What is Tysabri and How Does It Work?
Tysabri, known by its generic name natalizumab, is a humanized monoclonal antibody used to treat relapsing forms of multiple sclerosis (MS) and moderate-to-severe Crohn's disease. Unlike broad immunosuppressants that affect the entire immune system, Tysabri is a selective adhesion molecule inhibitor that targets a specific pathway of the inflammatory process. Its primary mechanism involves blocking certain immune cells, particularly T cells, from migrating into the central nervous system (CNS) or the gut, where they cause inflammation and tissue damage.
In both MS and Crohn's disease, the immune system mistakenly attacks healthy tissue, leading to chronic inflammation. Tysabri works by binding to a protein called alpha-4 integrin, which is found on the surface of most white blood cells (leukocytes). This action blocks the integrin from attaching to its corresponding receptors on the blood vessel walls. By blocking this adhesion molecule, Tysabri prevents the immune cells from transmigrating across the endothelial lining of blood vessels and entering the target organs. The ultimate result is a significant reduction in inflammation within these specific, affected tissues.
The Mechanism in Multiple Sclerosis
In MS, inflammation causes damage to the myelin sheath that protects nerve fibers in the brain and spinal cord. Tysabri's mechanism directly counters this process:
- Blocks the Blood-Brain Barrier (BBB): In MS, activated T cells cross the BBB to enter the CNS and trigger an inflammatory cascade. Tysabri binds to the alpha-4 integrin on these T cells, preventing their interaction with the vascular cell adhesion molecule-1 (VCAM1) on the endothelial cells of the BBB.
- Reduces Lesions and Relapses: By inhibiting the influx of inflammatory cells, Tysabri helps to reduce the formation of new brain lesions and decreases the frequency of clinical relapses. MRI scans of patients on Tysabri often show a significant reduction in new lesion activity.
- Decreases Inflammatory Proteins: Studies analyzing cerebrospinal fluid (CSF) have demonstrated that natalizumab treatment leads to a decrease in inflammatory proteins and an increase in proteins associated with neurological function, confirming its anti-inflammatory and potential repair effects.
The Mechanism in Crohn's Disease
For patients with Crohn's disease, Tysabri's anti-inflammatory action targets the gastrointestinal tract:
- Targets Gut Inflammation: Tysabri binds to both alpha-4 beta-1 and alpha-4 beta-7 integrins. The alpha-4 beta-7 integrin is particularly relevant for gut inflammation, as it allows immune cells to home to the intestinal mucosa.
- Blocks Adhesion in the Gut: By blocking the alpha-4 beta-7 integrin, Tysabri prevents its interaction with the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is overexpressed in the gut of Crohn's patients. This prevents the infiltration of lymphocytes into the gut wall.
- Induces Remission: By reducing lymphocyte infiltration and inflammation, Tysabri can induce and maintain clinical remission in patients with moderately to severely active Crohn's disease.
Comparison of Tysabri with Other DMTs for MS Inflammation
While many Disease Modifying Therapies (DMTs) for MS have anti-inflammatory effects, their mechanisms differ. For example, Ocrevus targets B cells, while Tysabri prevents cell migration.
| Feature | Tysabri (Natalizumab) | Ocrevus (Ocrelizumab) | Gilenya (Fingolimod) |
|---|---|---|---|
| Mechanism | Blocks immune cell migration into the CNS via alpha-4 integrin blockade. | Depletes CD20+ B cells, a type of immune cell. | Traps immune cells (lymphocytes) in lymph nodes. |
| Inflammation Target | Specifically prevents immune cells from crossing the blood-brain barrier. | Reduces circulating B cells, which can contribute to inflammation. | Reduces the number of lymphocytes circulating in the bloodstream. |
| Infusion Frequency | Monthly intravenous infusion. | Administered every six months after initial doses. | Oral medication, daily dose. |
| Relative Efficacy | Highly effective at reducing relapses and lesion activity. | Also highly effective, used for both relapsing and progressive MS. | Effective, though potentially less so than Tysabri in some studies. |
| PML Risk Factor | Elevated risk, particularly with long-term use and anti-JCV antibody status. | Also associated with a risk of PML, but generally considered lower than Tysabri in certain patient populations. | Can also increase the risk of PML, especially after Tysabri treatment. |
Potential Risks and Immune System Effects
As Tysabri is an immunosuppressant, its use comes with notable risks, most famously the risk of Progressive Multifocal Leukoencephalopathy (PML). PML is a rare and often fatal viral infection of the brain caused by the JC virus, which can become active when the immune system is weakened.
Other immune-related side effects include an increased risk of other infections, such as herpes encephalitis, meningitis, and acute retinal necrosis. Monitoring patients is critical, and a special prescribing program (TOUCH program) is required to manage these risks.
During treatment, Tysabri causes increases in circulating lymphocytes, monocytes, eosinophils, and basophils in the bloodstream. This is because the drug prevents these immune cells from migrating out of the blood and into the CNS or gut, causing them to accumulate in the peripheral circulation. These cell levels typically return to normal after treatment is stopped.
Conclusion
To conclude, Tysabri does reduce inflammation by preventing the infiltration of immune cells into specific inflamed tissues. In multiple sclerosis, it blocks these cells from crossing the blood-brain barrier into the CNS, which significantly reduces lesion formation and clinical relapses. In Crohn's disease, it prevents similar migration into the intestinal mucosa, helping to induce and maintain remission. The medication's selective mechanism, targeting the alpha-4 integrin on immune cells, is what makes it so effective at managing inflammation in these autoimmune conditions. However, this immunosuppressive effect is also the source of its most serious risks, particularly PML, highlighting the need for careful patient monitoring.
How does Tysabri reduce inflammation?
- Integrin Blockade: Tysabri (natalizumab) binds to the alpha-4 integrin protein on the surface of immune cells.
- Prevents Migration: This binding blocks the immune cells from adhering to and crossing blood vessel walls into the brain or gut.
- Reduces Tissue Damage: By preventing inflammatory cells from reaching the target tissue, Tysabri reduces inflammation and subsequent damage.
- Selectively Immunosuppressive: It specifically targets the migration process rather than wiping out a broad range of immune cells.
- Decreases Relapse Rate: This action is highly effective in reducing relapses in multiple sclerosis and maintaining remission in Crohn's disease.
Note: The specific mechanism(s) by which Tysabri exerts its effects has not been fully defined, but the blockade of leukocyte migration is the primary understood action. For more information, healthcare professionals can refer to the Tysabri Prescribing Information.
