Macrophages Contribute to Cellular But Not Humoral Mechanisms of Acute Rejection in Rat Renal Allografts

Frank, Y.; Woodman, N.; Mulley, William R.; Kanellis, John; Nikolic-Paterson, David J.

doi:10.1097/tp.0b013e3182a4befa

Cited by 25 publications

(20 citation statements)

References 24 publications

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“…The role of macrophages in contributing to graft tissue injury during acute cellular rejection of allografts has been investigated using many different approaches, including macrophage deletion by various strategies that may not always target only macrophages (11, 30, 31). CCL2 is produced by many cell types following inflammatory stimulation including endothelial and epithelial cells, vascular smooth muscle cells, fibroblasts and many leukocyte populations cells and is a key chemoattractant regulating the infiltration of monocytes/macrophages into inflammatory tissue sites (14, 15).…”

Section: Discussionmentioning

confidence: 99%

Graft-Derived CCL2 Increases Graft Injury During Antibody-Mediated Rejection of Cardiac Allografts

Abe

Iida

et al. 2014

American Journal of Transplantation

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The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5−/−/CD8−/− recipients rejected MHC-mismatched wild type A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2−/− allografts induced low donor-reactive antibody titers and C4d deposition at day 7 post-transplant. Decreased donor-reactive CD4 T cells producing IFN-γ were induced in response to A/J.CCL2−/− vs. wild type allografts. Consequently, A/J.CCL2−/− allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from wild type allografts expressed high levels of IL-1β and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR.

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Section: Discussionmentioning

confidence: 99%

Graft-Derived CCL2 Increases Graft Injury During Antibody-Mediated Rejection of Cardiac Allografts

Abe

Iida

et al. 2014

American Journal of Transplantation

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“…Similarly, DT treatment of CD11b-DTR mice protects the renal allograft from acute injury and rejection 162. Use of a pharmacological antagonist of the csf-1/csf-1R pathway reduces tubulointerstitial injury163, Mac infiltration, acute cellular rejection and T cell activation164. Interestingly, the treatment had no effect on humoral rejection that occurred later in the model.…”

Section: Targeting DC and Mac Regulates Experimental Renal Diseasementioning

confidence: 99%

Dendritic cells and macrophages in the kidney: a spectrum of good and evil

et al. 2014

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Renal dendritic cells (DC) and macrophages (Mac) represent a constitutive, extensive and contiguous network of innate immune cells that provide sentinel and immune intelligence function. They induce and regulate inflammatory responses to freely-filtered antigenic material and protect the kidney from infection. Tissue–resident or infiltrating DC and Mac are key to the initiation and propagation of renal disease, as well as essential contributors to subsequent tissue regeneration regardless of its etiology and pathogenesis. Their identification, functional and phenotypic distinction, interplay and relationship with effector and regulatory adaptive immune cells is complex and incompletely understood. This review discusses both the common and distinct characteristics of these cells, as well as recent key advances in the field that have identified renal-specific functions of DC and Mac that enable these important, phagocytic, antigen-presenting, cells to mediate or mitigate intrinsic kidney disease. We also identify priority areas for further investigation and prospects for translational and therapeutic application of acquired knowledge.

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“…We have previously identified Syk activation in infiltrating leucocytes in rat models of kidney disease and kidney transplantation based on phosphorylation of the activation loop of the Syk enzyme (Ryan et al 2011;Ma et al 2013); however, recent batches of this anti-human p-Syk polyclonal antibody have been unable to detect Syk activation in rat tissue sections, and thus we were unable to confirm that CC0482417 inhibited Syk activation in the rat allograft model. We have previously identified Syk activation in infiltrating leucocytes in rat models of kidney disease and kidney transplantation based on phosphorylation of the activation loop of the Syk enzyme (Ryan et al 2011;Ma et al 2013); however, recent batches of this anti-human p-Syk polyclonal antibody have been unable to detect Syk activation in rat tissue sections, and thus we were unable to confirm that CC0482417 inhibited Syk activation in the rat allograft model.…”

Section: Discussionmentioning

confidence: 78%

“…Orthotopic transplantation of a Wistar kidney into bilateral nephrectomized Sprague Dawley (SD) recipients was performed as previously described (Kerr et al 1994;Ma et al 2013). Briefly, the donor Wistar kidney was isolated and perfused with ice-cold Ross solution and then implanted orthotopically in recipient Sprague-Dawley rats with end-toend anastomosis of renal artery (sleeve), vein (stent) and ureter (stent).…”

Section: Rat Model Of Acute Renal Allograft Rejectionmentioning

confidence: 99%

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

Chandran

Tesch

Han

et al. 2014

Int J Experimental Path

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Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague-Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation.

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Macrophages Contribute to Cellular But Not Humoral Mechanisms of Acute Rejection in Rat Renal Allografts

Cited by 25 publications

References 24 publications

Graft-Derived CCL2 Increases Graft Injury During Antibody-Mediated Rejection of Cardiac Allografts

Graft-Derived CCL2 Increases Graft Injury During Antibody-Mediated Rejection of Cardiac Allografts

Dendritic cells and macrophages in the kidney: a spectrum of good and evil

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

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