Analytical Essay on Immune System Issues: Tolerogenic Immune Modulation of Type I Diabetes

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Autoimmune Diseases

According to the Office of Women’s Health at HHS, there are over 80 different types of autoimmune diseases, and around 5-8% (400 Million People) of the world’s population is affected by them1,2. However, an autoimmune disease is not a specific condition, rather it’s an umbrella term that encompasses multiple diseases such as rheumatoid arthritis, multiple sclerosis, celiac disease, lupus, and type I diabetes1. Diseases like these occur when the immune system is unable to tell the difference between normal and unhealthy cells, leading to the attack of healthy tissues and organs, which affects regular bodily functions1-3.

There are many treatments for autoimmune diseases, however, most focus on treating the symptoms of the disease rather than addressing their root cause2,3. One example of a treatment would be autoimmune drugs. In fact, there are over 300 drugs currently in the research pipeline of various pharmaceutical and research, including drugs such a biotherapeutics, corticosteroids, and immunosuppressive agents1-4. These ameliorate most effects of autoimmune diseases but are unable to stop the diseases due to their chronic nature. As a result, patients are known to become reliant on the drugs which can result in developing resistance to these drugs3. There is also a high rate of drug site effects and toxicity which can affect patient adherence to the proposed drug regimen3,4. There are also biosimilars, which are a cheaper alternative to autoimmune drugs (similar to generics). These provide the same positives as autoimmune drugs, in addition to being cheaper alternatives. However, many biosimilars contain the same negatives as autoimmune drugs; as well as the fact that most are not available for sale due to legal litigation from major pharmaceutical companies3. Another available treatment for autoimmune disorders is stem cell transplantation5. Stem cell transplantation can be used to correct the immune system, modulate its effect, and correct the somatic version of the gene responsible for autoimmune targeting5. Thus, one can modulate the autoimmune disease while also giving rise to tissue regeneration at the injured or defective tissue/organ site by supplying the affected site with healthy stem cells4,5. However, not much is known about this treatment method because many of the treatment mechanisms remain unclear, and this can lead to various side effects when applied to a broader population4. Finally, one can also treat autoimmune diseases using micronutrients. Nutrients such as Zinc and Vitamin D are helpful in balancing immune function by either treating or preventing the established disease6. This method provides a cheap and broad alternative to balancing the immune system, instead of suppressing it, unlike other treatment methods (biotherapeutics) which reduces exposure to other diseases3,6. However, it is not a guarantee that nutrients will work with all patients6. Also, there are more factors to autoimmune diseases than just nutrient imbalances; thus, nutrients are often used as supplements to other major therapies, instead of being used as a sole treatment method6.

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Type I Diabetes

In this proposal, we plan to focus on Type I diabetes (T1D), which is one of the most prevalent types of autoimmune diseases3. According to the World Health Organization, nearly 35 million patients suffer from T1D, and due to its increasing prevalence, predictions believe this number will double by 20253. This is supported by population-based registries which have demonstrated a global variation in the incidence, prevalence, and temporal trends of T1D3.

From a pathological perspective, T1D is an autoimmune disease where pancreatic ß-cells are attacked and destroyed by autoantigens, resulting in depleted insulin levels3,4. In terms of the current research, there is significant credible evidence that highlights autoimmunity as being one of the root causes for T1D3,4. This is shown by the infiltration of antigen presenting macrophages, dendritic cells, as well as B/T lymphocytes into the pancreatic islets3,4. By destroying these ß-cells, there is a lower level of insulin secretion which leads to an elevation in blood glucose levels, resulting in hyperglycemia1,3,4. This is because insulin is used to facilitate glucose uptake in cells; and without insulin, glucose is unable to enter the cell, leading to cell starvation and eventual death if the cell is unable to utilize and break down this glucose for energy3,4.

However, like other autoimmune diseases, T1D cannot be currently “cured.” Most treatments focus on alleviating the symptoms, as mentioned before2-4. The most popular treatment method for T1D is exogenous insulin2,3. Exogenous insulin involves providing the patient with an external insulin source which is injected in order to control the patient’s blood sugar levels2,3. However, exogenous insulin is an expensive alternative in addition to the fact that some patients can develop resistance to their insulin regimen2,3. There are also antigenic and non-antigenic preventative strategies such as the replacement of ß cells via transplantation/regeneration; but, like mentioned before, the transplantation treatment mechanisms remain unclear, and this can lead to various side effects when applied to a broader population3,5. Therefore, an ideal intervention for T1D would require a method to halt the autoimmune response4,5.

