MRI image of a brain hemisphere from a multiple sclerosis patient, false-colored to highlight affected areas. Credit: Govind Bhagavatheeshwaran and Daniel Reich at NIH.
Johns Hopkins researchers have made strides in a study focusing on multiple sclerosis. By applying microparticles to activate regulatory T cells, they were able to reverse MS-like symptoms in mice.
There is no cure for multiple sclerosis (MS). But a recent study by Johns Hopkins Medicine shows encouraging progress towards: They have demonstrated the ability to reverse, and in many instances, entirely mitigate symptoms similar to multiple sclerosis in mice.
The study, published in the peer-reviewed journal Science Advances, found a reversal of the MS-like symptoms in 100% of mice receiving received tolerogenic microparticles (Tol-MPs). A total of 38% achieved a full recovery. The researchers measured improvement using a scoring system, where a lower score indicates less severe symptoms. Here, 100% refers to the portion of mice with a reduction in symptoms, lowering their score to 0.5 or less. The 38%, conversely, refers to the fraction of mice with a complete recovery, with their symptom severity score dropping to 0, representing no symptoms by the end of the study.
The bar chart below visualizes the median number of days for disease onset and the mean peak disease severity score for different treatments in the study. Each pair of bars represents a different treatment, with the left bar indicating the median time in days for disease onset and the right bar indicating the mean peak disease severity score. Lower values for both metrics indicate more effective treatments. The data for this chart are from the study published in Science Advances.
Bar chart showing the comparison of median days of disease onset and mean peak disease score for different treatments in a multiple sclerosis study. The treatments include control, rapamycin, tolerogenic microparticles and a combination of rapamycin and microparticles.
“To be truly honest, I was surprised by how effective the therapy was in this mouse model,” said Dr. Giorgio Raimondi, one of the principal researchers involved in the study.
Raimondi noted that the study demonstrates a proof of principle for a strategy to address autoimmune diseases – type 1 diabetes is another potential application.
While results are promising, Raimondi stressed the need to “keep both feet on the ground. “There are many aspects that still need to be developed,” he noted.
Unveiling the promise of microparticles in multiple sclerosis
Polymeric microparticles show promise for inducing immune tolerance. While microparticles have existed for decades, the research was unique inits focus on using them as a framework to deliver multiple components simultaneously.
“These microscopic particles act as couriers, delivering therapeutic agents directly to the immune cells,” Raimondi explained. “They can interact with cell surface receptors or, following cellular internalization, deliver delicate biological cargo directly within cells.”
The biodegradability of these particles, made from a blend of poly(lactic co-glycolic acid) and poly(beta-amino ester), enables their dual functionality: The particles use both targeting ligands to direct therapy to the right cells and signaling ligands to deliver specific messages. They can also locally release encapsulated cargo, such as the immunosuppressant drug rapamycin as they biodegrade.
Targeting the immune system
In this research, ligands are involved in directing immunotherapy treatments to the appropriate immune cells and prompting the therapeutic response. Ligands are molecules that bind to specific sites on a target protein, triggering a change in its behavior. In the context of this research, two types of ligands are at work:
- Targeting ligands: These molecules help guide the therapy to the correct cells. They bind to specific receptors on the desired cell types to ensure that the therapy is delivered where it’s needed most. In this study, the researchers used an immunocytokine F5111 as a targeting ligand. F5111 IC is a modified version of interleukin-2 (IL-2), a protein that stimulates the growth and activity of T lymphocytes.
- Signaling ligands: These are molecules that, once inside the cell, send specific messages or instructions. These could include triggering the cell to behave in a certain way or to initiate specific processes. In this study, the researchers used MHC class II/peptide complexes as signaling ligands.
Using pathways that naturally induce immune tolerance, the researchers’ approach enables the delivery of therapeutic molecules to antigen-presenting cells (APCs). These APCs then stimulate an anti-inflammatory response.
Other notable recent examples of microparticle research include Rice University’s time-released drug delivery system and MIT’s ‘self-boosting’ vaccines.
Targeting T cells to combat multiple sclerosis
The Johns Hopkins study unveiled the potential use of microparticles to target and stimulate regulatory T cells (Tregs).
Tregs are a crucial type of immune cell that help keep the immune system in check, preventing it from mistakenly attacking the body’s own cells. In autoimmune diseases like MS, the number and function of these Tregs cells are often impaired or deficient, contributing to the immune system’s attack on its own tissues.
In the study, researchers engineered microparticles with F5111 IC and MHC class II/peptide complexes and laden with the immunosuppressant drug rapamycin, demonstrated the potential to both prevent and reverse paralysis in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis or EAE).
The microparticles (MPs) in the research, also known as tolerogenic MPs (Tol-MPs), engage selectively with antigen-specific CD4+ T cells. Once administered intravenously, these MPs predominantly end up in the liver and spleen. Both local and systemic administrations of Tol-MPs effectively curbed the severity of EAE in mice.
The findings highlight the promise that Tol-MPs could offer. They have shown the capability to enable antigen-specific T cell engagement and selective Treg expansion, offering protection from autoimmune diseases like EAE.
Collaborators in the fight against multiple sclerosis
Dr. Jamie Spangler, an expert in engineering cytokines, developed a specialized interleukin-2 complex, targeting regulatory T cells to support their expansion and help maintain immune balance.
Another collaborator, Dr. Jordan Green, applied his expertise in material science and particles. Initially investigating microparticles that activate the immune system against cancer, Green learned that such particles could also modulate other immune responses. Green and Spangler worked together to create microparticles carrying the tailored interleukin-2 (IL-2) complex that could target immune cells.
A collaborative approach to modulating the immune system
The team’s approach could treat MS and other autoimmune diseases with fewer side effects. “The particles attract cells and interact with cells and they can interact successfully only with cells that recognize that MHC,” says Raimondi. “Only the regulatory T cells will actually receive the signal from these interleukin-2 because it’s modified to communicate just with these regulatory cells and receive the signal to grow and expand as a population.”
Their system expands regulatory T cells without overly suppressing immunity. Green’s particles engage the T cells and deliver Spangler’s complex, promoting T cell growth to restore balance. “The whole point here is practically to work on the principle of the balance of the immune system in an autoimmune condition,” adds Raimondi.
This research marks a significant step toward personalized autoimmune therapies. Spangler, Green, and Raimondi’s work harnesses immunity in a precise and safe manner. It shows promise in transforming the treatment of autoimmune diseases and transplantation. “There are there is an activation and expansion of these autoreactive cells that need to be controlled,” Raimondi concludes, “Our approach is to use these particles to engage the population of regulatory cells, then it’s imbalanced, then it’s low, and bring it back up in a very antigen-specific way.”
The future of multiple sclerosis research: Next steps
Raimondi and his team have filed a patent application and plan to test the approach in other animal models of autoimmunity to explore its potential as a “platform technology.” As Raimondi points out, “We first demonstrated it can work and can work as a platform to indicate that we have these building blocks that are adaptable.” For example, they plan to swap the antigen target in the MS mouse model for one related to type 1 diabetes, indicating their versatility in application.
“I believe the future of autoimmune therapy is moving in the direction of more specific, more targeted approaches,” Raimondi said. “The microparticle platform offers this potential.”
Filed Under: Cell & gene therapy, Drug Delivery, Drug Discovery, Drug Discovery and Development, Uncategorized
