Health care is rapidly evolving.

From new ways to harness the immune system’s natural capabilities to advances in nanotechnology and the advent of omics and big data, we are continuously improving and developing novel ways to treat diseases. In this article, we will discuss advances for autoimmune diseases, specifically type-1 diabetes, and multiple sclerosis.

Type 1 Diabetes (T1D)

T1D is an autoimmune disease characterized by T-cell-mediated destruction of pancreatic β cells, which leads to a lack of insulin production. Currently, approximately 300, 000 individuals are living with T1D in Canada, and the incidence is rising. T1D is caused by both genetic and environmental factors. Genetics contribute around 70% of the risk, as supported by twin concordance. The genetic allele which contributes to T1D is strongly associated with the HLA region “HLA class II, DQ and DR loci and HLA class I region” on chromosome 6p21 that accounts for ~50% of familial T1D.

Promising Therapies for T1D

β cell replacement using either allogenic solid organ pancreas or islet transplantation has been shown to reverse T1D but requires lifelong immunosuppression to prevent graft rejection. One option, which replaces the need to obtain islets from allogeneic cadaveric donors is to use donor-derived human Pluripotent Stem Cells (hPSCs). hPSCs are immature cells that have the capacity to differentiate into different cell types of the body. Thus, researchers are looking to use them to differentiate into pancreatic β cells. The goal of this approach is to generate a ready supply of β cells for transplantation into T1D patients. Since these cells are donor-derived, also known as autologous, these patients will not require lifelong immunosuppression. In the lab, scientists have successfully induced a PSC-derived β cell with the ability to respond to glucose. Recently, one man was able to be effectively cured with injections using these β cells. This is a promising first step for T1D patients.

Scientists are also turning to the immune system to modulate the occurrence of T1D. The goal of immune-modulating therapies in T1D is to prevent the immune system from attacking the β cell mass. Efforts have focused on blocking cell- or cytokine-directed interactions, which have been successful in other autoimmune diseases. However, these approaches have been only partly successful. Nevertheless, one human trial of T1D prevention to date has been met with success. In this clinical trial, patients were treated with teplizumab, which is a monoclonal antibody that binds to CD3, one of the major surface proteins on T cells. In phase 2 clinical trials, a single course of teplizumab in high-risk relatives of people with T1D was able to delay progression to clinical T1D by 2 years. In comparison, 72% of high-risk individuals with stage 2 disease were found to progress to clinical T1D in the placebo arm of the trial. Combination therapies that aim to integrate immune modulation with a β cell-specific component are now being explored. In the future, a curative treatment for T1D will most likely require therapies which restore the production of insulin and modulate the immune system.

Multiple Sclerosis (MS)

MS is characterized as a chronic demyelinating disorder of the central nervous system (CNS) with inflammatory cells infiltrating around the nerve, leading to demyelination of the myelin sheath and immune attack of the surrounding tissue. Immune cells implicated in MS pathogenesis include macrophages, T helper type 1 (Th1) cells, Th17 cells, CD8+ T cells and B cells. The World Health Organization (WHO) estimates that globally, more than 2.5 million people are affected by MS. The incidence of MS in young adults is expected to rise exponentially, suggesting that environmental factors are contributing to disease risk. MS can be categorized into three main subtypes (i) relapse/remitting MS (RRMS), (ii) secondary progressive MS (SPMS), and (iii) primary progressive MS (PPMS). RRMS accounts for 85% of cases, and eventually, 50% of those cases will progress to SPMS, and the remaining 15% of cases have PPM.

Promising therapies for MS

Currently, there is a great need for new treatments to stop MS progression and decrease side effects. Many therapy types are being researched for efficacy. Given the immune cell-based nature of MS, research in immune targeting therapies have advanced in recent years. Examples include vaccines, using dendritic cells to induce immune tolerance, blocking pro-inflammatory mediators, cell-directed immunotherapies, and peptide-carrier conjugates. In preclinical studies using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), peptide-based immune modulating conjugates have shown promise by switching immune responses from pro-inflammatory to anti-inflammatory and inducing protection against EAE. Additionally, nanoparticles have been used to deliver MS antigens to the immune system to tolerize T cells and drive an anti-inflammatory response. Recently, chloroquine, an anti-malarial drug, was shown to suppress EAE in mice by modulating dendritic cells, Th17 cells, astrocytes, oligodendrocytes, and microglia. These data highlight the many promising therapies currently being testing in mouse models for MS treatment.

The rising incidence of MS is suggested to be influenced by factors such as lifestyle, eating habits, and exercise. This suggests that the gut microbiota may play a role in the rising incidence and are a potential therapeutic target for MS. Gut microbiota can be modulated through dietary factors, such as probiotics, or medicinal approaches. To date, select probiotics have been shown to have anti-inflammatory effects on immune cells in disease settings, such as asthma and allergy. One study showed that the probiotic Streptococcus thermophilus was able to switch pro-inflammatory T cells against a MS agonist MBP83–99 peptide to an anti-inflammatory

profile. This study suggests that the consumption of Streptococcus thermophilus may be beneficial in the management and treatment of MS and other autoimmune diseases, and more research is needed in this promising field.

Conclusion

As we begin to better understand how autoimmune diseases arise, we can design more specific therapies. Targeted therapies are necessary as many broad therapies have been proven to be ineffective or may have side effects with long-term treatment. Hopefully, we can bridge the gap between our disease understanding and disease cures in the future.


References

1. Bone, R. N., and C. Evans-Molina. 2017. Combination Immunotherapy for Type 1 Diabetes. Curr. Diab. Rep.17: 50.

2. Burke, G. W., F. Vendrame, S. K. Virdi, G. Ciancio, L. Chen, P. Ruiz, S. Messinger, H. K. Reijonen, and A. Pugliese. 2015. Lessons From Pancreas Transplantation in Type 1 Diabetes: Recurrence of Islet Autoimmunity. Curr. Diab. Rep.15: 121.

3. Jacobson, A. M., B. H. Braffett, P. A. Cleary, R. A. Gubitosi-Klug, and M. E. Larkin. 2013. The Long-Term Effects of Type 1 Diabetes Treatment and Complications on Health-Related Quality of Life. Diabetes Care36: 3131–3138.

4. Bluestone, J. A., J. H. Buckner, M. Fitch, S. E. Gitelman, S. Gupta, M. K. Hellerstein, K. C. Herold, A. Lares, M. R. Lee, K. Li, W. Liu, S. A. Long, L. M. Masiello, V. Nguyen, A. L. Putnam, M. Rieck, P. H. Sayre, and Q. Tang. 2015. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med.7: 315ra189.

5. Shapiro, A. M. J., M. Pokrywczynska, and C. Ricordi. 2017. Clinical pancreatic islet transplantation. Nat. Rev. Endocrinol.13: 268–277.

6. Apostolopoulos, V., and J. Matsoukas. 2020. Advances in Multiple Sclerosis Research–Series I. Brain Sci.10: 795.

7. Chountoulesi, M., and C. Demetzos. 2020. Promising Nanotechnology Approaches in Treatment of Autoimmune Diseases of Central Nervous System. Brain Sci. 10: E338.

8. Metaxakis, A., D. Petratou, and N. Tavernarakis. 2020. Molecular Interventions towards Multiple Sclerosis Treatment. Brain Sci.10: E2

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Sarah Colpitts

Sarah is a PhD student in the department of Immunology. Other than science-ing, she enjoys playing with her dog, winning card games and attempting to become the next Picasso by smearing paint on a canvas.
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