RESUMO
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.
RESUMO
CTLA4 is an inhibitory regulator of immune responses. Therapeutic CTLA4 blockade enhances T cell responses against cancer and provides striking clinical results against advanced melanoma. However, this therapy is associated with immune-related adverse events. Paraneoplastic neurologic disorders are immune-mediated neurological diseases that develop in the setting of malignancy. The target onconeural antigens are expressed physiologically by neurons, and aberrantly by certain tumour cells. These tumour-associated antigens can be presented to T cells, generating an antigen-specific immune response that leads to autoimmunity within the nervous system. To investigate the risk to develop paraneoplastic neurologic disorder after CTLA4 blockade, we generated a mouse model of paraneoplastic neurologic disorder that expresses a neo -self antigen both in Purkinje neurons and in implanted breast tumour cells. Immune checkpoint therapy with anti-CTLA4 monoclonal antibody in this mouse model elicited antigen-specific T cell migration into the cerebellum, and significant neuroinflammation and paraneoplastic neurologic disorder developed only after anti-CTLA4 monoclonal antibody treatment. Moreover, our data strongly suggest that CD8 + T cells play a final effector role by killing the Purkinje neurons. Taken together, we recommend heightened caution when using CTLA4 blockade in patients with gynaecological cancers, or malignancies of neuroectodermal origin, such as small cell lung cancer, as such treatment may promote paraneoplastic neurologic disorders.
Assuntos
Anticorpos/toxicidade , Antígeno CTLA-4/metabolismo , Síndromes Paraneoplásicas do Sistema Nervoso/etiologia , Síndromes Paraneoplásicas do Sistema Nervoso/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Linhagem Celular Tumoral , Cerebelo/patologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Atividade Motora/fisiologia , Transtornos dos Movimentos/etiologia , Neuropeptídeos/metabolismo , Síndromes Paraneoplásicas do Sistema Nervoso/complicações , Síndromes Paraneoplásicas do Sistema Nervoso/patologia , Células de Purkinje/efeitos dos fármacos , Células de Purkinje/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismoRESUMO
Although CD8 T cells are key players in neuroinflammation, little is known about their trafficking cues into the central nervous system (CNS). We used a murine model of CNS autoimmunity to define the molecules involved in cytotoxic CD8 T-cell migration into the CNS. Using a panel of mAbs, we here show that the α4ß1-integrin is essential for CD8 T-cell interaction with CNS endothelium. We also investigated which α4ß1-integrin ligands expressed by endothelial cells are implicated. The blockade of VCAM-1 did not protect against autoimmune encephalomyelitis, and only partly decreased the CD8(+) T-cell infiltration into the CNS. In addition, inhibition of junctional adhesion molecule-B expressed by CNS endothelial cells also decreases CD8 T-cell infiltration. CD8 T cells may use additional and possibly unidentified adhesion molecules to gain access to the CNS.
Assuntos
Encéfalo/imunologia , Linfócitos T CD8-Positivos/fisiologia , Movimento Celular , Encefalomielite/etiologia , Integrina alfa4beta1/fisiologia , Animais , Encéfalo/citologia , Linfócitos T CD8-Positivos/citologia , Moléculas de Adesão Celular/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microglia/fisiologia , Molécula 1 de Adesão de Célula Vascular/fisiologiaRESUMO
Central nervous system (CNS) inflammation occurs in a large number of neurological diseases. The type and magnitude of CNS inflammation, as well as the T-cell contribution, vary depending on the disease. Different animal models of neurological diseases have shown that T cells play an important role in CNS inflammation. Furthermore, recent studies of human neurological disorders have indicated a significant role for T cells in disease pathology. Nevertheless, how individual T-cell subsets affect neuronal survival, damage and/or loss remains largely unclear. In this review we discuss the processes by which T cells mediate either beneficial or deleterious effects within the CNS, with emphasis on the direct interaction between T cells and neurons, as occurs in multiple sclerosis, paraneoplastic cerebellar degeneration, and viral encephalitis. The therapeutic approaches targeting T cells and their mediators as treatment for neurological diseases are also described here.
Assuntos
Encefalite Viral/imunologia , Esclerose Múltipla/imunologia , Degeneração Paraneoplásica Cerebelar/imunologia , Linfócitos T/imunologia , Animais , Sobrevivência Celular/imunologia , Modelos Animais de Doenças , Encefalite Viral/patologia , Humanos , Esclerose Múltipla/patologia , Neurônios , Degeneração Paraneoplásica Cerebelar/patologia , Linfócitos T/patologiaRESUMO
Paraneoplastic neurological disorders (PNDs) are syndromes that develop in cancer patients when an efficient antitumor immune response, directed against antigens expressed by both malignant cells and healthy neurons, damages the nervous system. Herein, we analyze existing data on the mechanisms of loss of self tolerance and nervous tissue damage that underpin one of the most frequent PNDs, the anti-Hu syndrome. In addition, we discuss future directions and propose potential strategies aimed at blocking deleterious encephalitogenic immune responses while preserving the antineoplastic potential of treatment.