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2.
Front Immunol ; 14: 1122409, 2023.
Article in English | MEDLINE | ID: mdl-36891297

ABSTRACT

Mast cells (MCs) are innate immune cells with a versatile set of functionalities, enabling them to orchestrate immune responses in various ways. Aside from their known role in allergy, they also partake in both allograft tolerance and rejection through interaction with regulatory T cells, effector T cells, B cells and degranulation of cytokines and other mediators. MC mediators have both pro- and anti-inflammatory actions, but overall lean towards pro-fibrotic pathways. Paradoxically, they are also seen as having potential protective effects in tissue remodeling post-injury. This manuscript elaborates on current knowledge of the functional diversity of mast cells in kidney transplants, combining theory and practice into a MC model stipulating both protective and harmful capabilities in the kidney transplant setting.


Subject(s)
Hypersensitivity , Kidney Transplantation , Humans , Mast Cells , Cytokines/metabolism , T-Lymphocytes, Regulatory/metabolism
3.
Pediatr Transplant ; 21(2)2017 Mar.
Article in English | MEDLINE | ID: mdl-28084679

ABSTRACT

AMR is a risk factor for graft failure after SBTx. We studied impact of DSAs and AMR in 22 children transplanted between 2008 and 2012 (11 isolated SBTx, 10 liver inclusive Tx, and one modified multivisceral Tx). Three patients never developed DSA, but DSAs were found in seven in the pre-Tx period and de novo post-Tx in 19 children. Pathology revealed cellular rejection (15/19), with vascular changes and C4d+. Patients were treated with IV immunoglobulins, plasmapheresis, and steroids. Rescue therapy included antithymocyte globulins, rituximab, eculizumab, and bortezomib. Pathology and graft function normalized in 13 patients, graft loss occurred in two, and death in seven. At the end of the follow-up, 15 children were alive (68%), 13 with functioning graft (59%). Prognosis factors for poor outcome after Tx were the presence of symptoms at AMR suspicion (P +.033). DSAs were often found following SBTx, mostly de novo. Resistant ACR or severe AMR is still difficult to differentiate, with a high need for immunosuppression in both. DSAs may precede development of severe disease and pathology features on the graft: relationship and correlation need to be better investigated with larger groups before and after Tx.


Subject(s)
Antibodies/immunology , Graft Rejection/immunology , HLA Antigens/immunology , Intestines/transplantation , Transplantation , Adolescent , Antibodies, Monoclonal, Humanized/therapeutic use , Antilymphocyte Serum/therapeutic use , Bortezomib/therapeutic use , Child , Child, Preschool , Cohort Studies , Complement C4b/immunology , Female , Graft Survival , Humans , Immunoglobulins, Intravenous/therapeutic use , Immunosuppression Therapy , Infant , Isoantibodies/immunology , Male , Peptide Fragments/immunology , Plasmapheresis , Prognosis , Rituximab/therapeutic use , Steroids/therapeutic use , Tissue Donors , Treatment Outcome
4.
Am J Transplant ; 17(1): 28-41, 2017 01.
Article in English | MEDLINE | ID: mdl-27862883

ABSTRACT

The XIII Banff meeting, held in conjunction the Canadian Society of Transplantation in Vancouver, Canada, reviewed the clinical impact of updates of C4d-negative antibody-mediated rejection (ABMR) from the 2013 meeting, reports from active Banff Working Groups, the relationships of donor-specific antibody tests (anti-HLA and non-HLA) with transplant histopathology, and questions of molecular transplant diagnostics. The use of transcriptome gene sets, their resultant diagnostic classifiers, or common key genes to supplement the diagnosis and classification of rejection requires further consensus agreement and validation in biopsies. Newly introduced concepts include the i-IFTA score, comprising inflammation within areas of fibrosis and atrophy and acceptance of transplant arteriolopathy within the descriptions of chronic active T cell-mediated rejection (TCMR) or chronic ABMR. The pattern of mixed TCMR and ABMR was increasingly recognized. This report also includes improved definitions of TCMR and ABMR in pancreas transplants with specification of vascular lesions and prospects for defining a vascularized composite allograft rejection classification. The goal of the Banff process is ongoing integration of advances in histologic, serologic, and molecular diagnostic techniques to produce a consensus-based reporting system that offers precise composite scores, accurate routine diagnostics, and applicability to next-generation clinical trials.


