The immune system is deeply involved in the intricate, complex processes of tissue regeneration, and the research community has much left to catalog of the countless interactions that take place between immune cells and other cell populations during regeneration. One interesting discovery is that a subclass of T helper cells can encourage growth of blood vessels. Thus, given a way of attracting and retaining the appropriate T helper cells in a tissue suffering ischemia, it may be possible to encourage sufficient regrowth of blood vessels to treat conditions involving inadequate blood flow, such as critical limb ischemia. Researchers here report on positive results from an implementation of this approach in mice.
Peripheral artery disease (PAD) is a narrowing of the arteries in the legs or arms. A new approach to generating new blood vessels to treat PAD takes advantage of the surprising combination of implantable biomaterial scaffolds and childhood vaccines. In models of mice with hindlimb ischemia (a severe form of PAD), the technique increased the concentration of T cells at the ischemic site and stimulated angiogenesis, blood flow, and muscle fiber regeneration for up to two weeks. "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. Also, it more broadly suggests that advances in bioengineered T-cell therapies, which have traditionally been used to treat cancers, may be utilized to promote wound healing and regeneration."
The researchers focused on T helper 2 (TH2) cells, a type of immune cell that has been found to secrete molecules that promote blood vessel growth in addition to producing cytokines that initiate immune responses. TH2 cells are also the crucial "memory" element of vaccinations against pathogens. For reasons that are not yet fully understood, delivering a small amount of aluminum in a vaccine greatly enhances TH2 cell formation, and nearly all Americans receive aluminum-containing childhood vaccines that protect them from a variety of diseases. The researchers had a hunch that vaccinated people could potentially mount a stronger TH2 cell response if the right triggering antigen was introduced; and, if that antigen was incorporated into a biomaterial scaffold located near a blocked artery, TH2 cells could be recruited to the scaffold and release their angiogenesis-promoting compounds where they are needed to help treat ischemia.
Researchers injected mice with ovalbumin, the primary protein found in egg whites, to create a mild immune reaction like an infectious antigen, along with aluminum hydroxide. Two weeks later the mice got a "booster" of the same vaccine, and four weeks later they were implanted with an ovalbumin-containing scaffold in their ischemic hindlimbs. These mice displayed higher numbers of ovalbumin-specific TH2 cells and eosinophils (angiogenesis-promoting cells that are activated by TH2 cells) in their ischemic muscles than mice that received the implant without the priming vaccine. Vaccinated mice also displayed a lower level of tissue death, higher blood vessel density, greater blood perfusion, and more regenerating muscle fibers in their ischemic hindlimbs after two weeks than unvaccinated mice that received the implant.