Novel Approaches to T1D Treatments

Current novel approaches to the treatment of T1D have begun to focus on T-regulatory cells (Treg)4,8. This is because Tregs can be found at the forefront of the mucosal immune system, which is responsible for regulating the body’s adaptive immune system8. In this mucosal immune system, there is a high concentration of immune modulatory cells which can be found within the gut, nasal, and upper respiratory epithelia8. These immune modulatory cells have been found to be important when it comes to suppressing the pathological immune response that is characterized by T1D4,7,8. To target these regulatory cells, a vaccination with an autoreactive antigen or peptide is used to suppress the immune system by inducing Treg upregulation which can aid in the prevention of various autoimmune diseases, including T1D4,7,8. This method was used in Zhang et al. where an intraperitoneal (IP) tolerogenic vaccination was induced by using an insulin peptide B9-23 which was combined with dexamethasone. This treatment method induced antigen specific Treg upregulation which effectively reduced the effector CD4 memory T cell (Tm) population and prevented the development of T1D4. However, this delivery method, IP, has proven to be complex, requiring multiple IP injection over the course of a week. It also requires a needle that can penetrate the abdominal regions of the mice, in order to reach the peritoneal mucosal lining where the peptide and biologic are deposited4. To get around this, another simple delivery method could be used to target other Treg cell populations, because one only needs to reach the mucosal lining where there is a large abundance of Treg cell populations8,9. In other types of autoimmune diseases, researchers have targeted the oral and nasal mucosal linings, which also contain a large Treg cell population9,10. In these studies, they have been able to ameliorate or even prevent diseases such as lupus and autoimmune encephalomyelitis via the mentioned delivery routes with the same mechanism of action as mentioned in the treatment of T1D9,10. Thus, the question rises whether it would be possible to treat T1D using the mentioned delivery routes?

An Intranasal Hydrogel Delivery Platform

For the nasal route, hydrogels or nanoparticles are the most commonly used delivery carriers11. Hydrogels function as a biologically compatible carrier platform that can preserve the activity of the biotherapeutic11. They can be sprayable & muco-adhesive which helps increase drug permeation; and because they need to deliver the therapeutic beyond the tight junctions of the nasal epithelium, they are capable of transiently enhancing permeability by opening these tight junctions when partnered with the addition of permeability agents13,14. Therefore, hydrogels provide a simple and scalable platform that can be used to deliver therapeutics for T1D via the intranasal route. Like a nasal vaccine, the nasal hydrogel route provides easy administration access while still being able to target the Treg cells inside the nasal mucosa, which may be involved in suppressing the autoimmune nature of T1D. Therefore, we propose using an intranasal hydrogel delivery platform to deliver a known drug/peptide combination to target the Treg cells that would be located in the nasal mucosa. In doing so, we believe that the development of T1D would be ameliorated or prevented as seen by papers that focused on other autoimmune diseases with similar pathologies8,9. If this is the case, this research would provide a T1D treatment with a simple and scalable alternative, that not only treats the disease’s symptoms, but also prevents the development of the disease. And, as mentioned before, with T1D increasing in incidence and prevalence3, a successful solution would prove to be very marketable because there are no current alternatives to “curing.” T1D. In addition to this, as shown by the research, this platform is scalable to other autoimmune diseases,1,3,8-10. Thus, the potential to move the platform to treat other autoimmune diseases that follow similar pathologies could prove to be very lucrative.

References

  1. BASTICK, E. Autoimmune diseases: More targeted therapies on the horizon. Managed Healthcare Executive 28, 6 (2018).
  2. Singh, P. et al. in Therapeutic Perspectives in Type-1 Diabetes (ed SINGH, P. et al.) 29-78 (Springer Singapore, Singapore, 2016).
  3. Singh, P. et al. in Therapeutic Perspectives in Type-1 Diabetes (ed SINGH, P. et al.) 1-6 (Springer Singapore, Singapore, 2016).
  4. Zhang, J. et al. Tolerogenic vaccination reduced effector memory CD4 T cells and induced effector memory Treg cells for type I diabetes treatment. PLoS ONE 8, e70056 (2013).
  5. Vu, N. B. & Van Pham, P. in Stem Cell Transplantation for Autoimmune Diseases and Inflammation (ed Pham, P. V.) 3-25 (Springer International Publishing, Cham, 2019).
  6. Wessels, I. & Rink, L. Micronutrients in autoimmune diseases: possible therapeutic benefits of zinc and vitamin D. The Journal of Nutritional Biochemistry 77, 108240 (2020).
  7. Serra, P. & Santamaria, P. Nanoparticle-based approaches to immune tolerance for the treatment of autoimmune diseases. Eur. J. Immunol. 48, 751-756 (2018).
  8. Gill, N., Wlodarska, M. & B, B. F. The future of mucosal immunology: studying an integrated system-wide organ. Nat. Immunol. 11, 558 (2010).
  9. Wu, H., Quintana, F. & Weiner, H. Nasal Anti-CD3 Antibody Ameliorates Lupus by Inducing an IL-10-Secreting CD4+CD25−LAP+ Regulatory T Cell and Is Associated with Down-Regulation of IL-17+CD4+ICOS+CXCR5+ Follicular Helper T Cells. Journal of Immunology 181 (2008).
  10. Ochi, H., Abraham, M. & Ishikawa, H. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+CD25−LAP+ T cells. Nature Medicine 12, 627-635 (2006).
  11. Salatin, S. et al. Hydrogel nanoparticles and nanocomposites for nasal drug/vaccine delivery. Journal of Pharmacal Research 39, 1181-1193 (2016).
  12. Wu, S. et al. Novel thermal-sensitive hydrogel enhances both humoral and cell-mediated immune responses by intranasal vaccine delivery. European Journal of Pharmaceutics and Biopharmaceutics 81, 486-497 (2012).
  13. Stoltz, J. et al. Effect of soybean-lecithin as an enhancer of buccal mucosa absorption of insulin. Bio-Medical Materials & Engineering 22, 171-178 (2012).
  14. Arnold, J. J., Fryberg, M., Meezan, E. & Pillion, D. Reestablishment of the nasal permeability barrier to several peptides following exposure to the absorption enhancer tetradecyl‐β‐D‐maltoside. Journal of Pharmaceutical Sciences 99, 1912-1920 (2009).

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