Subject(s)
Arteritis/immunology , Complement C4b/immunology , Graft Rejection/classification , Graft Rejection/pathology , Isoantibodies/immunology , Kidney Transplantation/adverse effects , Peptide Fragments/immunology , Graft Rejection/etiology , Humans , Research Report
5.
Am J Transplant ; 16(10): 3033-3040, 2016 10.
Article in English | MEDLINE | ID: mdl-27232948

ABSTRACT

Urinary messenger RNA (mRNA) quantification is a promising method for noninvasive diagnosis of renal allograft rejection (AR), but the quantification of mRNAs in urine remains challenging due to degradation. RNA normalization may be warranted to overcome these issues, but the strategies of gene normalization have been poorly evaluated. Herein, we address this issue in a case-control study of 108 urine samples collected at time of allograft biopsy in kidney recipients with (n = 52) or without (n = 56) AR by comparing the diagnostic value of IP-10 and CD3ε mRNAs-two biomarkers of AR-after normalization by the total amount of RNA, normalization by one of the three widely used reference RNAs-18S, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Hypoxanthine-guanine phosphoribosyltransferase (HPRT)-or normalization using uroplakin 1A (UPK) mRNA as a possible urine-specific reference mRNA. Our results show that normalization based on the total quantity of RNA is not substantially improved by additional normalization and may even be worsened with some classical reference genes that are overexpressed during rejection. However, considering that normalization by a reference gene is necessary to ensure polymerase chain reaction (PCR) quality and reproducibility and to suppress the effect of RNA degradation, we suggest that GAPDH and UPK1A are preferable to 18S or HPRT RNA.


Subject(s)
Biomarkers/urine , Graft Rejection/diagnosis , Kidney Failure, Chronic/surgery , Kidney Transplantation/adverse effects , Polymerase Chain Reaction/standards , RNA, Messenger/urine , Female , Follow-Up Studies , Glomerular Filtration Rate , Graft Rejection/etiology , Graft Rejection/urine , Humans , Kidney Function Tests , Male , Prognosis , RNA, Messenger/genetics , Reference Standards , Retrospective Studies , Risk Factors , Transplantation, Homologous
6.
Am J Transplant ; 16(6): 1868-81, 2016 06.
Article in English | MEDLINE | ID: mdl-26694099

ABSTRACT

We monitored the urinary C-X-C motif chemokine (CXCL)9 and CXCL10 levels in 1722 urine samples from 300 consecutive kidney recipients collected during the first posttransplantation year and assessed their predictive value for subsequent acute rejection (AR). The trajectories of urinary CXCL10 showed an early increase at 1 month (p = 0.0005) and 3 months (p = 0.0009) in patients who subsequently developed AR. At 1 year, the AR-free allograft survival rates were 90% and 54% in patients with CXCL10:creatinine (CXCL10:Cr) levels <2.79 ng/mmoL and >2.79 ng/mmoL at 1 month, respectively (p < 0.0001), and 88% and 56% in patients with CXCL10:Cr levels <5.32 ng/mmoL and >5.32 ng/mmoL at 3 months (p < 0.0001), respectively. CXCL9:Cr levels also associate, albeit less robustly, with AR-free allograft survival. Early CXCL10:Cr levels predicted clinical and subclinical rejection and both T cell- and antibody-mediated rejection. In 222 stable patients, CXCL10:Cr at 3 months predicted AR independent of concomitant protocol biopsy results (p = 0.009). Although its positive predictive value was low, a high negative predictive value suggests that early CXCL10:Cr might predict immunological quiescence on a triple-drug calcineurin inhibitor-based immunosuppressive regimen in the first posttransplantation year, even in clinically and histologically stable patients. The clinical utility of this test will need to be addressed by dedicated prospective clinical trials.


