Protective effect of T cell depletion in murine renal ischemia-reperfusion injury.

Yokota, Naoko; Daniels, Frank; Crosson, John T.; Rabb, Hamid

doi:10.1097/00007890-200209270-00005

Cited by 125 publications

(104 citation statements)

References 15 publications

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“…Aberrant CALCA gene methylation arises universally and de novo during leukemic transformation in hematopoietic progenitors developing in the lymphoid pathway (B or T cell lineage) (51). Since it has been shown that CD4+ T cells may play a pathogenic role in ischemic acute renal failure (52,53) as well as in acute rejection, we believed that aberrant hypermethylation of the CALCA gene which seems to be involved in the lymphoid pathway may be a biomarker of the two main causes of acute kidney injury in transplantation; mainly acute rejection and acute tubular necrosis.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Detection of Promoter Hypermethylation as a Biomarker of Acute Kidney Injury During Transplantation

Mehta

Hoque

Ugarte

et al. 2006

Transplantation Proceedings

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Aberrant promoter hypermethylation, also known as epigenetics, is thought to be a promising biomarker approach to diagnose malignancies. Kidney repair after injury is a recapitulation of normal morphogenesis, with similarities to malignant transformation. We hypothesized that changes in urine epigenetics could be a biomarker approach during early kidney transplant injury and repair. We examined urine DNA for aberrant methylation of 2 gene promoters (DAPK CALCA) by quantitative methylation specific PCR from 13 deceased and 10 living donor kidney transplant recipients on postoperative day 2 and 65 healthy controls. Results were compared with clinical outcomes and to results of the kidney biopsy. Transplant recipients were significantly more likely to have aberrant hypermethylation of the CALCA gene promoter in urine than healthy controls (100% vs. 31%, p<0.0001). There was increased CALCA hypermethylation in the urine of deceased vs. living donor transplants (21.60 +/− 12.5 vs. 12.19 +/− 4.7 P=0.04). Furthermore, there was a trend towards increased aberrant hypermethylation of urine CALCA in patients with biopsy-proven acute tubular necrosis vs. acute rejection and slow or prompt graft function (mean: 20.40 +/− 6.9, 13.87 +/− 6.49, 17.17 +/− 13.4, P=0.67). However, there was no difference of CALCA hypermethylation in urine of patients with delayed graft function vs. those with slow or prompt graft function (16.9 +/− 6.2 vs. 18.5 +/− 13.7, respectively; P=0.5). There was no aberrant hypermethylation of DAPK in the urine of transplant patients. Urine epigenetics is a promising biomarker approach for acute ischemic injury in transplantation that merits future study.

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Section: Discussionmentioning

confidence: 99%

Quantitative Detection of Promoter Hypermethylation as a Biomarker of Acute Kidney Injury During Transplantation

Mehta

Hoque

Ugarte

et al. 2006

Transplantation Proceedings

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“…17,18 A role for CD8 þ T cells in ischemia-reperfusion injury of the kidney has also been demonstrated. 19,20 Ayala and colleagues showed that blockade of Fas/FasL interactions will ablate CLP-induced injury. 21,22 CD8 þ T and NK cells utilize the Fas/FasL pathway to induce cellular lysis and injury in a variety of scenarios.…”

