Autoimmune Disorders

Autoimmune disorders occur when the immune system, which typically protects the body from harmful invaders, mistakenly attacks its own healthy cells and tissues. This misdirected immune response is often triggered by a combination of genetic predisposition and environmental factors. Autoimmune diseases can target various organs and systems, leading to a wide range of conditions such as rheumatoid arthritis, lupus, and Type 1 Diabetes. The complexity of these diseases lies in the immune system’s inability to distinguish between foreign and self-antigens, causing chronic inflammation and tissue damage. Treating autoimmune disorders is challenging because, in principle, new therapies should suppress the autoimmune condition without compromising the body’s overall immune defense. Additionally, highly individualized treatments are necessary to address the diversity and unpredictability of these diseases, making effective long-term management very difficult to achieve.

Type I Diabetes

Diabetes is now one of the most common non-communicable diseases globally. It is the fourth or fifth leading cause of death in most developed countries and there is substantial evidence that it is epidemic in many developing and newly industrialized nations. Complications from diabetes, such as coronary artery and peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure and blindness are resulting in increasing disability, reduced life expectancy and enormous health costs for virtually every society. Diabetes is certain to be one of the most challenging health problems in the 21st century.

Understanding Type 1 Diabetes

Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by the immune system’s targeted destruction of pancreatic beta cells.

This leads to a progressive reduction in insulin secretion, resulting in persistent hyperglycemia and associated metabolic disturbances in lipid and protein metabolism.

Activated B cells interact with CD4+ and CD8+ T cells, as well as dendritic cells (DCs). Antigen presentation by B cells and DCs drives the activation of β-cell-specific T cells. In addition, the exposure of B cells to β-cell autoantigens leads to the production of islet-targeting autoantibodies, which serve as biomarkers of asymptomatic disease.

There is no cure for T1D, and clinical management of the disease is particularly challenging due to the need for lifelong reliance on exogenously injected insulin. Patients must administer insulin subcutaneously to maintain adequate basal and prandial insulin levels, aiming to recreate physiological insulin profiles and prevent life-threatening complications such as ketoacidosis and hyperglycemia. However, one of the most significant barriers to achieving optimal glycemic control is hypoglycemia, which occurs when blood glucose levels fall below 70 mg/dL (3.9 mmol/L). Hypoglycemia not only impacts the quality of life but also poses risks of acute complications, including seizures, coma, and even heart attacks. The fear of hypoglycemia often leads patients to maintain higher-than-desired glucose levels, further complicating metabolic control.

Managing T1D requires patients to make numerous daily decisions, including frequent self-monitoring of blood glucose (SMBG), precise carbohydrate counting, calculating the correct insulin-to-carbohydrate ratio, and estimating the impact of physical activity, illness, and stress. These demands can lead to a significant deterioration in quality of life. Furthermore, subcutaneous insulin administration is inherently non-physiological, as it disrupts the natural portal-to-periphery insulin concentration ratio, resulting in relative peripheral hyperinsulinemia and frequently unmatched insulin levels for the prevalent glucose concentrations. Consequently, T1D management is fraught with both long-term and short-term complications, including cardiovascular disease, stroke, neuropathy, hyper- or hypoglycemia, diabetic seizures, and ketoacidosis, all of which may require hospitalization and intensive medical intervention.

The estimated number of new cases of type 1 diabetes in children (<15 years of age) per 100,000 individuals in 2015.

The Challenges of Treatment

The clinical management of T1D is particularly challenging due to the need for lifelong reliance on exogenously injected insulin. Patients must administer insulin subcutaneously to maintain adequate basal and prandial insulin levels, aiming to recreate physiological insulin profiles and prevent life-threatening complications such as ketoacidosis and hyperglycemia. However, one of the most significant barriers to achieving optimal glycemic control is hypoglycemia, which occurs when blood glucose levels fall below 70 mg/dL (3.9 mmol/L). Hypoglycemia not only impacts the quality of life but also poses risks of acute complications, including seizures, coma, and even heart attacks. The fear of hypoglycemia often leads patients to maintain higher-than-desired glucose levels, further complicating metabolic control.

