Increased T Cell Recruitment to the CNS after Amyloid β1–42Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-β1

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Abstract
Immunotherapy targeting the amyloid β (Aβ) peptide is a novel therapy under investigation for the treatment of Alzheimer's disease (AD). A clinical trial using Aβ1–42(AN1792) as the immunogen was halted as a result of development of meningoencephalitis in a small number of patients. The cytokine TGF-β1 is a key modulator of immune responses that is increased in the brain in AD. We show here that local overexpression of TGF-β1 in the brain increases both meningeal and parenchymal T lymphocyte number. Furthermore, TGF-β1 overexpression in a mouse model for AD [amyloid precursor protein (APP) mice] leads to development of additional T cell infiltrates when mice were immunized at a young but not old age with AN1792. Notably, only mice overproducing both Aβ (APP mice) and TGF-β1 experienced a rise in T lymphocyte number after immunization. One-third of infiltrating T cells were CD4 positive. We did not observe significant differences in B lymphocyte numbers in any of the genotypes or treatment groups. These results demonstrate that TGF-β1 overproduction in the brain can promote T cell infiltration, in particular after Aβ1–42immunization. Likewise, levels of TGF-β1 or other immune factors in brains of AD patients may influence the response to Aβ1–42immunization.