Section: Discussionmentioning

confidence: 99%

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Sherwood

Enoh

Murphey

et al. 2004

Laboratory Investigation

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We previously showed that beta 2 microglobulin knockout mice depleted of NK cells by treatment with antiasialoGM1 (b2MKO/aAsGM1 mice) are resistant to sepsis caused by cecal ligation and puncture (CLP). b2MKO mice possess multiple immunological defects including depletion of CD8 þ T cells. This study was designed to determine the contribution of CD8 þ T and NK cell deficiency to the resistance of b2MKO/aAsGM1 mice to CLPinduced injury. b2MKO/aAsGM1 mice and CD8 knockout mice treated with anti-asialoGM1 (CD8KO/aAsGM1 mice) survived significantly longer than wild-type mice following CLP. Improved long-term survival was also observed in wild-type mice rendered CD8 þ T/NK cell-deficient by treatment with both anti-CD8a and antiasialoGM1. Blood gas analysis and body temperature measurements showed that CD8 þ T and NK cell-deficient mice have significantly reduced metabolic acidosis and less hypothermia compared to control mice at 18 h after CLP. CD8 þ T/NK cell-deficient mice also showed an attenuated proinflammatory response as indicated by decreased expression of mRNAs for IL-1, IL-6 and MIP-2 in spleen and heart. IL-6, KC and MIP-2 levels in blood and peritoneal fluid were also significantly decreased CD8 þ T/NK cell-deficient mice compared to controls. CD8 þ T/NK cell-deficient mice exhibited decreased bacterial concentrations in blood, but not in peritoneal fluid or lung, compared to wild-type controls. These data show that mice depleted of CD8 þ T and NK cells exhibit survival benefit, improved physiologic function and an attenuated proinflammatory response following CLP that is comparable to b2M/aAsGM1 mice. We previously demonstrated that b2 microglobulin knockout mice that were depleted of natural killer (NK) cells by treatment with anti-asialoGM1 (b2MKO/aAsGM1 mice) are resistant to systemic injury caused by cecal ligation and puncture (CLP). 1 Specifically, b2MKO/aAsGM1 mice exhibit improved survival, less metabolic acidosis, reduced hypothermia and better hemodynamic function compared to control mice following CLP. 1,2 These improvements in physiological function are associated with attenuation of the CLP-induced proinflammatory response.b2MKO/aAsGM1 mice have multiple immunological defects including an absence of CD8 þ T, natural killer (NK) and natural killer T (NKT) cells as well as deficient expression of the class I major histocompatability complex (MHC-I) and CD1 molecules. 1,3-5 One of our goals is to determine which of these immunological alterations confers resistance to the CLP-induced sepsis syndrome. We previously showed that adoptive transfer of CD8 þ T and NK cells into b2MKO/aAsGM1 mice will re-establish CLP-induced mortality. 1 In addition, we showed improved post-CLP survival in mice that are deficient of both CD8 þ T and NK cells. Based on this observation, we hypothesize that CD8 þ T and NK cell depletion contributes to the resistance of b2MKO/aAsGM1 mice to CLP-induced injury. To test this hypothesis, we directly compared CLP-induced mortality in b2MKO/aAsGM1 mice and CD8 þ T/NK cell-d...

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“…Mice deficient in both CD4 + and CD8 + T cells had reduced functional and structural abnormalities after IRI [37]. Athymic nu/nu mice were also protected from renal IRI, and adoptive transfer of wild type T cells abolished these effects both in clamp and whole body IRI models [38,39]. Interestingly, neither neutrophil nor macrophage infiltration was changed in this model, suggesting a neutrophil/macrophage-independent effect of T cells in IRI.…”

mentioning

confidence: 88%

“…This combination depleted T cells but did not protect renal function after ischemia. However, the addition of a third antibody (30.H12) that targets Th1.2 antigen decreased T cells further, in particular the CD4 + subset, and led to renal protection [39]. In the late phase (6 weeks) of severe renal IRI, there was a marked infiltration of CD4 + T cells throughout the injured kidney, which may promote the development of chronic renal disease [41].…”

Section: Different Roles Of T Cell Subsets In Irimentioning

confidence: 99%

Ischemia–reperfusion and immediate T cell responses

Huang¹,

Rabb²,

Womer³

2007

Cellular Immunology

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Protective effect of T cell depletion in murine renal ischemia-reperfusion injury.

Abstract: These data demonstrate that T cell depletion can improve the course of experimental renal IRI. However, more aggressive T cell depletion strategies were required compared with that needed to prevent experimental allograft rejection.

Cited by 125 publications

References 15 publications

Quantitative Detection of Promoter Hypermethylation as a Biomarker of Acute Kidney Injury During Transplantation

Quantitative Detection of Promoter Hypermethylation as a Biomarker of Acute Kidney Injury During Transplantation

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Ischemia–reperfusion and immediate T cell responses

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