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The Journal of Neuroscience, November 1, 2006, 26(44):11437-11441; doi:10.1523/JNEUROSCI.2436-06.2006

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Brief Communications
Increased T Cell Recruitment to the CNS after Amyloid _1–42 Immunization in Alzheimer's Mice Overproducing Transforming Growth Factor-1

Marion S. Buckwalter,¹ Bronwen S. Coleman,¹ Manuel Buttini,² Robin Barbour,² Dale Schenk,² Dora Games,² Peter Seubert,² and Tony Wyss-Coray^1,3

¹Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, ²Elan Pharmaceuticals, South San Francisco, California 94080, and ³Geriatric Research, Education, and Clinical Center, Veterans Administration Palo Alto Health Care System, Palo Alto, California 94304

Correspondence should be addressed to Tony Wyss-Coray, Geriatric Research, Education, and Clinical Center, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304. Email: twc{at}stanford.edu

Immunotherapy targeting the amyloid (A) peptide is a novel therapy under investigation for the treatment of Alzheimer's disease (AD). A clinical trial using A_1–42 (AN1792) as the immunogen was halted as a result of development of meningoencephalitis in a small number of patients. The cytokine TGF-1 is a key modulator of immune responses that is increased in the brain in AD. We show here that local overexpression of TGF-1 in the brain increases both meningeal and parenchymal T lymphocyte number. Furthermore, TGF-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 (APP mice) and TGF-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-1 overproduction in the brain can promote T cell infiltration, in particular after A_1–42 immunization. Likewise, levels of TGF-1 or other immune factors in brains of AD patients may influence the response to A_1–42 immunization.

Key words: A peptide; Alzheimer's disease; immunity; immunotherapy; inflammation; lymphocyte; neuropathology; T cell; vaccination

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Received June 8, 2006; revised Aug. 28, 2006; accepted Sept. 25, 2006.

Correspondence should be addressed to Tony Wyss-Coray, Geriatric Research, Education, and Clinical Center, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304. Email: twc{at}stanford.edu

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