Subject(s)
Biomarkers/urine , Chemokine CXCL10/urine , Chemokine CXCL9/urine , Graft Rejection/diagnosis , Kidney Transplantation/adverse effects , Female , Graft Rejection/etiology , Graft Rejection/urine , Humans , Longitudinal Studies , Male , Middle Aged , Prospective Studies , Transplantation, Homologous
7.
Am J Transplant ; 14(6): 1439-45, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24804568

ABSTRACT

Anti-HLA donor-specific antibodies (DSAs) cause acute and chronic antibody-mediated rejection (AMR). However, the clinical relevance of anti-HLA-C antibodies remains unclear. We evaluated the clinical relevance of the presence of anti-HLA-C DSA at day 0 in renal transplant recipients. In this retrospective, case-controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti-HLA-C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530-17,941). The mean fluorescence intensity in the anti-C group was 4966 (978-17,941) in the AMR group and 981 (530-8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti-C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti-HLA-C DSAs are likely to develop acute AMR during the first year after transplantation.


Subject(s)
Antibodies/immunology , Graft Rejection/immunology , HLA-C Antigens/immunology , Kidney Transplantation/adverse effects , Tissue Donors , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective Studies , Treatment Outcome
8.
Rev Med Interne ; 35(4): 222-30, 2014 Apr.
Article in French | MEDLINE | ID: mdl-23743480

ABSTRACT

PURPOSE: Myeloproliferative neoplasms (MPN) are hematological disorders characterized by clonal expansion of one or more medullary lines. Renal complications are rare, chiefly as acute renal failure. Glomerular involvement is exceptional METHODS: We report on a retrospective multicenter case series of eight patients who presented with a glomerulopathy (GP) associated with MPN RESULTS: All GP were revealed by a major proteinuria frequently associated with nephrotic syndrome and oedema. Histology was mainly characterized by lesions of focal segmental glomerulosclerosis associated with increased mesangial cellularity. The pathophysiology is still unclear but platelet-derived growth factor (PDGF) and transforming growth factor-ß (TGF-ß), which play a central role in the MPN may be involved. A majority of patients developed chronic renal failure despite of a therapy intended to block the renin-angiotensin system CONCLUSION: Monitoring of proteinuria during the follow-up of MPN would allow earlier diagnosis of renal involvement. Further studies on a larger scale are needed to specify the pathophysiological mechanisms involved and the management of these complications.


Subject(s)
Kidney Diseases/etiology , Myeloproliferative Disorders/complications , Acute Kidney Injury/diagnosis , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Acute Kidney Injury/pathology , Adult , Aged , Aged, 80 and over , Biopsy , Female , Humans , Kidney Diseases/diagnosis , Kidney Diseases/epidemiology , Kidney Diseases/pathology , Kidney Glomerulus/pathology , Male , Middle Aged , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/epidemiology , Retrospective Studies
9.
Am J Transplant ; 13(8): 2179-85, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23763583

ABSTRACT

Thrombotic microangiopathy (TMA) is one of the hallmark vascular lesions of antiphospholipid syndrome nephropathy (APSN). These lesions are at high risk of recurrence after kidney transplantation. The complement pathway is thought to be active in this process. We used eculizumab to treat three consecutive kidney transplant recipients with posttransplant TMA due to APSN recurrence that was resistant to plasmapheresis and explored the complement deposition and apoptotic and vascular cell markers on the sequential transplant biopsies. Treatment with eculizumab resulted in a rapid and dramatic improvement of the graft function in all three patients and in improvement of the TMA lesions within the graft. None of these patients had TMA flares after eculizumab was withdrawn. At the time of TMA diagnosis, immunofluorescence studies revealed intense C5b-9 and C4d depositions at the endothelial cell surface of the injured vessels. Moreover, C5b-9 colocalized with vessels exhibiting a high rate of apoptotic cells. Examination of sequential biopsies during eculizumab therapy showed that TMA lesions, C4d and apoptotic markers were rapidly cleared but the C5b-9 deposits persisted for several months as a footprint of the TMA. Finally, we noticed that complement inhibition did not prevent the development of the chronic vascular changes associated with APSN. Eculizumab seems to be an efficient method for treating severe forms of posttransplant TMA due to APSN recurrence. Terminal complement inhibition does not prevent the development of chronic APSN.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antiphospholipid Syndrome/complications , Apoptosis/drug effects , Postoperative Complications , Thrombotic Microangiopathies/prevention & control , Vascular Diseases/drug therapy , Adult , Antibodies, Antiphospholipid/blood , Antiphospholipid Syndrome/therapy , Chronic Disease , Female , Fluorescent Antibody Technique , Humans , Lymphocyte Depletion , Male , Plasmapheresis , Prognosis , Recurrence , Thrombotic Microangiopathies/etiology , Thrombotic Microangiopathies/pathology , Vascular Diseases/etiology , Vascular Diseases/pathology
10.
Am J Transplant ; 12(12): 3184-90, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23057777

