Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration

Abstract

Patients with paraneoplastic cerebellar degeneration (PCD) offer the opportunity to explore the mechanisms underlying tumor immunity and immune-mediated neuronal degeneration. Cytotoxic T lymphocytes (CTLs) specific for the PCD onconeural antigen cdr2 found in the blood of patients with PCD are likely to be effectors of PCD tumor immunity. Here, we suggest a role for CTLs in the autoimmune destruction of Purkinje neurons. More than 75% of the cells obtained from the cerebrospinal fluid (CSF) of PCD patients were CD3+ alphabeta T cells. In patients with active/progressive disease, 20% to 40% of CSF cells were activated T cells, and the CD4+ helper cells were Th1-type cells. Three PCD patients were given tacrolimus, a specific inhibitor of activated T cells, which markedly reduced these cells in the CSF. Tacrolimus also reduced the number of activated cdr2-specific CTLs in the peripheral blood, but did not lead to tumor recurrence. We suggest that activated cdr2-specific CTLs in the CSF contribute to Purkinje degeneration in PCD, and that tacrolimus therapy may benefit patients with paraneoplastic neurological disease and other T cell-mediated autoimmune neurological disorders.

Onconeuronal cerebellar degeneration-related antigen, Cdr2, is strongly expressed in papillary renal cell carcinoma and leads to attenuated hypoxic response

“…clinical and pathological signs of suppression of tumor growth compared with other breast and ovarian cancer patients (Peterson et al, 1992;Albert et al, 2000). Furthermore, Santomasso et al (2007) recently cloned the T-cell receptor genes from Cdr2-specific T lymphocytes.…”

Managing Paraneoplastic Neurological Disorders

“…Most paraneoplastic antigens are located in the cytoplasm (e.g., the Yo antigen) or nucleus (e.g., the Hu and Ri antigens), and a pathogenic role for the respective antibodies has not be demonstrated [12]. In these disorders, indirect lines of evidence support the view that the cellular immune response against these antigens is responsible for the neurological damage [13][14][15]. The relative contribution of the cellular and humoral immunity to the clinical and pathological manifestations has not been resolved [13][14][15].…”

“…In these disorders, indirect lines of evidence support the view that the cellular immune response against these antigens is responsible for the neurological damage [13][14][15]. The relative contribution of the cellular and humoral immunity to the clinical and pathological manifestations has not been resolved [13][14][15]. The paraneoplastic antibodies may, in these cases, be surrogate markers for T-lymphocyte activation [16].…”

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

“…However, antibodies are unlikely to be the sole cause of the neuronal destruction for those PNDs in which the target antigens are intracellular 2, 3. Moreover, PND antigen‐specific CD8 + T cells are present in the peripheral blood and CSF of patients with both paraneoplastic cerebellar degeneration (PCD) and the paraneoplastic Hu syndrome subtypes of PND 4, 5, 6…”

“…FK506 reduces the number of activated T cells in the CSF of patients with PCD 4. Not all PND patients demonstrate dramatic clinical improvements with this treatment,7 perhaps in part because most patients are diagnosed and referred after the onset of the neuronal destruction that is characteristic of PND 1.…”