Neurobiology of Aging 24 (2003) 969–976 Immune responses against A1–42 in HLA class II transgenic mice: implications for A1–42 immune-mediated therapies Pritam Das a,1 , Svetlana Chapoval b,1 , Victor Howard a , Chella S. David b , Todd E. Golde a,∗ a Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA b Department of Immunology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA Received 4 October 2002; received in revised form 6 January 2003; accepted 3 February 2003 Abstract We have investigated whether polymorphic differences in the major histocompatibility complex (MHC) class II molecules influence humoral and cellular immune responses against A1–42. To analyze the effects of mouse MHC class II and tolerance effects of overexpres- sion of human APP in mice, we immunized Tg2576 and non-transgenic littermates bred into two different MHC backgrounds with A1–42 and compared both B and T cell responses. We found that in the presence of the mouse C57BL/6 background, both B and T cell responses against A1–42 were significantly suppressed. To directly test the contribution of human MHC class II, we immunized various human HLA class II transgenic (TG) mice with A1–42 and analyzed anti-A immune responses. HLA-DR3 and HLA-DQ8 TG mice generated modest B and T cell responses against A1–42. The presence of HLA-DR3/DQ8 in double TG mice enhanced the overall immune response against A1–42. In contrast, HLA-DR4 TG mice mounted strong T cell responses but failed to generate high titer antibody responses against A1–42, whereas, the HLA-DQ6 TG mice were not able to mount significant B or T cell responses against A1–42. These studies in mice suggest that the presence of certain MHC class II molecules or combinations of class II molecules can potentially influence the overall immune response against A1–42. © 2003 Elsevier Science Inc. All rights reserved. Keywords: A vaccination; A1–42; Tg2576 mice; Alzheimer’s disease; MHC class II 1. Introduction Amyloid beta peptides (A) appear to play a causal role in the neuropathology of Alzheimer’s disease (AD) [14,27,29]. Work by Schenk et al. [26] has shifted attention to the ther- apeutic potential of increasing A clearance by inducing a robust humoral immune response to A in the PDAPP trans- genic (TG) mouse model of AD [12]. Using fibrillar A1–42 as an immunogen, they found that in animals, which de- veloped a high anti-A antibody titer, there was a signif- icant reduction in biochemically detected A load, plaque burden, neuritic dystrophy and gliosis. Significantly, this study not only showed that A immunization prevented A deposition in young PDAPP mice, but also attenuated A deposition in mice that were not immunized until they had developed A deposits. These studies have now been ex- tended to other models and strategies [2,4,9–11,18–20,22]. ∗ Corresponding author. Tel.: +1-904-953-1086; fax: +1-904-953-7370. E-mail address: golde.todd@mayo.edu (T.E. Golde). 1 These authors contributed equally. Passive transfer of anti-A-specific antibodies [4] or direct application of A-specific antibodies to the brain [2] were shown to reduce amyloid burden in the APP TG mice, pro- viding strong evidence that the efficacy of A immunization could be attributed directly to the production of anti-A an- tibodies. Both active immunization of A1–42 [11,18,22] and passive transfer of A-specific antibodies [19] in APP TG mice have now been shown to prevent and/or reverse cognitive deficits in these mice without significantly alter- ing A plaque loads. The overall hypothesis in these stud- ies is that A antibodies enter the CNS, bind and neutralize soluble A that may be affecting cognitive function. This hypothesis differs from the one suggested in the report by DeMattos et al. [10] where they show that anti-A antibod- ies can induce A accumulation in plasma and alter brain levels of A. In this later report, it is suggested that anti-A antibodies acts outside the CNS, by creating a peripheral sink that draws A out of the brain. In any case, irrespec- tive of the mechanisms, in order for direct A immuniza- tion to be efficacious in humans, the generation of robust anti-A1–42 humoral responses appear to be prerequisite. 0197-4580/$ – see front matter © 2003 Elsevier Science Inc. All rights reserved. doi:10.1016/S0197-4580(03)00036-8