ABSTRACT

Adaptive responses to hypoxia, including hypoxia-inducible factor signaling, allow the cell to satisfy its basal metabolic demand and avoid death, but these responses can also be deleterious by promoting inflammation, cell dedifferentiation and fibrogenesis. Therefore, targeting hypoxia constitutes a promising therapeutic avenue. Recombinant human erythropoietin (rhEPO) appeared as a good candidate therapy because its hematopoietic properties could reverse anemia, and its tissue-protective properties could reduce cell death and limit maladaptive cellular responses to hypoxia. Despite experimental evidence on the nephroprotecive properties of rhEPO, recent clinical trials provided evidence that rhEPO was ineffective in preventing delayed graft function after ischemic acute injury but that the normalization of hemoglobin values preserved kidney function deterioration and reduced graft loss. Our aim here is to provide a survey of the rationale for evaluating the administration of rhEPO in the setting of kidney transplantation. We will discuss the intriguing findings that emerged from the clinical trials and the discrepancies between promising experimental results and negative clinical studies, as well as the differences in terms of the benefits and safety profiles of the normalization of hemoglobin values in chronic kidney disease patients and kidney transplant patients.


Subject(s)
Anemia/drug therapy , Erythropoietin/therapeutic use , Kidney Transplantation/adverse effects , Neuroprotective Agents/therapeutic use , Recombinant Proteins/therapeutic use , Animals , Humans
11.
Am J Transplant ; 11(12): 2635-46, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21883915

ABSTRACT

The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long-term lesions in renal-transplant patients who received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney-transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3-month, 24-month and 10-year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten-year biopsy results showed that 92% of patients in the CsA-treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity.


Subject(s)
Arterioles/pathology , Biomarkers/analysis , Cyclosporine/adverse effects , Immunosuppressive Agents/adverse effects , Kidney Diseases/chemically induced , Kidney Diseases/diagnosis , Kidney Transplantation , Adult , Arterioles/drug effects , Cyclosporine/administration & dosage , Female , Glomerular Filtration Rate , Graft Rejection/mortality , Humans , Immunosuppressive Agents/administration & dosage , Kidney Diseases/mortality , Kidney Function Tests , Male , Prognosis , Retrospective Studies , Survival Rate
12.
Am J Transplant ; 10(9): 2051-60, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20883539

ABSTRACT

The impact of antiphospholipid antibodies (APA) on clinical outcome and graft histology following renal transplantation remains poorly known and controversial. We retrospectively explored the functional and histological significance of APA, primarily lupus anticoagulant (LA), in kidney transplant recipients using a systematic evaluation of 3- and 12-month posttransplant screening biopsies and glomerular filtration rate measurements (mGFR). During the study period, 37 patients had APA (2.7%), primarily LA, and 12 fulfilled antiphospholipid syndrome (APS) diagnostic criteria (0.8%) at the time of transplantation. Early after transplantation, 4 of the 12 APS patients died. Early thrombosis of graft vessels and deep venous thrombosis occurred more frequently in APA+ patients than in controls (27% vs. 7%, p < 0.05 and 35% vs. 14%, p < 0.05, respectively). The survival rate was significantly lower in patients with APS. Strikingly, the hallmark lesions of APS-associated nephropathy (APSN) were found in most of screening graft biopsies in APA+ patients but not in the controls. Accordingly, APA+ patients had a dramatic increase in chronic vascular scores and a faster decline in mGFR at 1 year. In conclusion, renal transplantation may be life-threatening in APS patients, and the presence of LA at the time of transplantation is associated with a high rate of allograft APSN and poor transplantation outcomes.


