Improved techniques for kidney transplantation in mice

Zhang, Zheng; Schlachta, Christopher M.; Duff, John; Stiller, C. R.; Grant, David; Zhong, Robert

doi:10.1002/micr.1920160212

Cited by 96 publications

(78 citation statements)

References 17 publications

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“…of MCMV (Smith strain) and housed for 3-6 months in the Northwestern University Center for Comparative Medicine. Donor kidneys from latently infected BALB/c mice were transplanted into recipient C57BL/6 mice as previously described (Zhang et al, 1995), except that recipients were bilaterally nephrectomized at the time of the transplant. The pararenal glands were left intact.…”

Section: Methodsmentioning

confidence: 99%

Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Liu

Jie

Zhang

et al. 2016

Journal of General Virology

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Reactivation of latent human cytomegalovirus is a significant infectious complication of organ transplantation and current therapies target viral replication once reactivation of latent virus has already occurred. The specific molecular pathways that activate viral gene expression in response to transplantation are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. Murine cytomegalovirus (MCMV) is a valuable model for studying latency and reactivation of CMV in vivo. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces reactivation of immediate early (IE) gene expression and epigenetic reprogramming of the major immediate early promoter (MIEP) within 48 h. We hypothesize that these events are mediated by activation of signalling pathways that lead to binding of transcription factors to the MIEP, including AP-1 and NF-k B. Here we show that transplantation induces rapid activation of several members of the AP-1 and NF-k B transcription factor family and we demonstrate that canonical NF-k B (p65/p50), the junD component of AP-1, and nucleosome remodelling complexes are recruited to the MIEP following transplantation. Proteomic analysis of recipient plasma and transcriptome analysis of kidney RNA identified five extracellular ligands, including TNF, IL-1b, IL-18, CD40L and IL-6, and three intracellular signalling pathways associated with reactivation of IE gene expression. Identification of the factors that mediate activation of these signalling pathways may eventually lead to new therapies to prevent reactivation of CMV and its sequelae.

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Section: Methodsmentioning

confidence: 99%

Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Liu

Jie

Zhang

et al. 2016

Journal of General Virology

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“…55 Surgical inflammation was allowed to subside for 1 week before antibody transfer. Only mice with normal creatinine values were used for experiments.…”

Section: Orthotopic Renal Transplantationmentioning

confidence: 99%

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Kuo

Fan²,

Dvorina³

et al. 2015

Journal of the American Society of Nephrology

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Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100-to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses.

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“…Kidneys from BALB/c (H-2 d ) donor mice were orthotopically transplanted into C57BL/6 (H-2 b ) WT or Ccr5 À/À mice as described [46] (nZ10/group). For isograft controls C57BL/6 donor kidneys were transplanted into C57BL/6 recipient mice (n 5 5).…”

Section: Orthotopic Kidney Transplantationmentioning

confidence: 99%

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

et al. 2009

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The chemokine (C-C motif) receptor 5 (CCR5) has been implicated in experimental and clinical allograft rejection. To dissect the function of CCR5 in acute and chronic renal allograft rejection, bilaterally nephrectomized WT and Ccr5 À/À C57BL/6 mice were used as recipients of WT BALB/c renal allografts and analyzed 7 and 42 days after transplantation. Lesion scores (glomerular damage, vascular rejection, tubulointerstitial inflammation) and numbers of CD4 1 , CD8 1 , CD11c 1 and alpha smooth muscle actin (aSMA) 1 cells were reduced in allografts from Ccr5 À/À recipients during the chronic phase. Increasing creatinine levels indicated deterioration of allograft function over time. While mRNA expression of Th1-associated markers decreased between 7 and 42 days, Th2-associated markers increased. Markers for alternatively activated macrophages (arginase 1, chitinase 3-like 3, resistin-like a, mannose receptor, C type 1), were strongly upregulated (mRNA and/or protein level) only in allografts from Ccr5 À/À recipients at 42 days. Ccr5 deficiency shifted intragraft immune responses during the chronic phase towards the Th2 type and led to accumulation of alternatively activated macrophages. Additionally, splenocytes from unchallenged Ccr5 À/À mice showed significantly increased arginase 1 and mannose receptor 1 mRNA levels, suggesting constitutive alternative activation of splenic macrophages. We conclude that Ccr5 deficiency favors alternative macrophage activation. This finding may be relevant for other inflammatory diseases that involve macrophage activation and may also influence future therapeutic strategies targeting CCR5.

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Improved techniques for kidney transplantation in mice

Cited by 96 publications

References 17 publications

Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter

Platelets in Early Antibody-Mediated Rejection of Renal Transplants

Chemokine receptor Ccr5 deficiency induces alternative macrophage activation and improves long‐term renal allograft outcome

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