CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

Gerdes, Lisa Ann; Held, Kathrin; Beltrán, Eduardo; Berking, Carola; Prinz, Jörg C.; Junker, Andreas; Tietze, Julia K.; Ertl‐Wagner, Birgit; Straube, Andreas; Kümpfel, Tania; Dornmair, Klaus; Hohlfeld, Reinhard

doi:10.1002/ana.24715

Cited by 107 publications

(87 citation statements)

References 28 publications

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“…T‐cell receptor gene sequencing of a patient presenting with increased T2/fluid‐attenuated inversion recovery (FLAIR) hyperintensities and gadolinium enhancing lesions on magnetic resonance imaging after receiving CTLA‐4 inhibitor revealed 2 distinct oligoclonal CD4 and CD8 T‐cell populations in patient CSF and melanoma. These findings support the hypothesis that in irAE‐N not resembling classic paraneoplastic phenotype, the antitumor response and antineural autoimmune response may be directed against different antigens . Some of these patients may have pre‐existing predisposition to neurological autoimmunity, which is precipitated by the ICI therapy …”

Section: Atypical Overlapping Spectrum Of Irae‐nsupporting

confidence: 80%

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

Dubey

David

Reynolds

et al. 2020

Annals of Neurology

174

189

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Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined.

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Section: Atypical Overlapping Spectrum Of Irae‐nsupporting

confidence: 80%

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

Dubey

David

Reynolds

et al. 2020

Annals of Neurology

174

189

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“…More recently, 0.1% of patients administered nivolumab were reported to develop MG. Furthermore, multiple sclerosis after CTLA‐4 blockade by ipilimumab has been reported in one case where the clonally expanded T cell receptor sequences shared between the CSF and melanoma suggest preformed T cell memory led to the CNS disease 16. Similar close clonal relationships of T cells are recognized between tumor and cardiac tissue in post‐checkpoint inhibitor myocarditis,12 supporting the notion that many irAEs are T cell‐mediated.…”

Section: Discussionmentioning

confidence: 81%

Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

Wilson

Menassa

Davies

et al. 2018

Ann Clin Transl Neurol

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Checkpoint inhibitor medications have revolutionized oncology practice, but frequently induce immune‐related adverse events. During autoimmune neurology practice over 20 months, we prospectively identified four patients with likely antibody‐mediated neurological diseases after checkpoint inhibitors: longitudinally extensive transverse myelitis, Guillain–Barré syndrome, and myasthenia gravis. All patients shared three characteristics: symptoms commenced 4 weeks after drug administration, responses to conventional immunotherapies were excellent, and autoantibodies traditionally associated with their syndrome were absent. However, serum immunoglobulins from the myelitis and Guillain–Barré syndrome patients showed novel patterns of tissue reactivity. Vigilance is required for antibody‐mediated neurology after checkpoint inhibitor administration. This phenomenon may inform the immunobiology of antibody‐mediated diseases.

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“…CTLA‐4, PD‐1, Tim‐3 and LAG‐3 are the most studied and emphasized immune regulatory receptors in this context which have been addressed in various occasions of autoimmunity. Treatment of metastatic melanoma patients with CTLA‐4 blockade antibody, ipilimumab, is associated with the induction of multiple sclerosis . Protective roles of PD‐1 have been documented in mouse models of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Expression analysis of PD‐1 and Tim‐3 immune checkpoint receptors in patients with vitiligo; positive association with disease activity

Rahimi

Hossein-Nataj

Hajheydari

et al. 2019

Experimental Dermatology

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The contribution of immune checkpoint receptors in the immunopathogenesis of various autoimmune diseases has been addressed in previous reports. In this study, the expression profile of T‐cell immunoglobulin and mucin‐domain containing‐3 (Tim‐3) and programmed cell death‐1 (PD‐1) checkpoint molecules was investigated in CD8+ T cells of Vitiligo patients. The association of Tim‐3 and PD‐1 expression with disease activity was also explored. The frequency of Tim‐3+/PD‐1+/CD8+ T cells in 30 patients with vitiligo and 30 sex‐ and age‐matched controls was determined by flow cytometry. CD8+ T cells were then positively isolated by magnetic beads, and the mRNA expression of PD‐1 and Tim‐3 was determined by TaqMan‐based real‐time PCR. To measure the cytokines production, PBMCs were stimulated with PMA/ionomycin and concentrations of IL‐4, IFN‐γ and TNF‐α were measured in culture supernatants by ELISA. Disease activity of patients with vitiligo was determined using the Vitiligo Area Severity Index. Patients with vitiligo have significantly shown more expression of Tim‐3 and PD‐1 on their CD8+ T cells compared with controls. Expression analysis of Tim‐3 mRNA, but not PD‐1, confirmed the results obtained from flow cytometry. While the production levels of TNF‐α and IFN‐γ were found higher by patients with vitiligo, IL‐4 production was lower in patients compared with controls. A direct association was observed between the Tim‐3 and PD‐1 expression and also the production of pro‐inflammatory cytokines with disease activity of patients with vitiligo. Our results indicate that Tim‐3 and PD‐1 are involved in immune dysregulation mechanisms of CD8+ T cells in vitiligo and may introduce as potential biomarkers for disease progression and targeted immunotherapy.

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CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis

Cited by 107 publications

References 28 publications

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum

Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

Expression analysis of PD‐1 and Tim‐3 immune checkpoint receptors in patients with vitiligo; positive association with disease activity

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