Date: 4th August 2020
Multiple sclerosis (MS) is a potentially disabling chronic autoimmune neurological disease, which affects an estimated 2.5 million people worldwide. Now scientists have engineered immunological niches to monitor disease activity and treatment efficacy in relapsing multiple sclerosis.
MS is a lifelong condition that can affect the brain and spinal cord, causing a wide range of symptoms, including problems with vision, arm and leg movements, sensations and balance. It occurs when the immune system attacks the myelin which protects the nerve fibres in the central nervous system (CNS).
Whilst there are a variety of therapies that can be used to slow down the relapse rate, there is variability in patient responses to them, they have to be administered long-term and they often have adverse effects. As such there is an urgent need for improved methods of detecting disease activity and in understanding pathogenic mechanisms in order for rapid treatments to be administered before irreversible damage occurs. Furthermore, better ways of identifying relapses would be greatly beneficial for managing disease progression and could profoundly change treatment approaches.
Now scientists led by Lonnie Shea from the University of Michigan, US, have investigated the application of tissue engineering to create easily accessible, subcutaneous immunological niches (IN) to study MS in mouse models. These niches reflect aspects of the immune status of CNS tissues and can be used as biomarkers for MS, allow monitoring of disease dynamics and gauging the effectiveness of treatments.
Implantable immunological niches
To start the team implanted microporous poly(ε-caprolactone) (PCL) scaffolds subcutaneously into SJL mice. These mice are prone to contracting experimental encephalomyelitis (EAE), a neurodegenerative disorder which resembles many aspects of multiple sclerosis in humans. The team hypothesised that these INs would elicit chronic inflammation and would therefore serve as niches with similar cell infiltrates and phenotypes to other inflammatory sites within the host.
There are two widely used methods for inducing EAE in SJL mice: active induction by immunisation with myelin antigens and passive induction by the adoptive transfer of pre-activated myelin-specific T cells, the team used both methods to induce EAE 14 days after IN implantation. The INs were then subsequently removed for analysis at two time points post disease induction; the first whilst the mice were asymptomatic, and the second at a symptomatic phase.
EAE alters gene expression
Gene analysis showed that EAE was associated with numerous changes in gene expression at the INs in both models and that these changes were detectable before disease symptoms occurred. Computational approaches were used to identify a 21 gene signature that could distinguish healthy from diseased mice (for the passive model) suggesting that this was a powerful predictive method of disease onset.
INs were also characterised for cell populations residing within them, here the team found disease-relevant innate and adaptive immune cells. Furthermore, analysis of blood harvested from symptomatic EAE mice or controls indicated that the gene signature in the blood did not mirror that from the IN, suggesting that INs and blood provide distinct information which may be an important distinction for disease monitoring.
Whilst, the evidence so far suggested that INs could be useful during disease onset the team also wished to determine the capacity of the INs to monitor disease dynamics that are associated with remission and relapses which occur frequently in MS patients.
INs monitor disease dynamics
Therefore, IN- implanted mice were induced for the disease (as before), then allowed to progress toward symptomatic remission, then a relapse was induced by a second adoptive transfer. Samples isolated from INs during disease remission exhibited INs with similar gene expression to those of the controls. In contrast, those isolated during the relapse showed a similar gene expression to disease onset, suggesting a return to cell phenotypes associated with disease. Interestingly, the cellular makeup of the niches during disease remission were similar to that during disease onset, this implied that the cell phenotypes were responsible for observed alterations in gene expression and were not due to a change in cell types residing within the INs.
These data suggested that alterations in disease and molecular signature of the INs were dynamic and were able to predict disease state. But could the system be used for pre-emptive treatment to abrogate the condition?
To answer this the team induced EAE and then the INs were biopsied and analysed at 7 days post-transfer, before the team delivered one of two therapies; pulse glucocorticoids known to benefit MS relapses, or an experimental antigen specific nanoparticle therapy. In both cases, when administered upon IN-indication of disease state, the therapeutics almost completely mitigated disease symptoms in the short term. Furthermore, the emerging nanoparticle therapy appeared to sufficiently induce a longer-term abrogation of the disease. These results support the use of INs to prevent disease relapses and support the further investigation of the nanoparticle therapy.
Conclusion and future applications:
Autoimmune diseases collectively have a prevalence of 15–24 million patients in the US alone and are typically not diagnosed until substantial damage occurs. The implantable IN presented here forms a vascularised inflammatory tissue that is dynamic with the status of the immune system and therefore can be harnessed to diagnose, monitor and test the efficacy of treatments in this case for MS.
The team identified a molecular signature that was differentially expressed at the IN in disease animals and could be used to determine the onset or relapse of MS, allowing treatment interventions that could ameliorate or even prevent disease development and damage. This type of strategy could transform MS patient care by treating relapses before they occur.
Indeed, it is likely the IN could be used to monitor other autoimmune diseases by establishing other sets of disease molecular signatures. In fact, the team here set the stage for using INs as an implantable molecular biosensor that can continuously monitor the functional status of the immune system. Perhaps it could be adapted to other types of diseases which have an inflammatory element such as diabetes, obesity or cancer.
We are starting to see the rapid development of diagnostic biosensors, such as nanosensors that can diagnose lung disease from exhaled biomarkers in the breath, ultra-sensitive biosensors which detect cancer markers in patient blood or serum, or those that can detect early signs of infection and rejection following organ transplants or detection of SARS-CoV-2. It is hoped this new IN platform will offers a new approach to monitor organ-specific autoimmunity in otherwise inaccessible target tissues and that this is will change the way certain diseases are treated, pre-empting and eliminating those susceptible to relapses.
Morris, A. H., K. R. Hughes, R. S. Oakes, M. M. Cai, S. D. Miller, D. N. Irani and L. D. Shea (2020). “Engineered immunological niches to monitor disease activity and treatment efficacy in relapsing multiple sclerosis.” Nature Communications 11(1): 3871.
https://doi.org/10.1038/s41467-020-17629-z