Subject(s)
Kidney Transplantation/adverse effects , Kidney/blood supply , Kidney/pathology , Lupus Coagulation Inhibitor/blood , Vascular Diseases/immunology , Vascular Diseases/pathology , Adult , Antibodies, Antiphospholipid/blood , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/mortality , Biopsy , Case-Control Studies , Cohort Studies , Female , Glomerular Filtration Rate , Humans , Incidence , Kaplan-Meier Estimate , Kidney Diseases/complications , Kidney Diseases/etiology , Kidney Diseases/pathology , Kidney Diseases/surgery , Kidney Transplantation/mortality , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Thrombosis/epidemiology , Thrombosis/etiology , Transplantation, Homologous , Treatment Outcome , Venous Thrombosis/epidemiology , Venous Thrombosis/etiology
13.
Am J Transplant ; 10(3): 681-6, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20121729

ABSTRACT

Persistence of donor-specific anti-HLA antibodies (DSA) associated with antibody-mediated graft injuries following kidney transplantation predicts evolution toward chronic humoral rejection and reduced graft survival. Targeting plasma cells, the main antibody-producing cells, with the proteasome inhibitor bortezomib may be a promising desensitization strategy. We evaluated the in vivo efficacy of one cycle of bortezomib (1.3 mg/m(2)x 4 doses), used as the sole desensitization therapy, in four renal transplant recipients experiencing subacute antibody-mediated rejection with persisting DSA (>2000 [Mean Fluorescence Intensity] MFI). Bortezomib treatment did not significantly decrease DSA MFI within the 150-day posttreatment period in any patient. In addition, antivirus (HBV, VZV and HSV) antibody levels remained stable following treatment suggesting a lack of efficacy on long-lived plasma cells. In conclusion, one cycle of bortezomib alone does not decrease DSA levels in sensitized kidney transplant recipients in the time period studied. These results underscore the need to evaluate this new desensitization agent properly in prospective, randomized and well-controlled studies.


Subject(s)
Boronic Acids/therapeutic use , HLA Antigens/biosynthesis , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/methods , Pyrazines/therapeutic use , Adult , Biopsy , Bortezomib , Female , Graft Survival , HLA Antigens/chemistry , Humans , Immunohistochemistry/methods , Male , Middle Aged , Randomized Controlled Trials as Topic , Time Factors , Treatment Outcome
14.
15.
Am J Transplant ; 9(11): 2542-51, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19843032

ABSTRACT

It has been suggested that dual kidney transplantation (DKT) improves outcomes for expanded criteria donor (ECD) kidneys. However, no criteria for allocation to single or dual transplantation have been assessed prospectively. The strategy of DKT remains underused and potentially eligible kidneys are frequently discarded. We prospectively compared 81 DKT and 70 single kidney transplant (SKT) receiving grafts from ECD donors aged >65 years, allocated according to donor estimated glomerular filtration rate (eGFR): DKT if eGFR between 30 and 60 mL/min, SKT if eGFR greater than 60 mL/min. Patient and graft survival were similar in the two groups. In the DKT group, 13/81 patients lost one of their two kidneys due to hemorrhage, arterial or venous thrombosis. Mean eGFR at month 12 was similar in the DKT and SKT groups (47.8 mL/min and 46.4 mL/min, respectively). Simulated allocation of kidneys according to criteria based on day 0 donor parameters such as those described by Remuzzi et al., Andres et al. and UNOS, did not indicate an improvement in 12-month eGFR compared to our allocation based on donor eGFR.


Subject(s)
Glomerular Filtration Rate , Kidney Transplantation/mortality , Kidney Transplantation/methods , Primary Graft Dysfunction/mortality , Primary Graft Dysfunction/prevention & control , Tissue Donors , Age Factors , Aged , Biopsy , Delayed Graft Function/mortality , Delayed Graft Function/pathology , Delayed Graft Function/prevention & control , Female , Graft Rejection/mortality , Graft Rejection/pathology , Graft Rejection/prevention & control , Graft Survival , Humans , Kaplan-Meier Estimate , Kidney/pathology , Kidney/physiology , Logistic Models , Male , Middle Aged , Postoperative Complications/mortality , Primary Graft Dysfunction/pathology , Prognosis , Tissue and Organ Procurement
16.
Am J Transplant ; 9(1): 64-73, 2009 Jan.
Article in English | MEDLINE | ID: mdl-18976292

