THE INNER WORKINGS OF YOUR IMMUNE SYSTEM
What do monoclonal antibodies, CAR-T therapy, and 3D vaccines all have in common? They are immunotherapies, or therapies that activate a patient’s own immune system to fight or prevent a disease. While immune system activation can help save a life, an overactive immune system can potentially attack the body it is charged with protecting—the basis for autoimmune disorders.
The biotech industry has elegantly hacked the immune system—a highly complex network of cells, tissues, and signaling molecules—to make some of the leading immunotherapies, like Abbvie’s (North Chicago, IL) Humira. Let’s discover how the immune system operates at the cellular level.
NON-SPECIFIC IMMUNITY: MACROPHAGES AND NEUTROPHILS
Non-specific (or innate) immunity is the front line defense against invading pathogens—think viruses and bacteria. The troops defending against foreign invaders are specialized white blood cells (WBC). Most WBC in the body are non-specific defenders, meaning they will attack in the same fashion without stopping to consider the weakness of the enemy.
Freely circulating in the bloodstream are macrophages and when they encounter a foreign invader, they simply eat it. Macrophages recognize that a bacterium is foreign because its surface contains fats, proteins, and carbohydrates that are different from those found on human cells. Other types of non-specific defenders include neutrophils (which also recognize and engulf invaders) and natural killer cells, which inject the protein granzyme B into invaders, triggering cell death.
Non-specific defenders become activated by a threat and release “inflammatory cytokines,” or signaling molecules that activate other immune cells. The inflammatory response is kicked into gear, ensuring a rapid and comprehensive retaliation.
SPECIFIC IMMUNITY: T-CELLS AND B-CELLS
When non-specific defenses are unable to rid the body of an invading pathogen, it’s time to call for back up. Waiting for the call are T-cells and B-cells, which make up specific (or adaptive) immunity, ready to fight foreign proteins.
T-cells and B-cells are highly specialized to recognize unique targets, thanks to distinctly shaped receptors. Once a match is made, the receptor binds to the target and the T-cell or B- cell is activated.
T-cells attack infected cells floating around the body. These cells display foreign proteins on their surface and when the T-cell encounters a non-self signal, it begins its mission.
Activated T-cells divide rapidly and produce two types of cells: killer T-cells and helper T-cells. Killer T-cells roam the body in search of their preprogrammed target, and seal the deal by injecting granzyme B. In contrast, helper T-cells do not actively target infected cells, they release inflammatory cytokines and activate antibody-producing B cells, killer T-cells, and macrophages to respond en masse. Helper T-cells are so critical that the immune system is crippled when they unable to do their job—remember the human immunodeficiency virus (HIV) only infects helper T-cells.
B-cells divide and alert other cells to destroy the pathogen once activated. They also clean up the battlefield and plan for future attacks instigated by the same foreign invader. Most B-cells produce plasma cells that secrete antibodies. Antibodies recognize and bind to any bacterium or virally-infected cell that bears an activating protein (antigen). The binding action triggers other immune cells, such as killer T-cells or macrophages, to sweep in and destroy the invader attached to the antibody.
Immunotherapies use concepts from specific immunity to their advantage. Antibodies have been adapted for use as therapeutic monoclonal antibodies and bispecific antibodies. Also, T-cells are engineered to recognize and attack cancer cells in CAR-T therapy.
THE WATCHMEN: DENDRITIC CELLS
In order for T-cells to become fully activated, they must encounter the foreign invader in the context of a “professional antigen-presenting cell,” called a dendritic cell. They are white blood cells that engulf a virus or bacterium, digest their protein components, and “display” portions of those proteins on their surface. Dendritic cells play a key role in developing therapies, especially with Dendreon’s (Seattle, WA) 3D Vaccine Provenge.
THE OTHER SIDE OF THE COIN: AUTOIMMUNITY
The immune system prevents us from falling deathly ill as it responds to constant microbe exposure; however, an overactive immune system can cause serious problems.
When the immune system goes into overdrive, chronic inflammatory disorders such as Crohn’s disease, rheumatoid arthritis, and psoriasis wreak their havoc, mistakenly attacking the body. White blood cells are activated to target innocent cells in the body and release inflammatory cytokines to sustain the response.
Biologic drugs that treat these disorders—like Humira, Enbrel (Amgen, Thousand Oaks, CA), and Rituxan (Genentech, South San Francisco, CA)—work by shutting down key parts of the response. Humira and Enbrel inhibit the inflammatory cytokine TNF-alpha and are approved for a range of inflammatory diseases. Rituxan, approved for rheumatoid arthritis, works by reducing the number of B-cells that target the synovial tissue of joints.
The body has natural checks on the immune system in order to prevent inflammatory disorders. A part of the specific immune system development is a screening process that terminates T-cells or B-cells that mistakenly recognize the body’s own tissues. Even after passing the screening test, T-cells have certain protein activators (called checkpoints) that must be turned on in order for the T-cell to become fully active. Some types of cancer cells exploit these immune checkpoints; however, checkpoint inhibitor therapies dismantle this evasive mechanism used by cancer cells to stay hidden from T-cells.
From one side of the coin to the other, the immune system continues to amaze the industry as new pathways and targets are discovered. A delicate balance of the body’s toughest fighters, understanding and optimizing the immune system is central to the immunotherapy paradigm.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.