T-lymphocyte populations and cytokines in childhood nephrotic syndrome

Lama, Giuliana; Luongo, Ilaria; Tirino, Giuseppina; Borriello, Adriana; Carangio, Ciro; Salsano, Maria Esposito

doi:10.1053/ajkd.2002.32769

Cited by 118 publications

(109 citation statements)

References 23 publications

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“…This was in contrast to the published study by Gulati et al (4), in which patients with late steroid + expression in FSGS rituximab responders compared with those in both nonresponders and controls, and it was associated with significantly reduced mitogen-stimulated CD3 production of IFN-g and IL-2. The baseline immunologic signature in our FSGS rituximab responders was also significantly different from that in patients with MCNS in relapse as shown in Table 3, indicating that the immunologic basis underlying the nephrotic syndrome is likely to be distinct in this group of FSGS rituximab responders compared with those in patients with MCNS, in whom increased mitogen-stimulated lymphocyte production of IL-2 and IFN-g has been shown (27)(28)(29)(30)(31).…”

Section: Discussionmentioning

confidence: 79%

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Chan

Liu

Resontoc

et al. 2016

CJASN

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Background and objectives Rituximab is used with variable success in difficult FSGS. Because B cell depletion significantly affects T cell function, we characterized T cell subsets in patients with FSGS to determine if an immunologic signature predictive of favorable response to rituximab could be identified.Design, setting, participants, & measurements Twenty-two consecutive patients with FSGS (median age =14.4 years old; range =6.2-25.0 years old) and age of onset of nephrotic syndrome 1-18 years old receiving rituximab for clinical indications between October of 2009 and February of 2014 were studied. Indications for rituximab were lack of sustained remission despite calcineurin inhibitors (CNIs) and mycophenolate in steroid-resistant patients and lack of steroid-sparing effect with cyclophosphamide and CNI or CNI toxicity in steroid-dependent patients. Exclusion criteria were infantile onset, known genetic mutations, and secondary causes. Rituximab (375 mg/m 2 ) was given fortnightly up to a maximum of four doses. Immunologic subset monitoring was performed at baseline and regular intervals until relapse. Median follow-up duration postrituximab was 26.7 months (range =6.5-66.5 months). Baseline immunologic subsets were examined for association with rituximab response defined as resolution of proteinuria with discontinuation of prednisolone and CNI 3 months postrituximab.Results Twelve patients (54.5%) responded to rituximab. Mitogen-stimulated CD154 + CD4 + CD3 + subset before rituximab was significantly lower in FSGS responders compared with nonresponders (54.9%628.1% versus 78.9%616.4%; P=0.03). IFN-g + CD3 + and IL-2 + CD3 + were similarly decreased in responders compared with nonresponders (0.6%60.8% versus 7.5%66.1%; P=0.003 and 0.2%60.5% versus 4.0%64.7%; P,0.01, respectively). Recovery of all three activation subsets occurred 6 months postrituximab treatment (CD154 + CD4 + CD3 + , 74.8%617.2%; IFN-g + CD3 + , 7.1%67.7%; and IL-2 + CD3 + , 7.9%610.9%; P,0.01). Receiver-operating characteristic analysis using optimal cutoff values showed that activated CD154 + CD4 + CD3 + ,83.3% (area under the curve [AUC], 0.81; 95% confidence interval [95% CI], 0.61 to 1.00), IFN-g + CD3 + ,2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2 + CD3 + ,0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response.Conclusions We have identified prognostic markers that define a subset of patients with FSGS bearing an immunologic signature representing hyporesponsiveness to T cell stimulation and therefore, who respond better to rituximab.

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Section: Discussionmentioning

confidence: 79%

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

Chan

Liu

Resontoc

et al. 2016

CJASN

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“…ϩ and CD8 ϩ T cell populations 30,31 and an increased synthesis of several cytokines, such as TNF-␣, 31,32 soluble IL-2 receptor, 32 and IL-13. 33 In our model, we showed that peripheral CD3 ϩ cells of patients were not capable of inducing albuminuria in mice, even in cases in which CD3 ϩ cells could proliferate in mice, after depletion of Treg and injection in more immunocompromised mice.…”

Section: Studies Of T Cell Compartments In Mcns Demonstrated Expansiomentioning

confidence: 99%

A Humanized Mouse Model of Idiopathic Nephrotic Syndrome Suggests a Pathogenic Role for Immature Cells

Sellier‐Leclerc

Duval²,

Riveron

et al. 2007

Journal of the American Society of Nephrology

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Idiopathic nephrotic syndrome is characterized by glomerular proteinuria in the absence of infiltrating cells or immunoglobulin deposits. Although it is suspected that T cells secrete a circulating factor that leads to proteinuria by altering the permeability of the glomerular filtration barrier, the precise etiology of this syndrome is unknown. Because an animal model that mimics human idiopathic nephrotic syndrome does not exist, we developed a humanized mouse model of the disease by injecting CD34 ϩ stem cells or CD34 Ϫ peripheral blood mononuclear cells from afflicted patients into immunocompromised mice. Even though both CD34 ϩ and CD34 Ϫ cells induced the engraftment of human CD45 ϩ leukocytes in mice, only the injection of CD34 ϩ stem cells induced albuminuria. Ultrastructural analysis of glomeruli from the resulting proteinuric mice revealed effacement of podocyte foot processes, similar to the pathology observed in the human disease. Therefore, our data suggest that the cells responsible for the pathogenesis of idiopathic nephrotic syndrome are more likely to be immature differentiating cells rather than mature peripheral T cells.

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“…and CD8? memory T cells that express the CD45RO marker during NS relapse [10][11][12][13]. B cell expansion was also recently reported during NS relapses [18].…”

Section: Discussionmentioning

confidence: 90%

“…Activated T cell activation might be associated with the relapse of NS [10][11][12][13]. A number of studies have revealed an imbalance in the distribution of CD4?…”

Section: Discussionmentioning

confidence: 99%

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A distinct lymphocyte distribution in relapse after rituximab for steroid-dependent nephrotic syndrome

et al. 2012

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Rituximab (RTX) is a new steroid-sparing therapy for childhood steroid-dependent nephrotic syndrome (NS). However, relapses frequently occur immediately after CD19 recovery. We report the cases of two steroid-dependent NS patients treated with RTX followed by mizoribine (MZB). One patient relapsed, and the other developed proteinuria after CD19 recovery until the MZB was replaced by mycophenolate mofetil. These patients exhibited different lymphocyte phenotypes, with the CD4?/CD8? profile favoring CD8? T lymphocytes, while CD3? HLA-DR-expressing activated T lymphocyte expansion occurred in the relapsed patient. Based on these findings, we suggest that T cell activation may influence outcome and that phenotypic analysis in addition to B cell monitoring may facilitate the detection of NS relapse.

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T-lymphocyte populations and cytokines in childhood nephrotic syndrome

Cited by 118 publications

References 23 publications

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

A Humanized Mouse Model of Idiopathic Nephrotic Syndrome Suggests a Pathogenic Role for Immature Cells

A distinct lymphocyte distribution in relapse after rituximab for steroid-dependent nephrotic syndrome

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