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Jul 16, 2023

Microparticles Trigger Treg Expansion to Cure Mice With Multiple Sclerosis

While there is no cure for the autoimmune disease multiple sclerosis (MS), the

While there is no cure for the autoimmune disease multiple sclerosis (MS), the results of a new study by Johns Hopkins Medicine researchers have pointed to the therapeutic potential of a promising approach that can reverse—and in many cases, completely alleviate—MS-like symptoms in mice. The strategy, tested in a mouse model of MS, harnesses biodegradeable microparticles (MPs) loaded with the immunosuppressant drug rapamycin, and functionalized with immune-modulating molecules, to create tolerogenic MPs (Tol-MPs) that support the expansion of regulatory T cells (Tregs).

"We developed a method for ‘tipping the balance’ of the T cells reaching the central nervous system from effectors to regulatory T cells, or Tregs, that modulate the immune system and have been shown to prevent autoimmune reactions," said Giorgio Raimondi, PhD, associate director of the Vascularized Composite Allotransplantation Research Laboratory and assistant professor of plastic and reconstructive surgery at the Johns Hopkins University School of Medicine. Raimondi is co-senior author of the team's published paper in Science Advances, which is titled "Bioengineered particles expand myelin-specific regulatory T cells and reverse autoreactivity in a mouse model of multiple sclerosis."

National Institute of Neurological Disorders and Stroke figures cited by the Johns Hopkins team suggest that nearly three million people worldwide—almost a third of whom are in the US — live with multiple sclerosis, a disabling neurological disease in which the body's immune system mistakenly attacks nerves feeding information to the central nervous system. Although rarely fatal, MS can lead to long-term disabilities, and impair movement, muscle control, vision and cognition.

For an unknown reason in people with MS, some of the body's first line of defense against foreign invaders—immune cells known as CD4+ T cells—fail to recognize that myelin, the insulating, fatty material surrounding and protecting nerve cells, is a normal part of the human system. If these wayward effector T cells become dominant, they may provoke inflammation that damages or destroys the myelin sheath, which in turn, can severely disrupt or curtail transmission of nerve impulses from all parts of the body to the brain.

Multiple sclerosis (MS) is an autoimmune disease that develops when autoreactive immune cells recognize and attack the protective myelin sheath surrounding nerves in the central nervous system (CNS), causing irreversible

damage that can impair movement, muscle control, vision, and cognition," the authors further explained. MS can't be cured, and current treatments for the lifelong disease are untargeted, and often lead to patients to become immunocompromised. "Because of the damaging side effects of broad-based immunosuppressants, alternative therapies that induce specific immune tolerance toward autoantigens, without disrupting unrelated immune activity, are being actively explored," the authors continued. "Treatments aim for tolerance induction to re-educate the immune system to recognize myelin as "self" rather than "foreign.""

For their newly reported study, the team developed biodegradable polymeric microparticles — tiny bioengineered polymer spheres — to deliver three key therapeutic agents. One is a fusion of the protein interleukin-2 (IL-2), which stimulates T cell production and growth, and an antibody that blocks certain binding sites on IL-2 to optimize the ones relevant to Treg expansion. Another is a major histocompatibility complex (MHC) class II molecule with a myelin peptide (protein fragment) presented on its surface to immunologically select myelin-specific (and therefore, protective of the nerve cell covering) Tregs rather than other T cell types. The third component is rapamycin, an immunosuppressant drug that helps lower the number of effector T cells.

The team tested the resulting Tol-MPs in mice with autoimmune encephalomyelitis (EAE), a model of human MS. "We inject the loaded microparticles near lymphatic tissues to stimulate the production and growth of Tregs and facilitate their travel to the central nervous system via the lymphatic system," explained study co-senior and corresponding author Jordan Green, PhD, director of the Biomaterials and Drug Delivery Laboratory and professor of biomedical engineering at the Johns Hopkins University School of Medicine. "Our study findings showed that in all of our mice, the Tregs stopped the autoimmune activity of the effectors against myelin, prevented further damage to the nerves and gave them the time needed to recover."

Raimondi further noted, "Using this therapy on mice bred to exhibit symptoms modeling those seen in humans with MS, we found we could enhance the growth of Tregs while simultaneously reducing the number of effectors, resulting in reversal of the MS-like symptoms in 100% of the mice, and even more exciting, achieving a full recovery in 38%—in other words, more than a third were cured of their disease." Along with further studies to confirm the effectiveness of their potential MS therapy, Raimondi, Green and colleagues plan to try their microparticle therapy-delivery system on other autoimmune diseases.

The authors further noted, "Together, our study demonstrates that Tol-MPs show great promise as a safe and effective preventative and therapeutic treatment for this mouse model of EAE and potentially for MS and other autoimmune diseases … The modular design of Tol-MPs allows for ready adaptation to expand specific Treg populations to treat many autoimmune conditions." Co-senior author Jamie Spangler, PhD, added, "First in line will be a mouse version of type 1 diabetes. To engage and grow Tregs specific for the insulin-producing cells in the pancreas damaged or threatened by that disease's autoimmune activity, we’ll exchange the myelin peptide we used in the MHC-peptide portion of the MS therapy with one from those cells." Spangler is director of the Spangler Lab at the Johns Hopkins University School of Medicine, and assistant professor of biomedical engineering and chemical and biomolecular engineering at The Johns Hopkins University Whiting School of Engineering.

"The belief is that by simply changing the presented peptide each time, we can target our therapy to tackle a wide variety of autoimmune diseases," commented Green. "We hope to have a cache of potential therapies ready to go before moving forward to safety and efficacy studies in mice, followed hopefully by human trials." And as the authors concluded, "Together with the increasing understanding of key antigenic targets in human autoimmune disorders or transplant rejection, we envision a rapid implementation of derivatives of this construct in clinically relevant scenarios. We envision that this platform for in situ antigen-specific T cell–activating therapy via an off-the-shelf acellular biodegradable particle product will have great potential for immunoengineering and next-generation immunotherapies."

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