ABSTRACT

Alloreactive T-cell memory is present in every transplant recipient and endangers graft survival. Even in the absence of known sensitizing exposures, heterologous immunity and homeostatic T-cell proliferation generate 'endogenous' memory T cells with donor-reactivity. We have recently shown that endogenous donor-reactive CD8 memory T cells infiltrate murine cardiac allografts within hours of reperfusion and amplify early posttransplant inflammation by producing IFN-gamma. Here, we have tested the role of ICOS co-stimulation in eliciting effector function from these memory T cells. ICOS is not expressed on the cell surface of circulating CD8 memory T cells but is rapidly upregulated during cell division within the allograft parenchyma. Donor-reactive CD8 memory T-cell infiltration, proliferation and ICOS expression are regulated by donor class I MHC molecule expression. ICOS blockade significantly reduced IFN-gamma production and other proinflammatory functions of the activated CD8 memory T cells. Our data demonstrate that this induction of ICOS expression within peripheral tissues is an important feature of CD8 memory T-cell activation and identify ICOS as a specific target for neutralizing proinflammatory functions of endogenous CD8 memory T cells.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/metabolism , Bone Marrow Cells/immunology , CD8-Positive T-Lymphocytes/immunology , Heart Transplantation , Immunologic Memory , Tissue Donors , Animals , Antigens, Differentiation, T-Lymphocyte/genetics , Flow Cytometry , Genes, MHC Class I , Inducible T-Cell Co-Stimulator Protein , Interferon-gamma/biosynthesis , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Receptors, Antigen, T-Cell/immunology , Reverse Transcriptase Polymerase Chain Reaction , Transplantation, Homologous
17.
Nephrol Ther ; 5 Suppl 6: S365-70, 2009 Dec.
Article in French | MEDLINE | ID: mdl-20129447

ABSTRACT

Nephrotoxicity of calcineurin inhibitors (CNIs) is an acute, reversible and chronic, irreversible pathology. Histologically, acute nephrotoxicity manifests as hemodynamic modifications caused by vasoconstriction of the essentially afferent arterioles resulting in a drop in the glomerular filtration rate. Chronic nephrotoxicity is characterized by arteriolar hyalinosis resulting in a variety of tubulointerstitial and glomerular lesions with an essentially ischemic mechanism. However, these histological lesions, whether chronic or acute, are not specific of CNI toxicity and can be seen in the course of many pathological circumstances in kidney transplantation. This absence of specificity makes the histological diagnosis of CNI nephrotoxicity difficult. In addition, the individual risk of developing CNI nephrotoxicity, difficult to predict based solely on the pharmacokinetic parameters of systemic CNI exposure, also involves local exposure (CNI concentrations in the graft) modulated by several, notably pharmacogenetic factors. The difficulty of diagnosing CNI nephrotoxicity and the interindividual variability of its risk require development of new diagnostic tools so that the patients at highest risk of developing severe CNI nephrotoxicity lesions, in whom minimization protocols would produce the best risk-benefit ratio, can be identified.


Subject(s)
Calcineurin Inhibitors , Kidney Diseases/chemically induced , Kidney Diseases/diagnosis , Diagnosis, Differential , Humans , Risk Factors
18.
Am J Transplant ; 8(11): 2283-96, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18785955

ABSTRACT

The molecular mechanisms by which cyclosporine induces chronic nephrotoxicity remain poorly understood. A previous transcriptomic study suggested that cyclosporine might induce endoplasmic reticulum (ER) stress in human tubular cells. The aim of the present study was to characterize the features of tubular ER stress induced by cyclosporine and to investigate its effects on cell differentiation and viability. Using primary cultures of human tubular cells, we confirmed that cyclosporine is responsible for ER stress in vitro. This was also confirmed in vivo in the rat. In vitro, cyclosporine and other ER stress inducers were responsible for epithelial phenotypic changes leading to the generation of protomyofibroblasts, independent of transforming growth factor-beta signaling. RNA interference directed against cyclophilin A supported the role of its inhibition in triggering ER stress as well as epithelial phenotypic changes induced by cyclosporine. Salubrinal, which is known to protect cells from ER stress, significantly reduced epithelial phenotypic changes and cytotoxicity induced by cyclosporine in vitro. Salubrinal also reduced cyclosporine nephrotoxicity in rat kidneys. Thus, we describe a novel mechanism that initiates dedifferentiation and tubular cell death upon cyclosporine treatment. These results provide an interesting framework for further nephroprotective therapies by targeting ER stress.