Managing T1D requires patients to make numerous daily decisions, including frequent self-monitoring of blood glucose (SMBG), precise carbohydrate counting, calculating the correct insulin-to-carbohydrate ratio, and estimating the impact of physical activity, illness, and stress. These demands can lead to a significant deterioration in quality of life. Furthermore, subcutaneous insulin administration is inherently non-physiological, as it disrupts the natural portal-to-periphery insulin concentration ratio, resulting in relative peripheral hyperinsulinemia and frequently unmatched insulin levels for the prevalent glucose concentrations. Consequently, T1D management is fraught with both long-term and short-term complications, including cardiovascular disease, stroke, neuropathy, hyper- or hypoglycemia, diabetic seizures, and ketoacidosis, all of which may require hospitalization and intensive medical intervention.

The Search for Effective Therapies

The pathophysiology of T1D is complex, involving multiple defects in immune regulation and inherent problems within the β cells themselves. Despite numerous efforts to address T1D from various angles, successful long-term solutions have remained elusive. Stem cell therapies have been at the forefront of these interventions, utilizing a wide range of cell sources, including bone marrow, embryonic, hepatic, pancreatic, adipose-derived, and induced pluripotent stem cells. Other approaches have involved lymphocytes conditioned by cord blood-derived stem cells, autologous umbilical cord blood, and combined cell therapies. However, these studies have led to the general conclusion that reversing T1D requires novel therapeutic strategies capable of tackling the disease from multiple fronts simultaneously. Ideal interventions should be specific, effective, long-lasting, and have minimal adverse effects. A critical challenge in developing new therapies for T1D is the need to reestablish immunological tolerance while simultaneously generating new β cells. 

Alopecia Areata

Alopecia areata (AA) is a common autoimmune disorder affecting millions of people worldwide. It manifests as a sudden non-scarring loss of hair without visible skin inflammation. Alopecia usually starts abruptly with one or multiple patches of hair loss that usually enlarge in a centrifugal pattern. The entire scalp (alopecia totalis) or body (alopecia universalis) can be affected. Although the exact etiology and pathogenesis of AA are not well understood, loss of immune privilege in hair follicles (HFs) is believed to play a key role in the pathogenesis of AA. The histopathological finding of peri- and intra-follicular infiltration of CD4+ and CD8+ lymphocytes, targeting anagen stage HFs, suggests T cell involvement in the pathogenesis of AA. Additionally, the expression of a wide array of proinflammatory cytokines and molecules is associated with collapse of immune privilege in HFs and AA development.

The natural history of AA is unpredictable, which contributes to the devastating nature of the condition and the serious impact it can have on the quality of life of the patients. Alopecia areata affects nearly 2% of the general population at some point during their lifetime. No cure currently exists for AA, and available treatments are mainly unsatisfactory either because of lack of efficacy or due to serious side effect potential. Additionally, none of the currently available therapies can prevent future relapse of the disease. Thus, development of an effective, long-lasting treatment is highly desirable for patients suffering from AA.

Psoriasis

Psoriasis is one of the most common recurrent chronic inflammatory skin diseases, affecting 2% to 3% of the general population. Recent studies demonstrated that interleukin-23 (IL-23) T helper 17 (Th17) pathway is linked to psoriasis. It is reported that inflammatory myeloid dendritic cells expressing IL-23 initiate a set of signals that are crucial for the development and maintenance of Th17. The activated Th17 cells further secrete IL-17 and IL-22, which promote further recruitment of immune cells, keratinocyte proliferation, and sustained chronic inflammation. There are several commercially available biological monoclonal antibodies (LY-2439821, AMG-827, and AZ17) at different phases of human clinicaltrials, which target the IL-23/IL-17 axis. Although the use of these injectable biologics is far more effective than other treatments, the cost and high risk of side effects make them still less desirable. This is because patients treated with anti-IL-12 and/or IL-23 cytokine showed potential opportunistic infections such as salmonellosis and mycobacterial. These reports showed that immunity against these microorganisms depends on the expression of IL-12 and/or IL-23. As such, there is still a need to find a new strategy through which psoriasis can be treated without compromising the functionality of the immune system and any potential side effects.