Aβ Immunotherapy—Human T Cell Activation: Less Is More

They say that the best things come in small packages. That sentiment may sum up some new approaches to Aβ immunotherapy. In previous meeting coverage we described how smaller Aβ antigens developed by Cynthia Lemere and colleagues may avoid potentially toxic T cell responses (see ARF related news story). Now we can report that that work has just been published and includes some new mouse behavioral data. In other immunology news this week, researchers in San Diego report a major difference between human and chimpanzee T cells that might, among other things, explain the recent “cytokine storm” and systemic organ failure that sent six drug trial volunteers to intensive care in London’s Northwick Park Hospital. Human cells, it turns out, are lacking suppressors that quell T cell proliferation in other primates.

Lemere, from Brigham and Women’s Hospital, Boston, has developed short Aβ1-15 antigens as potential vaccines for AD. These fragments lack the T cell reactive sites found in full-length Aβ1-42, yet elicit fairly robust antibody responses and reduced plaque load in mouse AD models (see ARF Keystone Symposia meeting report). In the May 3 Journal of Neuroscience, Lemere and colleagues also report that vaccination with Aβ1-15 cross-linked dimers can improve cognition.

First authors Marcel Maier and colleagues used the Morris water maze to test the antigen therapy in J20 mouse line, which expresses human Aβ precursor protein harboring Swedish and Indiana mutations. They found that the antigen, together with an E. coli heat-labile enterotoxin adjuvant, resulted in a subtle, though statistically significant improvement in learning and memory. Specifically, in a reversal maze task (where the platform is moved and the mice must learn the new location), the untreated transgenic mice continued to search for the platform in the old location while the antigen-treated mice spent more time searching for the platform in its new quadrant. The reduced plaque load and improved cognition elicited by such N-terminal Aβ epitopes suggests that they may be suitable for vaccination therapy in AD patients.

Of course, such therapies would need to be tested in primates first. That’s why the paper in this week’s PNAS from Ajit Varki and colleagues at the University of California at San Diego makes interesting reading. The researchers report subtle differences between chimpanzee and human gene expression that may underlie much stronger human T cell responses. The finding may explain why T cell-related diseases such as AIDS and chronic hepatitis are so severe in humans, and it also provides a caveat to those testing potential human vaccines in other primates.

First author Dzung Nguyen and colleagues found that inhibitory signaling proteins called Siglecs, normally expressed on mammalian immune cells, are either totally absent or very poorly expressed in human T cells. Their data indicate that suppression of T cell Siglecs evolved about 100,000 to 200,000 years ago, leading to much more active T cell responses. In support of this, Nguyen and colleagues report that they can calm human T cell proliferation by making them express Siglec-5, while chimp T cells mount stronger proliferative responses when the same Siglec is inhibited with antibodies.

This genus difference may make chimps and monkeys less than ideal models for testing human immunotherapies. “As a general rule, it would be good to test antibodies in monkeys prior to use in humans. However, there will be cases where humans will be uniquely different,” suggested Varki via e-mail. The evolutionary difference between us and our primate “cousins” might also explain the massive immune response to TeGenero’s “super” agonist antibody TGN1412 (see related news from the BBC). Monkeys had received doses of TGN1412 that were 500 times higher than those given to the trial volunteers with no signs of adverse side effects. “It [T cell differences] could very well explain what happened—and at present it is the only explanation I know of. Regardless, this particular case is a special one, where even testing in chimpanzees may not have predicted the problems in humans. I think that this incident should not be used to make any broad generalizations about antibody therapies,” wrote Varki.—Tom Fagan

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References

News Citations

  1. Sorrento: Immunotherapy Update Hot Off Lectern of AD/PD Conference
  2. Keystone Symposia Meeting, Part 8—Animal Models and Therapeutics; Therapeutics and Imaging

External Citations

  1. related news

Further Reading

Primary Papers

  1. Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA. Short amyloid-beta (Abeta) immunogens reduce cerebral Abeta load and learning deficits in an Alzheimer's disease mouse model in the absence of an Abeta-specific cellular immune response. J Neurosci. 2006 May 3;26(18):4717-28. PubMed.
  2. Nguyen DH, Hurtado-Ziola N, Gagneux P, Varki A. Loss of Siglec expression on T lymphocytes during human evolution. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7765-70. PubMed.

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