The Wyss Institute for Biologically Inspired Engineering at Harvard University works in a range of cutting-edge med-tech fields. Only a few years ago, it opted to incorporate one focus specifically on what it calls immuno-materials. The idea is to develop biomaterials that can concentrate or manipulate immune cells in order to identify new patient treatments while avoiding some of the systemic risks associated with drug-based immunotherapy.

The effort has resulted thus far in several advances and published papers on immuno-materials. The latest comes from Wyss researchers working alongside those from Harvard's John Paulson School of Engineering and Applied Sciences (SEAS). They developed an implantable biomaterial scaffold that incorporates an antigen to attract T-cell activity to repair damaged blood vessels and surrounding tissue in mice. The mice were first treated to approximate vaccination in humans, with the antigen used then in the biomaterial to trigger a subsequent immune response. Their work was published in the July 31, 2019, issue of Science Advances.

Triggering immunity

"One of the most surprising findings is that memory T cells can induce blood vessel regeneration, just because most people typically don't associate T cells with use in regeneration. They mostly think of them as cells that combat disease or combat cancer. . . .[T]his is something that not a lot of people are pursuing," study first author Brian Kwee, who was a graduate student at Wyss and SEAS and has since moved on to become a postdoctoral research fellow at the FDA, told BioWorld.

In a mouse model of hindlimb ischemia, which is a severe form of peripheral artery disease (PAD), the researchers successfully concentrated the most relevant T cells at the ischemic site, which stimulated angiogenesis, blood flow and muscle fiber regeneration for up to two weeks.

There are about 8.5 million people in the U.S. with PAD, which is a narrowing of the arteries in the arms or legs that is often due to the build-up of fatty plaque. Lost blood flow to the limbs can cause tissue death, gangrene and amputation. The condition is common among diabetes patients. Treatment typically starts with cholesterol medications and can move to angioplasty or bypass surgery; treatment for later-stage disease is difficult and can be ineffective.

Investigational attempts to treat PAD have included approaches to promote angiogenesis, but they have thus far failed to improve patient outcomes.

"One of the most exciting aspects of this work is that it provides a new method of enhancing blood vessel formation that does not rely on traditional biologics, such as cells, growth factors and cytokines, that are typically used to promote vascularization," said Kwee.

To treat ischemia, the research focused on a kind of immune cells known as T helper 2 (Th2) cells, which have been found to secrete molecules that encourage blood vessel growth and cytokines that start immune responses. They are also involved in the immunological 'memory' of vaccines, enabling the body to mount a response. The small amount of aluminum typically included in vaccines enhances Th2 cell formation.

The Wyss researchers incorporated a triggering antigen into the biomaterial scaffold that was introduced near a blocked artery. The idea was to recruit the Th2 cells to the site to promote angiogenesis.

"This method essentially takes advantage of the fact that standard vaccines 'prime' the immune system to recognize specific antigens. By reintroducing an antigen via a scaffold in a very localized place, we're able to attract and retain enough Th2 cells that they can effectively treat ischemic tissue and promote the growth of new blood vessels," said senior author David Mooney, who is a founding core faculty member at the Wyss Institute as well as the Robert Pinkas professor of bioengineering at SEAS.

Immuno-materials

In an attempt to replicate the reaction in a vaccinated human, the researchers injected mice with a protein from egg whites known as ovalbumin to create a mild immune reaction along with aluminum hydroxide. The mice got another shot two weeks later and then four weeks after that were implanted with the scaffold in their ischemic hindlimbs.

Control mice received the scaffold implant without the priming vaccine mimic. The treated mice demonstrated a lower level of tissue death, higher blood vessel density, greater blood perfusion and more regeneration of muscle fibers in the ischemic hindlimbs during the subsequent two weeks than the mice who did not receive the vaccine mimic.

Up next, the researchers aim to better understand the timing between vaccination and scaffold implant and how that alters the cell response. That should help shed light on if this approach would be effective in humans who are typically vaccinated at a young age, but develop PAD and ischemia when they are much older.

"What we demonstrated in the paper is a proof of concept that this idea works. But I think there's still some kind of major limitations to what we've done that we need to further explore it to make it translate on humans," said Kwee. "The time span between receiving your childhood vaccines and receiving the scaffold could be on the order of years to decades. So, mimicking that timescale is critical to really understanding that this will work in humans. Also, the way this technology works is based on diffusion of the antigen from the scaffold. The research is required to see how this biomaterial can be scaled up to treat larger human limbs, rather than smaller mouse limbs."

Since it was first launched as a focus area in June 2017, immuno-materials at Wyss have resulted in published research on biomaterials that can trap and concentrate T cells, as well as those that can boost immune response as a cancer treatment. Last year, Novartis AG partnered with Wyss and SEAS to develop therapeutic, biomaterial-based, cancer vaccine technology to boost cancer immunity.

"We are at the dawn of a new age of beginning to understand the extent to which the immune system impacts human health and disease. This work from our Immuno-Materials Platform here at the Wyss Institute provides yet another example of how a bioinspired materials approach to reengineer the immune system can potentially lead to disruptive medical breakthroughs," summed up Wyss Institute founding director Donald Ingber, who is also the Judah Folkman professor of vascular biology at Harvard Medical School and the vascular biology program at Boston Children's Hospital, as well as a professor of bioengineering at SEAS.