Improper Inducements

Lymphoid tissue inducer (LTi) cells have been concealing a sinister secret. We’ve known them for their good works—stimulating the formation of lymph nodes during fetal development. But the cells also promote the neurological damage of MS, a new study suggests (Perry et al., 2012). The work indicates that the monoclonal antibody daclizumab, now in clinical trials for MS, curbs the numbers of LTi cells, providing a previously unknown MO for this drug.

Experts not involved in the research describe it as solid and surprising. “The fact that they worked on a human model is a strength and makes this paper quite compelling,” says neuroimmunologist Timothy Vollmer of the University of Colorado, Denver, School of Medicine in Aurora. LTi cells were not on the suspect list for MS, he adds. The report appeared August 1 in Science Translational Medicine.

Originally approved in 1997 for quashing rejection of transplanted kidneys, daclizumab has recently shone in MS trials. For example, the CHOICE study, a Phase II trial, found that the antibody curbed the number and size of brain lesions in 230 patients with relapsing-remitting MS (Wynn et al., 2010). Despite the interest in daclizumab, researchers haven’t sorted out how it works. According to the original rationale for pitting the drug against MS, daclizumab curtails multiplication of the activated T cells that might spur MS pathology (see "Altered Immunity, Crippled Neurons") by jamming the IL-2 receptors on their surface. But studies over the past 6 years by neuroimmunologist Bibiana Bielekova of the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, and colleagues reveal that the chemical exerts surprisingly diverse effects—and has little direct impact on activated T cells. The team discovered, for instance, that daclizumab treatment boosts the population of a type of natural killer (NK) cell called CD56^bright that slays activated T cells, possibly explaining at least part of daclizumab’s clinical benefit (Bielekova et al., 2006).

Now, Bielekova and colleagues have caught the field off-guard again. Blood samples from untreated MS patients, they found, harbor unusually large numbers of immune cells called innate lymphoid cells (ILCs). By contrast, daclizumab-treated patients have about as many ILCs as do healthy individuals. The ILC family includes NK and LTi cells, so at first glance the results don’t square with the previous observation that CD56^bright NK cell populations rise in response to daclizumab.

By comparing samples from treated and untreated people with MS, the team discovered that daclizumab not only diminishes the total number of ILCs but also preferentially slashes the number of ILCs sporting LTi cell markers. As these cells become rarer, the number of CD56^bright NK cells climbs. Although the genealogy of ILCs remains unclear, the researchers suspect that LTi cells and CD56^bright NK cells spring from the same stem cell. The findings therefore suggest that the antibody offers protection by steering ILC development toward CD56^bright NK cell production and away from LTi cell production.

Daclizumab might deliver this outcome by virtue of its distinct effects on two forms of the IL-2 receptor. Activated T cells carry a version of the receptor that grips IL-2. Daclizumab latches onto a protein known as CD25 that forms part of this so-called high-affinity receptor but that doesn’t dispatch signals into the cell. So when daclizumab attaches to CD25, it prevents IL-2 from binding to the receptor but doesn’t stimulate the T cell. Other types of cells, such as ILC precursors, display a version of the receptor that sticks less well to IL-2; it also lacks CD25, so daclizumab doesn’t affix to it. In patients treated with the antibody, the extra IL-2 that can’t bind to the high-affinity receptors might be available to bind to these receptors on ILC precursors, which respond by diverging into CD56^bright NK cells.

Bielekova and colleagues took a step toward assessing that notion by raising ILC precursor cells with and without IL-2. In the absence of IL-2, almost all of them morphed into LTi cells. But adding the cytokine nudged most of the cells to become CD56^bright NK cells.

LTi cells might promote neurological damage, Bielekova says, by infiltrating the central nervous system and triggering the formation of lymph tissue clusters. In these structures, self-reactive B cells might refine their antibodies so they adhere more tightly to antigens. The globules include follicles that often reside near lesions in the meninges of MS patients (see “B Cells Step Into the Limelight” ). The researchers’ analysis of cerebrospinal fluid samples from before and after daclizumab treatment supports this hypothesis. The drug cut amounts of CXCL13, a protein indicator of new lymph tissue, presumably because fewer LTi cells are around to spur formation of that tissue. In their cerebrospinal fluid, daclizumab-treated patients also showed reduced quantities of IgG antibodies whose refinement requires the lymph clusters. However, confirming this explanation for how LTi cells cause trouble will be difficult, says immunologist Peter Lane of the University of Birmingham Medical School in the United Kingdom, because the biopsies necessary to find the cells in MS brain lesions can’t be performed while patients are alive.

The study is important, researchers say, because it exposes another potential wrongdoer in MS—and a new potential drug target. To treat rheumatoid arthritis, pharmaceutical companies are already developing compounds that block a key molecule made by LTi cells, but Bielekova says that no candidate has reached the clinic. The group’s technical achievement of detecting elusive LTi cells in humans might also pay off for future studies, Lane says: “People have really struggled to find them in the blood.” The team likely succeeded, he says, because the investigators studied patients who had recently received influenza vaccinations, which could have lured LTi cells out of their hiding places in the bone marrow.

Although scientists didn’t anticipate that LTi cells might be involved in MS, they aren’t surprised that daclizumab has unexpected consequences. All drugs stray from the script once they get beyond small initial trials, Vollmer says. But in this case the drug’s side effects turn out to be beneficial. “It’s always better to be lucky than smart—and the best is to be both,” Bielekova says.

Image Credit

Thumbnail image on landing page. "Normal Lymph Node From a colectomy specimen," Ed Uthman, 2008. Released under a Creative Commons Attribution-Share Alike 2.0 Generic license.