic inflammation in xenograft recipients precedes activation of coagulation

Ezzelarab

Ekser

Azimzadeh

et al. 2014

Xenotransplantation

Self Cite

115

173

View full text Add to dashboard Cite

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“…12 Anticipating similar responses with endothelialized modules, we used tacrolimus, an immune-suppressant, and atorvastatin to enhance allograft survival. Atorvastatin may directly decrease the immune response to EC as demonstrated by decreased proliferation of T cells exposed to xenogeneic EC in vitro, 13 improved EC survival, 14 increased NO production, 15,16 and increased number of circulating endothelial progenitor cells. 17 With tacrolimus and atorvastatin treatment, inflammatory cell numbers (CD68 þ ) were significantly reduced at day 21 (Fig.…”

Section: Tissue Vascularization and Impact Of Inflammation And Immunementioning

confidence: 99%

Chimeric Vessel Tissue Engineering Driven by Endothelialized Modules in Immunosuppressed Sprague-Dawley Rats

Chamberlain

Gupta

Sefton

2011

Tissue Engineering Part A

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Modular tissue engineering is a means of building functional, vascularized tissues using small (*1 mm long 0.5 mm diameter) components. While this approach is being explored for its utility in adipose and cardiac tissue engineering and in islet transplantation, the initial question in this study was to assess the fate of the endothelial cells (EC) after transplantation delivered on the surface of modules, without an embedded cell. Rat aortic ECcovered collagen gel modules were transplanted into the omental pouch of allogeneic (outbred) Sprague-Dawley rats with and without immunosuppressive drug treatment (atorvastatin and tacrolimus) for 3-60 days. There was a significant increase in vessel density at all time points in the drug treated rats as compared to untreated rats. Green fluorescent protein (GFP)-positive donor rat aortic EC migrated from the surface of the modules and formed primitive vessels by day 7. In the untreated rats, the GFP-positive cells were not seen after day 7. In drugtreated rats, GFP-positive vessels matured over time, accumulated erythrocytes, were supported by host smooth muscle cells, and formed chimeric vessels that survived until day 60. This resulted in the formation of a densely vascularized, perfusable network by day 60. To our knowledge, this is the first study that demonstrates that primary unmodified EC, without the addition of supporting cells, form a chimeric and stable vascular bed in allogeneic, although drug-treated, animals.

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“…For example, pigs expressing the immunoregulatory molecule CTLA4-Ig have been produced [24] [25], and anti-inflammatory agents have been shown to reduce the human T cell response to pig cells in vitro [16]. Our previous studies indicated that a large number of MSC can be effectively harvested from GTKO/CD46 pig fat tissue [26].…”

Section: Discussionmentioning

confidence: 99%

“…Adherent cells were harvested using trypsin-EDTA (Invitrogen, Grand Island, NY) when MSC reached 90–95% confluence. pAECs were obtained from freshly-harvested GTKO pigs aortas, and cultured as previously described [16]. Both pMSC and pAEC were used from passages 2–6.…”

Section: Methodsmentioning

confidence: 99%

Human T cells upregulate CD69 after coculture with xenogeneic genetically-modified pig mesenchymal stromal cells

Andreyev

Chen

et al. 2013

Cellular Immunology

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Mesenchymal stromal cells (MSC) obtained from α1,3-galactosyltransferase gene knock-out pigs transgenic for the human complement-regulatory protein CD46 (GTKO/CD46 pMSC) suppress in vitro human anti-pig cellular responses as efficiently as allogeneic human MSC. We investigated the immunoregulatory effects of GTKO/CD46 pMSC on human CD4+ and CD8+ T cell proliferation in response to pig aortic endothelial cells (pAEC). pMSC efficiently suppressed T cell proliferation, which was associated with downregulation of granzyme B expression. No induction of CD4+CD25+Foxp3hi regulatory T cells or T cell apoptosis was documented. In correlation with T cell proliferation, CD25 expression was upregulated on T cells in response to pAEC but not to pMSC. In contrast, CD69 expression was upregulated on T cells in response to both pMSC and pAEC, which was associated with a significant increase in the phosphorylation of STAT5. GTKO/CD46 pMSC possibly regulate human T cell responses through modulation of CD69 expression and STAT5 signaling.

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Atorvastatin Down-Regulates the Primate Cellular Response to Porcine Aortic Endothelial Cells In Vitro

Cited by 24 publications

References 13 publications

Systemic inflammation in xenograft recipients precedes activation of coagulation

Systemic inflammation in xenograft recipients precedes activation of coagulation

Chimeric Vessel Tissue Engineering Driven by Endothelialized Modules in Immunosuppressed Sprague-Dawley Rats

Human T cells upregulate CD69 after coculture with xenogeneic genetically-modified pig mesenchymal stromal cells

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