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Comparative Study
. 2006 Nov 1;26(44):11437-41.
doi: 10.1523/JNEUROSCI.2436-06.2006.

Increased T cell recruitment to the CNS after amyloid beta 1-42 immunization in Alzheimer's mice overproducing transforming growth factor-beta 1

Marion S Buckwalter  1 , Bronwen S Coleman, Manuel Buttini, Robin Barbour, Dale Schenk, Dora Games, Peter Seubert, Tony Wyss-Coray
Affiliations
Comparative Study

Increased T cell recruitment to the CNS after amyloid beta 1-42 immunization in Alzheimer's mice overproducing transforming growth factor-beta 1

Marion S Buckwalter et al. J Neurosci. .

Abstract

Immunotherapy targeting the amyloid beta (Abeta) peptide is a novel therapy under investigation for the treatment of Alzheimer's disease (AD). A clinical trial using Abeta(1-42) (AN1792) as the immunogen was halted as a result of development of meningoencephalitis in a small number of patients. The cytokine TGF-beta1 is a key modulator of immune responses that is increased in the brain in AD. We show here that local overexpression of TGF-beta1 in the brain increases both meningeal and parenchymal T lymphocyte number. Furthermore, TGF-beta1 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 Abeta (APP mice) and TGF-beta1 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-beta1 overproduction in the brain can promote T cell infiltration, in particular after Abeta(1-42) immunization. Likewise, levels of TGF-beta1 or other immune factors in brains of AD patients may influence the response to Abeta(1-42) immunization.

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Figures

Figure 1.
Figure 1.
T lymphocytes are increased in brains of TGF-β1 mice. Six-month-old TGF-β1 transgenic (n = 7) and nontransgenic littermate control (n = 5) mice were analyzed for the number of T lymphocytes using immunohistochemistry on 40 μm sagittal vibratome sections. A, B, Immunohistochemistry for CD3 + lymphocytes in the hippocampus of wild-type and TGF-β1 mice. Scale bar, 100 μm. C–F, Average number of T cells in two sections per mouse in hippocampus, corpus callosum, cortex, and meninges. Error bars indicate mean ± SEM. *p ≤ 0.05, **p ≤ 0.005, unpaired Student's t test.
Figure 2.
Figure 2.
Active immunotherapy of APP/TGF-β1 mice with Aβ1–42 increased the number of T lymphocytes in the brain. A, Immunohistochemistry for the T cell marker CD3 on brain sections from an APP/TGF-β1 mouse treated with AN1792/QS21. Top row, Cortical infiltrates; bottom row, hippocampal and meningeal infiltrates. B, Examples of vascular (top) and parenchymal (bottom) infiltrates in an APP/TGF-β1 mouse treated with AN1792/QS21. β-Dystroglycan labels blood vessels. C, D, Mean number of CD3 + cells in cortex and total per sagittal section from APP, APP/TGF-β1, TGF-β1, and wild-type mice treated with AN1792, adjuvant alone (QS21), or untreated. E, B cells per sagittal section in the same mice as C and D. Graphs show means ± SEM. *p ≤ 0.05, ***p ≤ 0.001, Fishers PSLD. Scale bars, 25 μm.
Figure 3.
Figure 3.
T cell infiltrates in Aβ1–42-immunized APP/TGF-β1 mice contained helper and cytotoxic T cells and were associated with activated microglia but not with B lymphocytes or hemorrhages. Sagittal brain sections from AN1792-treated APP/TGF-β1 mice are shown. A–C, Immunohistochemistry for the pan-T cell marker CD3, the helper T cell marker CD4, and the B cell marker B220. D, Perl's iron stain for hemorrhages, counterstained with nuclear fast red. E, F, Staining for CD68, which labels activated microglia, and Iba1, which labels all microglia. G–J, Triple immunolabeling of a cortical infiltrate containing CD3 + T lymphocytes (green), some of which colabel with the helper T cell marker CD4 (red). The microglial marker Iba1 (white) reveals activated microglia. K, Immunostaining for the cytotoxic T cell marker CD8. Scale bars: A, 50 μm; G, K, 25 μm.
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