Increased T cell recruitment to the CNS after amyloid β1-42 immunization in Alzheimer's mice overproducing transforming growth factor-β1

Immunotherapy targeting the amyloid beta(A beta) peptide is a novel therapy under investigation for the treatment of Alzheimer's disease (AD). A clinical trial using A beta(1-42) (AN1792) as the immunogen was halted as a result of development of meningoencephalitis in a small number of patients. The cytokine TGF-beta 1 is a key modulator of immune responses that is increased in the brain in AD. We show here that local overexpression of TGF-beta 1 in the brain increases both meningeal and parenchymal T lymphocyte number. Furthermore, TGF-beta 1 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 A beta(APP mice) and TGF-beta 1 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-beta 1 overproduction in the brain can promote T cell infiltration, in particular after A beta(1-42) immunization. Likewise, levels of TGF-beta 1 or other immune factors in brains of AD patients may influence the response to A beta(1-42) immunization.