Cellular Infiltrates and NFκB Subunit c-Rel Signaling in Kidney Allografts of Patients With Clinical Operational Tolerance

Becker, Luis; Biazotto, Fuvia de Oliveira; Conrad, Heike; Schaier, Matthias; Kihm, Lars; Groß-Weißmann, Marie-Luise; Waldherr, Rüdiger; Bierhaus, Angelika; Nawroth, Peter P.; Zeier, Martin; Morath, Christian

doi:10.1097/tp.0b013e31826032be

Cited by 23 publications

(25 citation statements)

References 45 publications

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“…We have previously reported that CD4 + CD25 + FOXP3 + Treg-based mechanisms are likely to operate in our pediatric living-donor liver transplant (LDLT) recipients who could stop immunosuppression (IS) (referred to as 'operational tolerance' (OT) [5][6][7][8][9]. In support, a possible role of CD4 + CD25 + FOXP3 + Tregs in OT was reported by others in the settings of liver transplantation (Tx) and renal Tx [10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 77%

Utility of CD127 combined with FOXP3 for identification of operational tolerance after liver transplantation

Nafady-Hego

Liu

Ohe

et al. 2016

Transplant Immunology

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Section: Introductionmentioning

confidence: 77%

Utility of CD127 combined with FOXP3 for identification of operational tolerance after liver transplantation

Nafady-Hego

Liu

Ohe

et al. 2016

Transplant Immunology

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“…We previously demonstrated Nrf2‐mediated cytoprotective gene induction by a low level of anti‐HLA antibodies could promote acquisition of the resistance against complement‐mediated cytotoxicity . Recent findings suggested that NF‐kappaB was linked to kidney graft acceptance . Both transcription factors have been shown to be modulated through AMPK activation by resveratrol , which led us to hypothesize that AMPK activation might contribute accommodation under the complement‐ and thrombin‐mediated endothelial activated condition.…”

Section: Discussionmentioning

confidence: 99%

AMP-activated protein kinase as a promoting factor, but complement and thrombin as limiting factors for acquisition of cytoprotection: implications for induction of accommodation

et al. 2013

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SummaryAccommodation has been termed as a condition without graft rejection even in the presence of antidonor antibody. We previously reported an in vitro accommodation model, which demonstrated that preincubation of A/B antigen-expressing endothelial cells with anti-A/B antibody resulted in ERK inactivation followed by resistance to complement-mediated cytotoxicity through the induction of complement regulatory genes. However, under the in vivo condition, the effects of complement and coagulation system cannot be ignored. The purpose of this study is to find effective ways to navigate accommodation by exploring the relevant signal transduction. Preincubation with a low level of complement or thrombin failed to induce resistance to complement-mediated cytotoxicity. AMP-activated protein kinase (AMPK) activators such as resveratrol, AICAR and metformin protected endothelial cells against complement-mediated cytotoxicity through the increase in CD55, CD59, haem oxygenase-1 (HO-1) and ferritin heavy chain (ferritin H) genes, all of which were attenuated by AMPKa knock-down. Resveratrol counteracted the inhibitory effect of pretreated complement and thrombin on acquisition of resistance to complement-mediated cytotoxicity through AMPKa. AMPK regulation in endothelial cells could become the potential strategy to induce accommodation in clinical pro-inflammation and pro-coagulation.

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“…In animal studies, the claim that an individual has become tolerant has to meet very stringent criteria [46]. [18] 1976 1 40 months Uehling [19] 1976 1 36 months Seigler (reply to Uehling) [19] 1976 1 > 4 years Zoller [20] 1980 14 1-8 years Strober [21,22] 1989 2 69 months and 12 years Burlingham [23,24] 1995 1 7 years Fischer [25] 1996 1 9 years Christensen [26] 1998 1 > 3 years Van Buskirk [27] 2000 2 § > 5 and > 27 years Cai [28] 2004 1 § 32 years Starzl [5] 2004 7 3-38 years University of Nantes, France [29,30] 2006 27 ‡ 2-20 years (one missing data) Xu [31] 2007 2 Not available Indices of Tolerance (IOT) [32] 2010 11 2-21 years Immune Tolerance Network (ITN) [33][34][35] 2010 39 Divided into 3 groups: (1) n 5 25, mean time: 16 6 10Á4 (2) n 5 7, mean time: 14 6 17Á1 (3) n 5 7, not available Azancot [36] 2011 2 ‡ 14 months and > 6 years Inal [37] 2011 1 8 years University of São Paulo, Brazil [38][39][40] 2012 5 1Á5-8 years Becker [41] 2012 4 1-19 years Roedder [42] 2014 69 Not available GAMBIT study [43,44] 2016 14 # 1 common 1-22Á5 years DESCARTES-Nantes Survey [8] 2016 40 # 1 common 1-25 years (5 missing data) Kesiraju [45] 2016 1 > 3 years Total 41 years of reports 247 -It is l...…”

Section: Defining An Enigma: the Need For Operational Criteriamentioning

confidence: 99%

“…A few histological examinations of tolerant allografts have been published [21,24,27,[29][30][31]36,41]. Biopsies from stable tolerant patients revealed lymphoid infiltrates in peritubular regions of the cortical interstitium, without tubulitis [41]. Such infiltrates are common in wellfunctioning allografts [66].…”

Section: Patient Descriptionmentioning

confidence: 99%

Operational tolerance in kidney transplantation and associated biomarkers

Massart

Ghisdal

Abramowicz

et al. 2017

Clinical and Experimental Immunology

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SummaryIn the 1960s, our predecessors won a historical battle against acute rejection and ensured that transplantation became a common life-saving treatment. In parallel with this success, or perhaps because of it, we lost the battle for long-lived transplants, being overwhelmed with chronic immune insults and the toxicities of immunosuppression. It is likely that current powerful treatments block acute rejection, but at the same time condemn the few circulating donor cells that would have been able to elicit immunoregulatory host responses towards the allograft. Under these conditions, spontaneously tolerant kidney recipients -i.e. patients who maintain allograft function in the absence of immunosuppression -are merely accidents; they are scarce, mysterious and precious. Several teams pursue the goal of finding a biomarker that would guide us towards the 'just right' level of immunosuppression that avoids rejection while leaving some space for donor immune cells. Some cellular assays are attractive because they are antigen-specific, and provide a comprehensive view of immune responses toward the graft. These seem to closely follow patient regulatory capacities. However, these tests are cumbersome, and require abundant cellular material from both donor and recipient. The latest newcomers, nonantigen-specific recipient blood transcriptomic biomarkers, offer the promise that a practicable and simple signature may be found that overcomes the complexity of a system in which an infinite number of individual cell combinations can lead possibly to graft acceptance. Biomarker studies are as much an objective -identifying tolerant patients, enabling tolerance trials -as a means to deciphering the underlying mechanisms of one of the most important current issues in transplantation.

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Cellular Infiltrates and NFκB Subunit c-Rel Signaling in Kidney Allografts of Patients With Clinical Operational Tolerance

Abstract: Allografts from COT patients show significant cellular infiltrates but a distinct expression of proteins involved in the NFκB pathway and a higher proportion of forkhead box P3-positive cells.

Cited by 23 publications

References 45 publications

Utility of CD127 combined with FOXP3 for identification of operational tolerance after liver transplantation

Utility of CD127 combined with FOXP3 for identification of operational tolerance after liver transplantation

AMP-activated protein kinase as a promoting factor, but complement and thrombin as limiting factors for acquisition of cytoprotection: implications for induction of accommodation

Operational tolerance in kidney transplantation and associated biomarkers

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