Targeting CD40L: a Promising Therapeutic Approach

Daoussis, Dimitris; Andonopoulos, Andrew P.; Liossis, Stamatis–Nick C.

doi:10.1128/cdli.11.4.635-641.2004

Cited by 63 publications

(43 citation statements)

References 71 publications

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“…Lymphocyte activation results in the enhanced expression of several molecules that mediate interactions between T cells and other cell types (Daoussis et al, 2004). Indeed, CD154 is a key determinant of T cell-mediated injury through its cognate receptor CD40 (Toubi and Shoenfeld, 2004).…”

Section: Resultsmentioning

confidence: 99%

CD8+ Lymphocyte-Mediated Injury of Dorsal Root Ganglion Neurons during Lentivirus Infection: CD154-Dependent Cell Contact Neurotoxicity

Zhu¹,

Antony²,

Liu³

et al. 2006

J. Neurosci.

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Section: Resultsmentioning

confidence: 99%

CD8+ Lymphocyte-Mediated Injury of Dorsal Root Ganglion Neurons during Lentivirus Infection: CD154-Dependent Cell Contact Neurotoxicity

Zhu¹,

Antony²,

Liu³

et al. 2006

J. Neurosci.

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“…CD154 or CD40 ligand is a surface molecule expressed on activated CD4 + T cells mediating costimulation via antigen-presenting cells (B cells, dendritic cells, and macrophages) (35,36). Activated T cells expressing CD154 have been shown to produce IFN-g and IL-2 (37).…”

Section: Discussionmentioning

confidence: 99%

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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“…Therefore, the time course and underlying mechanisms of T-cell activation appears to differ between amoxicillin in the MDAM and DNFB in the LLNA. The potential differences in mechanism are further supported by the results from direct blocking of CD40L, a co-stimulatory molecule tightly regulated and induced by TCR ligation (Daoussis et al, 2004). Whereas MDAM responses were inhibited by anti-CD40L treatment, DNFB LLNA responses were not affected.…”

Section: Discussionmentioning

confidence: 48%

“…Once a lymphocyte recognizes an antigen, the activation process starts. Expression of co-stimulatory molecules on antigen-presenting cells and lymphocytes plays a critical role in driving lymphocytes towards full activation and the induction of an immune response (Daoussis et al, 2004;Elgueta et al, 2009). During an immune response, lymph node (LN) cell numbers markedly increase after antigen recognition (Mackay et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the draining lymph node response in the mouse drug allergy model: A model for drug hypersensitivity reactions

Zhu

Cole

Kawabata

et al. 2014

Journal of Immunotoxicology

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The mouse drug allergy model (MDAM) was developed as a tool to predict the potential of systemically administered drugs to produce hypersensitivity reactions (HR). Drugs associated with HR in the clinic produce a marked increase in the cellularity of the draining lymph nodes (DLN) in the MDAM. The objective of this study was to characterize the changes in the DLN following exposure to drugs associated with HR and to investigate whether lymphocyte migration and/or proliferation play a role in the response. These endpoints were also investigated in the local lymph node assay (LLNA) to determine whether responses between the two assays occur via similar mechanisms. Results demonstrated that total numbers of Tand B-cells were proportionally increased in the DLN of mice treated with positive control drugs (i.e. abacavir, amoxicillin, ofloxacin, and sulfamethoxazole) compared to animals administered the vehicle or negative control drugs (metformin and cimetidine). In contrast, a significant increase in the B-cell population of the DLN was observed for 2,4-dinitrofluorobenzene (DNFB) following the LLNA protocol. Down-regulation of CD62L and up-regulation of CCR7 were observed for T-cells from the DLN of the positive control treated mice in the MDAM, but not with DNFB in the LLNA. A mild increase in T-cell proliferation was observed in the MDAM with positive control drugs, while DNFB in the LLNA induced proliferation within the B-cell population only. Anti-CD40L antibody administration inhibited MDAM responses to positive control drugs, but did not affect DNFB-induced increases in total cell number in the LLNA. These results suggest that the increased cellularity of the DLN in the MDAM may be the result of drug-induced alterations in lymphocyte migration and/or effects on lymphocyte proliferation. Moreover, it appears that different mechanisms may be involved in driving the MDAM and LLNA responses.

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Targeting CD40L: a Promising Therapeutic Approach

Cited by 63 publications

References 71 publications

CD8+ Lymphocyte-Mediated Injury of Dorsal Root Ganglion Neurons during Lentivirus Infection: CD154-Dependent Cell Contact Neurotoxicity

CD8+ Lymphocyte-Mediated Injury of Dorsal Root Ganglion Neurons during Lentivirus Infection: CD154-Dependent Cell Contact Neurotoxicity

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

Characterization of the draining lymph node response in the mouse drug allergy model: A model for drug hypersensitivity reactions

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