The Atlantic is quite complicated because, to quote veteran science writer Ed Yongs'' simple yet powerful words. Science still doesn''t fully understand the sophisticated defense mechanisms that protect us from microbe invaders. Why do some people exhibit no symptoms when infected with SARS-CoV-2, while others suffer from severe fevers and body aches? Why do some succumb to cytokine threats of the bodys own making? We still have to provide clear answers to these questions.
A group of researchers at Harvard University cultured human B and T cells inside a microfluidic Organ Chip device and coaxed them to spontaneously form functional lymphoid follicles, structures that hide and form naive B cells and T cells, which together initiate a complete immune response when exposed to a specific antibody.
These lymphoid follicle chips are also available to monitor immune responses to various vaccinations and assist select the best performers, indicating an improvement over existing preclinical models such as cells in a dish and non-human primates. This achievement has been reported today inAdvanced Science.
Animals have been the gold-standard research methods for developing and testing new vaccines, but their immune systems are quite different from ours, and they do not accurately predict how humans will respond to them. According to first authorGirija Goyal, a senior staff scientist at the Wyss Institute, our LF Chip is a way to simplify the complicated choreography of humanimmune responses to infection and vaccination.
An accidental discovery
The LF Chip project is the result of serendipity in the lab. Goyal and other Wyss Institute researchers wanted to investigate how B and T cells circulating in the blood would alter their behavior once they entered a tissue, and they then cultured them inside a microfluidic Organ Chip device to replicate physical difficulties they experienced when they encountered an organ.
When cells were placed inside one of the two channels within the device, nothing happened but when the researchers began the flow of culture medium through the other channel to feed them, they were amazed to see that the B and T cells became spontaneously self-organized into 3D structures within the Organ Chip, which appeared to be similar to germinal centers structures within the LFs where complex immune reactions take place. It was so unexpected that we completely removed the original experiment and focused on trying to figure out what they were.
In response to chronic inflammation, researchers began looking at the mysterious structures inside the Organ Chip under flow conditions and discovered that the cells were scognizing a chemical called CXCL13. CXCL13 is a hallmark of LF formation, both within lymph nodes and in other parts of the body.
B cells within the LFs that self-assembled on-chip expressed an enzyme called activation-induced cytidine deaminase (AID), which is important for activating B cells against specific antigens and does not exist in B cells that circulate in the blood.
Neither CXCL13 nor AID were present in standard 2D dish structures, suggesting that the scientists had successfully created functional LFs from circulating blood cells.
B cells mature and differentiate into various types of progeny cells, including plasma cells, which secrete large amounts of antibodies against a specific pathogen. After, the team determined the presence of plasma cells in the LF Chips after applying several stimuli in the laboratory to activate B cells, such as the combination of the cytokine IL-4 and an anti-CD40 antibody, or dead bacteria. Remarkably, plasma cells were concentrated in clusters within the LFs, as they would bein vivo.
These findings were particularly exciting because they also confirmed that we had a functional approach that might be used to unravel some of the human immune system''s challenges, including its responses to various types of pathogens, according to Ranav Prabhala, a technical professor at the Wyss Institute and the second author of the paper.
Predicting vaccine efficacy on-a-chip
The scientists now have a functional LF model that could initiate an immune response, and they have recently explored whether their LF Chip might be used to replicate and investigate the human immune systems response to vaccines.
Vaccination enables special cells called dendritic cells to take up the injected pathogen and migrate to lymph nodes, where they present fragments of them on their surface. To replicate this process, the researchers used local T cells in the LF, causing the B cells to differentiate into plasma cells that produce antibodies against the pathogen. The researchers then applied a vaccination using a yeast called SWE, which is known to improve immune responses to the vaccine.
Chips that received the vaccine and the adjuvant produced significantly more plasma cells and anti-influenza antibodies than B and T cells grown in 2D cultures or LF Chips that received the vaccine but not the adjuvant.
The group then repeated the experiment with cells from eight different donors this time using the commercially available Fluzoneinfluenza vaccine, which protects against three different strains of the virus in humans. Once again, plasma cells and anti-influenza antibodies were present in significant numbers in the treated LF Chips, and found that three of them (IFN-, IL-10, and IL-2) were similar to those found in the serum of individuals who had been vaccinated with Fluzone.
In collaboration with pharmaceutical companies and the Gates Foundation, Wyss researchers are now using their LF Chips to test various vaccines and adjuvants.
The flurry of vaccine development efforts triggered by the COVID-19 epidemic were impressive for their speed, but increased demand slowed human immune responses. LF Chip is a cheaper, faster, and more predictive model for human immune responses to both infections and vaccines, and we hope it will improve vaccination development in the future, according to a correspondent author.Donald Ingber, M.D., and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.