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CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model.

ABSTRACT: Paraneoplastic neurological disorders (PNDs) are rare human autoimmune diseases that mostly affect the central nervous system (CNS). They are triggered by an efficient immune response against a neural self-antigen that is ectopically expressed in neoplastic tumors. Due to this shared antigenic expression, the immune system reacts not only to tumor cells but also to neural cells resulting in neurological damage. Growing data point to a major role of cell-mediated immunity in PNDs associated to autoantibodies against intracellular proteins. However, its precise contribution in the pathogenesis remains unclear. In this context, our study aimed at investigating the impact of anti-tumor cellular immune responses in the development of PND. To this end, we developed an animal model mimicking PND. We used a tumor cell line expressing the hemagglutinin (HA) of influenza virus to induce an anti-tumor response in CamK-HA mice, which express HA in CNS neurons. To promote and track the T cell response against the HA antigen, naïve HA-specific CD8+ and/or CD4+ T cells, originating from TCR-transgenic animals, were transferred into these mice. We demonstrate that HA-expressing tumors, but not control tumors, induce in vivo activation, proliferation and differentiation of naïve HA-specific CD4+ and CD8+ T cells into effector cells. Moreover, both T cell subsets were needed to control tumor growth and induce CNS inflammation in CamK-HA mice. Thus, this new mouse model provides further insight into the cellular mechanisms whereby a potent anti-tumor immunity triggers a cancer-associated autoimmune disease, and may therefore help to develop new therapeutic strategies against PND.

SUBMITTER: Gebauer C

PROVIDER: S-EPMC5353919 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model.

Gebauer Christina C Pignolet Béatrice B Yshii Lidia L Mauré Emilie E Bauer Jan J Liblau Roland R

Oncoimmunology 20161209 2

Paraneoplastic neurological disorders (PNDs) are rare human autoimmune diseases that mostly affect the central nervous system (CNS). They are triggered by an efficient immune response against a neural self-antigen that is ectopically expressed in neoplastic tumors. Due to this shared antigenic expression, the immune system reacts not only to tumor cells but also to neural cells resulting in neurological damage. Growing data point to a major role of cell-mediated immunity in PNDs associated to au ...[more]

PMID: 28344867

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Project description:ImportanceLittle is known of glutamic acid decarboxylase antibodies (GAD-abs) in the paraneoplastic context. Clinical recognition of such cases will lead to prompt tumor diagnosis and appropriate treatment.ObjectiveTo report the clinical and immunological features of patients with paraneoplastic neurological syndromes (PNS) and GAD-abs.Design, setting, and participantsRetrospective case series study and immunological investigations conducted in February 2014 in a center for autoimmune neurological disorders. Fifteen cases with GAD65-abs evaluated between 1995 and 2013 who fulfilled criteria of definite or possible PNS without concomitant onconeural antibodies were included in this study.Main outcomes and measuresAnalysis of the clinical records of 15 patients and review of 19 previously reported cases. Indirect immunofluorescence with rat hippocampal neuronal cultures and cell-based assays with known neuronal cell-surface antigens were used. One hundred six patients with GAD65-abs and no cancer served as control individuals.ResultsEight of the 15 patients with cancer presented as classic paraneoplastic syndromes (5 limbic encephalitis, 1 paraneoplastic encephalomyelitis, 1 paraneoplastic cerebellar degeneration, and 1 opsoclonus-myoclonus syndrome). When compared with the 106 non-PNS cases, those with PNS were older (median age, 60 years vs 48 years; P = .03), more frequently male (60% vs 13%; P < .001), and had more often coexisting neuronal cell-surface antibodies, mainly against γ-aminobutyric acid receptors (53% vs 11%; P < .001). The tumors more frequently involved were lung (n = 6) and thymic neoplasms (n = 4). The risk for an underlying tumor was higher if the presentation was a classic PNS, if it was different from stiff-person syndrome or cerebellar ataxia (odds ratio, 10.5; 95% CI, 3.2-34.5), or if the patient had coexisting neuronal cell-surface antibodies (odds ratio, 6.8; 95% CI, 1.1-40.5). Compared with the current series, the 19 previously reported cases had more frequent stiff-person syndrome (74% vs 13%; P = .001) and better responses to treatment (79% vs 27%; P = .005). Predictors of improvement in the 34 patients (current and previously reported) included presentation with stiff-person syndrome and the presence of a thymic tumor.Conclusions and relevancePatients with GAD-abs must be screened for an underlying cancer if they have clinical presentations different from those typically associated with this autoimmunity or develop classic PNS. The risk for cancer increases with age, male sex, and the presence of coexisting neuronal cell-surface antibodies.

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CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model.

Publications

CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model.

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