25 January 2007. In the future, could Alzheimer disease treatments come as an ointment, or a skin patch? That may not be as far out as it seems, with a new study published this week in PNAS online showing that mice produce amyloid-clearing antibodies after application of aggregated amyloid-β (Aβ)42 peptide onto their skin. But even more important than the easy delivery of such a vaccine is the scientists’ claim that going through the skin could make it safer. The work, a joint effort by Jun Tan of the University of South Florida in Tampa and Terrence Town of the Yale University School of Medicine in New Haven, Connecticut, suggests that skin vaccination could minimize the T cell inflammatory complications that stopped the clinical development of a human Aβ vaccine.
Continuing analysis of the halted human vaccine trial suggests the treatment might have been effective, but was not adequately safe. The Aβ42 vaccination was able to clear brain amyloid, and indications are that it stayed cognitive decline in some people. But the injected Aβ caused meningoencephalitis in some recipients, presumably by activating brain-infiltrating inflammatory T cells. After that, researchers began to search for better vaccines, with an emphasis on truncated Aβ peptides that would trigger a B cell-mediated antibody response while avoiding T cell-mediated inflammation.
Another way to tweak the immune response is by changing the vaccine’s entry portal.
Unlike injected peptides, preparations introduced across the skin encounter specialized antigen-presenting cells in the skin. These cells help to skew the T cell response away from the autoimmune inflammatory TH1-type and toward a more desirable TH2 response. Thus, Tan and Town thought skin application might minimize damaging inflammatory reactions.
In the new study, dual first authors William Nikolic and Yun Bai swabbed aggregated full-length Aβ1-42 peptides plus a cholera toxin adjuvant onto the shaved skin of mice weekly for 4 weeks, and then every 2 weeks for 12 more. The procedure stimulated the production of Aβ antibodies in serum. The spleens of immunized mice contained Aβ-reactive cells, and analysis of cytokine profiles suggested the mice were mainly making a TH2-type response.
The vaccine cleared brain amyloid deposits in the PSAPP mouse model of Alzheimer disease. After vaccination, serum levels of Aβ40 and 42 peptides increased, and brain amyloid decreased by about half, indicating mobilization and clearing of brain plaques. In agreement with this, the number of plaques was halved in brain sections from immunized mice.
Aβ clearance occurred in the absence of detectable T cell infiltration into the brain. It is important to note that the original vaccine did not produce T cell infiltration in mice, either, yet still caused problems in some people. As Town told ARF, “This is a case where if you don’t see T cell infiltration in the mice, you can’t say much. But if you do see it, you know you have a problem. With this vaccine, we didn’t see it.”
One side effect of some forms of anti-Aβ vaccination that has been noted in mice is bleeding in the brain, due to microhemorrhages induced by Aβ antibodies. That was not seen with the skin vaccine. Next, the scientists will test if the vaccine affects brain function in the mice. “That is really important, and we’d like to have behavioral results before we really get excited about the possibility of using this in humans,” Town said.
If you’re anticipating the launch of a combination anti-wrinkle/anti-AD face cream, prepare to wait at least 6-10 years, the time frame Town says to reasonably expect for development of any new vaccine therapy. And keep an eye on combined approaches to making a safer vaccine. Earlier work from Cynthia Lemere and colleagues at Brigham and Women’s Hospital, Boston, has already shown that transdermal immunization can work in mice, in this case with a truncated, dendromeric Aβ peptide that keeps the N-terminal B cell reactive epitope but lacks the C-terminal T cell epitope ( Seabrook et al., 2006).—Pat McCaffrey.
Nikolic WV, Bai Y, Obregon D, Hou H, Mori T, Zeng J, Ehrhart J, Shytle RD, GiuntaB, Morgan D, Town T, Tan J. Transcutaneous beta-amyloid peptide immunization of transgenic Alzheimer’s mice results in reduced cerebral B-amyloid deposits in the absence of T cell infiltration and microhemorrhage. PNAS Early Edition, week of Jan. 22. Abstract