05 Sep 2003

Genetic polymorphisms in the major histocompatibility complex (MHC)—a group of proteins that help the immune system distinguish self from non-self—can profoundly influence the immune response mounted against an amyloid β vaccine. That is the conclusion of a study by Todd Golde and colleagues from the Mayo Clinics in Jacksonville, Florida, and Rochester, New York. Their report, currently available online, will appear in the November issue of Neurobiology of Aging.

The scientists noticed the effect of the MHC when joint first authors Pritam Das and Svetlana Chapoval challenged transgenic Tg2576 mice, which express a mutated human version of amyloid β precursor protein (APP), with an Aβ1-42 vaccine. Tg2576 mice mounted a robust antibody response to the peptide, but when the researchers crossed them with C57BL/6 animals, the offspring responded more weakly. In contrast, offspring from crosses with C3H/129S mice, which express a different set of MHC alleles from their C57BL/6 cousins, had just as robust a response as their Tg2576 parents.

To examine whether human MHC antigens also influence the response to Aβ1-42, the authors used a set of transgenic mice that have their mouse MHC genes replaced with human ones. When Das and Chapoval immunized these animals with Aβ1-42, they found that the B and T cell responses were MHC-dependent. For example, T cell proliferation in animals expressing the HLA-DR4 gene, which occurs in about 22 percent of the human population, was more than four times higher than that in mice expressing HLA-DR3, HLA-DR8, or HLA-DR6. The B cell response was highest in animals expressing the HLA-DR3 allele (found in about seven percent of the human population); the Aβ antibody titer in these mice was twice that of animals expressing DR4.

Such results may explain why not all patients enrolled in the recent Elan trial for an Aβ vaccine generated robust antibody responses against the peptide. The authors write that "our results have significant implications for direct Aβ immunization as a therapeutic strategy for AD," and suggest that "HLA genotyping of patients prior to immunization may be required."—Tom Fagan