Subject(s)
Cyclosporine/pharmacology , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/pathology , Immunosuppressive Agents/pharmacology , Kidney/drug effects , Animals , Cell Differentiation , Cell Survival , Cinnamates/pharmacology , Cyclophilin A/metabolism , Endoplasmic Reticulum/metabolism , Humans , Male , Phenotype , Rats , Rats, Sprague-Dawley , Thiourea/analogs & derivatives , Thiourea/pharmacology , Transforming Growth Factor beta/metabolism
19.
Am J Transplant ; 8(8): 1652-61, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18557725

ABSTRACT

Normal immune responses stimulated by pathogenic and environmental antigens generate memory T cells that react with donor antigens and no currently used immunosuppressive drug completely inhibits memory T-cell function. While donor-reactive memory T cells clearly compromise graft outcomes, mechanisms utilized by memory T cells to promote rejection are largely unknown. In this study, we investigated how early endogenous memory cells infiltrate and express effector function in cardiac allografts. Endogenous CD8 memory T cells in nonsensitized recipients distinguish syngeneic versus allogeneic cardiac allografts within 24 h of reperfusion. CD8-dependent production of IFN-gamma and CXCL9/Mig was observed 24 to 72 h posttransplant in allografts but not isografts. CXCL9 was produced by donor cells in response to IFN-gamma made by recipient CD8 T cells reactive to donor class I major histocompatibility complex (MHC) molecules. Activated CD8 T cells were detected in allografts at least 3 days before donor-specific effector T cells producing IFN-gamma were detected in the recipient spleen. Early inflammation mediated by donor-reactive CD8 memory T cells greatly enhanced primed effector T-cell infiltration into allografts. These results suggest that strategies for optimal inhibition of alloimmunity should include neutralization of infiltrating CD8 memory T cells within a very narrow window after transplantation.


Subject(s)
CD8-Positive T-Lymphocytes/physiology , Chemokine CXCL9/metabolism , Heart Transplantation/immunology , Histocompatibility Antigens Class I/immunology , Interferon-gamma/metabolism , Animals , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Time Factors , Transplantation, Homologous , Transplantation, Isogeneic
20.
Am J Transplant ; 8(3): 497-506, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18294146

ABSTRACT

Donor-reactive memory T cells undermine the survival of transplanted organs through multiple pathways. We have previously reported that memory CD4 T cells resist treatment with anti-CD154 antibody and donor-specific transfusion (DST/MR1) and promote cardiac allograft rejection via generation of effector CD4 T cells and alloantibody. We hypothesized that the helper functions of memory CD4 T cells are independent of T-cell costimulation through CD154 but instead are regulated by alternative costimulatory pathways. This study investigated how blocking ICOS/B7RP-1 interactions affects functions of donor-reactive memory CD4 T cells. Treatment with blocking anti-ICOS mAb synergized with DST/MR1 and prolonged mouse cardiac allograft survival despite the presence of donor-reactive memory CD4 T cells. While blocking ICOS did not diminish the expansion of preexisting memory CD4 T cells or the induction of allospecific effector T cells, it did inhibit recruitment of the activated memory and effector T cells into the graft. In addition, anti-ICOS mAb treatment in combination with DST/MR1 prevented help provided by memory CD4 T cells for production of donor-specific IgG antibody. These results demonstrate the potential efficacy of ICOS blockade in sensitized transplant patients and provide the foundation for rational use of ICOS blockade in combination with other graft-prolonging strategies.


Subject(s)
Antigens, Differentiation, T-Lymphocyte/drug effects , Antigens, Differentiation, T-Lymphocyte/metabolism , CD4-Positive T-Lymphocytes/immunology , Graft Rejection/immunology , Graft Rejection/prevention & control , Heart Transplantation , Animals , Antibodies, Monoclonal/pharmacology , B7-1 Antigen/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , Carrier Proteins/drug effects , Cytoskeletal Proteins/drug effects , Dystonin , Female , Graft Rejection/pathology , Graft Survival/drug effects , Histocompatibility Antigens Class I/drug effects , Immunoglobulin Switch Region/drug effects , Immunologic Memory/drug effects , Inducible T-Cell Co-Stimulator Ligand , Inducible T-Cell Co-Stimulator Protein , Male , Mice , Mice, Inbred Strains , Minor Histocompatibility Antigens , Nerve Tissue Proteins/drug effects
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