| First Author | Yshii L | Year | 2019 |
| Journal | JCI Insight | Volume | 4 |
| Issue | 7 | PubMed ID | 30944244 |
| Mgi Jnum | J:295261 | Mgi Id | MGI:6453716 |
| Doi | 10.1172/jci.insight.127001 | Citation | Yshii L, et al. (2019) IFN-gamma is a therapeutic target in paraneoplastic cerebellar degeneration. JCI Insight 4(7) |
| abstractText | Paraneoplastic neurological disorders result from an autoimmune response against neural self-antigens that are ectopically expressed in neoplastic cells. In paraneoplastic disorders associated to autoantibodies against intracellular proteins, such as paraneoplastic cerebellar degeneration (PCD), current data point to a major role of cell-mediated immunity. In an animal model, in which a neo-self-antigen was expressed in both Purkinje neurons and implanted breast tumor cells, immune checkpoint blockade led to complete tumor control at the expense of cerebellum infiltration by T cells and Purkinje neuron loss, thereby mimicking PCD. Here, we identify 2 potential therapeutic targets expressed by cerebellum-infiltrating T cells in this model, namely alpha4 integrin and IFN-gamma. Mice with PCD were treated with anti-alpha4 integrin antibodies or neutralizing anti-IFN-gamma antibodies at the onset of neurological signs. Although blocking alpha4 integrin had little or no impact on disease development, treatment using the anti-IFN-gamma antibody led to almost complete protection from PCD. These findings strongly suggest that the production of IFN-gamma by cerebellum-invading T cells plays a major role in Purkinje neuron death. Our successful preclinical use of neutralizing anti-IFN-gamma antibody for the treatment of PCD offers a potentially new therapeutic opportunity for cancer patients at the onset of paraneoplastic neurological disorders. |
