Harvard’s Ulrich von Andrian makes immune system action movies.

Eric Bland

If the immune system can be pictured using military metaphors—armies of immune cells battling foreign invaders—then part of Ulrich von Andrian’s job is being a war cameraman. His videos show death and destruction at the cellular level.

Ulrich von Andrian (Courtesy: Immune Disease Institute)

Over the last five years, von Andrian, an immunologist with the Harvard-affiliated Immune Disease Institute (formerly called the CBR Institute for Biomedical Research) has emerged as a leader in the use of multiphoton intravital microscopy (IVM) to visualize and understand how various components of the immune system, such as T cells, B cells, and blood stem cells, work together to clear the body of pathogens and, sometimes, how they work against each other, too. IVM has been around for more than a century, but by coupling it with technology that enables the rapid collection of images, researchers can make 3-D videos of cells interacting inside a living animal.

By being able to watch immune reactions as they happen in animals, immunologists have seen interactions between immune cells in far more detail than when looking at tissue samples under a microscope. For example, they can see how long and how often a T cell needs to bind to other cells to be activated to kill pathogens. Through these videos, researchers have even discovered whole new behaviors among immune cells. This deeper understanding of how the immune system fends off pathogens may lead to insights into autoimmune disease and vaccine design, says von Andrian.

Cellular warfare

The von Andrian lab creates videos using IVM by taking a series of pictures of fluorescently stained cells in live, anesthetized rats—most often in the lymph nodes, where certain immune cells divide and become activated. Pictures are taken at four frames per minute and then linked together to make the video. The videos can survey entire lymph nodes or zoom in on individual cells. Von Andrian estimates that there are dozens of labs around the world using IVM.

One video from 2006 shows a fluorescently tagged green T cell chasing down a purple-stained B cell. The cells seem to trade blows as they move around the screen. Then suddenly the pursuit stops. The purple cell turns white as red-stained DNA oozes out from it. The T cell moves away in search of another victim.

To capture the footage, von Andrian’s team labeled the B cell with a specific antigen recognized by the T cell, in essence tricking the T cell into recognizing the B cell as a foreign pathogen. This was the first time a T cell had been filmed chasing and killing another cell, says von Andrian. (For more videos on this, click here)

Macrophage mayhem

His most recent research using IVM, published in Nature last month, describes how macrophages, a type of immune cell, capture invading viruses in the lymph nodes of mice and then present the viral remains to activate antibody-producing B cells. They found that the macrophages trigger an immune response faster if they present a larger piece of the virus. The videos made of this process revealed a new and more complex role for macrophages in lymph nodes.

“People have been intrigued by how important macrophages are and this was not anticipated,” says von Andrian.

The virus used in this experiment provoked such a strong immune response that von Andrian says it could be used as a carrier to deliver a wide range of vaccines. He, along with researchers from Brigham and Women’s Hospital and MIT, are working to start a company called Selecta Biosciences that will develop the vaccines.

Mike Dustin, an immunologist at the Skirball Institute of Biomolecular Medicine at New York University who is not involved in von Andrian’s research, says that Uli, as most people know him, is a pioneer in IVM.

“He got into [IVM] early and has been very successful at figuring out good questions,” says Dustin. “He’s not just developing technology but doing a lot of good biology as well.”

To see more videos from the von Andrian lab, click "here.":https://www.cbrinstitute.org/labs/vonandrian/Pages/Videos%20Page.html