Interesting finding with broad implications for understanding Tcell responses

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http://www.alzforum.org/new/detail.asp?id=1387

Aâ Immunotherapy—Human T Cell Activation: Less Is More

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4 May 2006. They say that the best things come in small packages.

That sentiment may sum up some new approaches to Aâ immunotherapy.

In previous meeting coverage we described how smaller Aâ antigens

developed by 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 Aâ1-15 antigens as potential vaccines for AD. These fragments

lack the T cell reactive sites found in full-length Aâ1-42, 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 Aâ1-15 cross-linked dimers can improve

cognition.

First authors Marcel Maier and colleagues used the water maze

to test the antigen therapy in J20 mouse line, which expresses human

Aâ 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 Aâ 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.

References:

Maier M, Seabrook TJ, Lazo ND, Jiang L, Das P, Janus C, Lemere CA.

Short amyloid-â (Aâ) immunogens reduce cerebral Aâ load and learning

deficits in an Alzheimer's disease mouse model in the absence of an

Aâ-specific cellular immune response. The Journal of Neuroscience.

May 3, 2006;26:4717-4728.

Nguyen DH, Hurtado-Ziola N, Gagneux P, Varki A. Loss of Siglec

expression on T lymphocytes during human evolution. PNAS early

edition. May 1, 2006.