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Nanoparticles Boost Antibody Produdion

Chemical Engineering Progress


The immune system is exquisitely controlled by cascades of chemical signals that trigger its cells to target and destroy invaders. Now, one step in this complex process can be done in a Petri dish.

Researchers have discovered a way to activate ? cells to produce specific human antibodies in the laboratory. ? cells are white blood cells that bind to and process foreign molecules called antigens as part of the body's immune response. Once they come in contact with an antigen, ? cells develop into plasma cells that secrete antibodies - Y-shaped proteins that bind to the foreign invaders and neutralize them or tag them for destruction by other immune cells. ? cells also present antigens to T cells, which are immune cells that further fight off infection.

Another reason to love your ? cells: Their receptors, known as ?-cell receptors (BCRs), are crucial to the long-term memory of the immune system. Once they have been presented with an antigen and activated, ? cells retain that antigen's information so they can even more rapidly boost the immune response the next time they detect it.

For all of these reasons, scientists would like a better understanding of how ? cell activation works - and ways to control that activation in the lab for the purpose of developing antibody-based drugs or for vaccine development. But it is very hard to specifically activate ? cells with a particular antigen, because only a handful of the ? cells in circulation are responsible for "memorizing" any given invader. For example, there might be just one ? cell in 10,000 or 100,000 primed for a pathogen like tetanus, says Facundo Batista, an immunobiologist at the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard Univ. In addition to encountering a specific antigen, ? cells must also internalize short DNA fragments called CpG oligonucleotides that activate a ?-cell protein called TLR9, which allows the ? cells to proliferate and develop into plasma cells.

To stimulate just the ? cells of interest to respond to a given disease, Batista and his colleagues developed a new, nanoparticle-based technique. They coated streptavidin nanoparticles with both CpG oligonucleotides and the antigen of interest. Treating patient-derived ? cells with CpG oligonucleotides alone stimulates every ? cell in the sample, not just the tiny fraction capable of producing a particular antibody. The coated nanoparticles, on the other hand, are internalized only by the ?-cells that recognize the particular antigen used. As a result, only those specific ? cells proliferate and develop into antibodysecreting plasma cells.

The researchers tested the technique on ? cells taken from donor blood, first coating their nanoparticles with antigens from tetanus, and then with different influenza strains. They were able to boost the numbers of pathogen-specific ? cells by more than 1,000-fold.

Most people have tetanus-specific ? cells circulating in their blood because they received childhood vaccinations, and natural exposure to the flu is likewise practically universal. To test their nanoparticles with something the immune system had not seen, the researchers presented an HIV protein to ? cells from HIV-negative blood donors. They again found an increase in ? cell activation, albeit at a lower level than in the tetanus or influenza experiments. Because the immune cells were naive to HIV, this finding indicates that it is not just memory ? cells that the nanoparticles are stimulating - they also seem capable of generating new immune responses.

The technique has not been put through the testing and regulatory rigor necessary for clinical use (that process would take years). But it is already useful as a lab tool, Batista says. In theory, the nanoparticles could be used to stimulate antibodies against a particular disease, or even cancer, that could then be used as a personalized treatment. The method could also be used in vaccine development, to test whether a vaccine has effectively triggered ? cells and embedded itself in their memory.

In the long run, Batista says, the researchers hope to integrate this new method of ?-cell stimulation with the next step in the immune cascade, the involvement of T cells. "In the future, we would like to have a full immunoresponse in a Petri dish," he says.

Sanjuan Nándin, I., et al., "Novel in vitro Booster Vaccination to Rapidly Generate AntigenSpecific Human Monoclonal Antibodies," Journal of Experimental Medicine. 214 (8), pp. 2471-2490, doi: 10.1084/jem.20170633 (Aug. 2017).

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