Natalizumab is a medication known by the brand name Tysabri. It is a monoclonal antibody that serves as a disease-modifying therapy for specific autoimmune conditions. The primary uses for natalizumab are for treating relapsing forms of multiple sclerosis (MS) and moderate-to-severe Crohn’s disease. It is considered for patients who have had an inadequate response to other therapies and is administered as an intravenous infusion every 28 days.
Targeting Immune Cell Trafficking
In autoimmune conditions like multiple sclerosis and Crohn’s disease, the body’s own immune system mistakenly attacks its own tissues. This process is driven by the movement of immune cells called lymphocytes from the bloodstream into protected areas of the body. In MS, these lymphocytes penetrate the central nervous system (CNS), while in Crohn’s disease, they infiltrate the lining of the gastrointestinal tract, causing inflammation and damage. This migration is not a random event; it is a highly specific process mediated by proteins on the cell surfaces.
The movement of these immune cells is dependent on the interaction between specific proteins. Lymphocytes have a surface protein called alpha-4 integrin, which is a molecular key. This key is designed to fit into a corresponding lock, a protein named vascular cell adhesion molecule-1 (VCAM-1), located on the surface of cells that line the blood vessels. When inflammation is present, the expression of VCAM-1 increases, presenting more locks for the lymphocytes’ keys.
This “key in lock” interaction allows the lymphocytes to adhere firmly to the blood vessel walls. Once attached, the cells can pass through the vessel lining and enter the surrounding tissue, a process known as transmigration. In MS, this allows activated T-lymphocytes to cross the otherwise restrictive blood-brain barrier and attack the myelin sheath that protects nerve fibers. In Crohn’s disease, a similar event occurs, enabling immune cells to move into the gut wall and cause chronic inflammation.
The entire process perpetuates a cycle of tissue damage. As lymphocytes enter the protected tissues, they release inflammatory signals that can cause further harm and attract even more immune cells to the site. The goal of therapies like natalizumab is to interrupt this destructive cycle by preventing the initial step of cell trafficking.
Blocking the Path into Protected Tissues
Natalizumab is engineered to identify and bind to a very specific target. Its objective is the alpha-4 subunit of the alpha-4-beta-1 integrin protein, which is found on the surface of circulating inflammatory lymphocytes. The medication latches onto the “key” before it has a chance to find its “lock.”
By binding to this alpha-4 integrin, natalizumab physically obstructs the protein. This blockage prevents the integrin from being able to recognize and interact with its counterpart, the VCAM-1 molecule on the blood vessel walls. Without this connection, the lymphocytes are unable to adhere to the endothelial cells lining the vessels. The result is that these immune cells cannot stop their journey through the bloodstream and are prevented from migrating out of the vascular space.
For individuals with multiple sclerosis, natalizumab’s action prevents immune cells from crossing the blood-brain barrier. This barrier is a highly selective membrane that normally protects the brain and spinal cord from substances in the blood. By inhibiting transmigration, the drug significantly reduces the infiltration of harmful immune cells into the central nervous system, which leads to a reduction in the inflammation that causes neural damage.
In the context of Crohn’s disease, the mechanism is parallel. The medication stops lymphocytes from entering the inflamed tissues of the gastrointestinal tract. This reduction in immune cell accumulation helps to lessen the chronic inflammation responsible for symptoms like abdominal pain and tissue damage. For both conditions, the therapeutic benefit is a decrease in the formation of new inflammatory lesions and a reduction in the frequency of disease relapses or exacerbations.
Consequences of Reduced Immune Surveillance
The same mechanism that makes natalizumab an effective therapy also introduces a significant risk. By design, the drug prevents immune cells from entering the central nervous system. This action, while beneficial for controlling autoimmune inflammation, also hampers the brain’s normal immune surveillance. This is the routine process where immune cells patrol the CNS to identify and eliminate pathogens like viruses and bacteria.
This reduction in immune oversight creates a vulnerability to certain infections. The most serious of these is associated with the John Cunningham (JC) virus. The JC virus is a common polyomavirus that infects a large portion of the adult population, but it remains dormant and causes no symptoms in individuals with a healthy immune system. The virus can reside in various tissues, including the kidneys and lymphoid organs, without causing harm as long as it is kept in check.
If the JC virus, which may have been dormant in the body, reactivates and reaches the brain, the immune system’s ability to mount a response is compromised. This allows the virus to replicate without opposition within the brain’s white matter.
This uncontrolled viral replication leads to a rare but serious brain infection known as Progressive Multifocal Leukoencephalopathy (PML). PML is characterized by the destruction of the myelin sheath that insulates nerve cells, leading to progressive and severe neurological damage. The risk of developing PML is a direct consequence of natalizumab’s mechanism of action. For this reason, patient monitoring is a component of treatment.