Our immune system guards us against pathogenic invaders and foreign cells. On rare occasions, however, it mistakes certain cells of the body and makes rogue autoantibodies against the body’s own cells. This results in an autoimmune disease. According to current estimates, there are 80 to 100 known autoimmune diseases. This family of diseases are rather varied and can affect any part of the body, with symptoms including but not limited to impaired eyesight, skin lesions and rashes, joint pains, weakened muscles, and nerve damage.
According to a conservative estimate by the Autoimmune Registry, more than 14 million Americans suffer from an autoimmune disease. While we do not understand the cause of each autoimmune disease, they appear to affect women more frequently than men. The increased susceptibility of women is evidenced by the fact that roughly 4 out of every 5 autoimmune patients are female.
What causes an autoimmune disease?
Rogue antibodies made by the over-reactive immune system attack and injure a tissue or organ, causing inflammation. For example, in the case of Sjögren’s syndrome, the mucous membrane and secretory glands in the eyes and mouth are affected. This results in a decreased production of saliva and tears, leading ultimately to excessive dryness, eyesight disorders, and poor oral health.
Genetic predisposition to autoimmune diseases may exist; for example, type 1 diabetes mellitus has a higher incidence rate among Scandinavians (35/100,000 individuals per year). At the same time, exposure to certain environmental factors (e.g., exposure to toxins, excessive stress, smoking) can trigger the onset of symptoms or worsen existing symptoms.
What are the treatment options for autoimmune diseases?
The autoimmune disease family is rather broad in terms of disease severity. While all autoimmune diseases affect quality of life and many shorten lifespan, some have milder phenotypes (e.g., many cases of type 1 diabetes mellitus) whereas others can be fatal (e.g., autoimmune myocarditis, which causes inflammation of cardiac tissue).
As cures for autoimmune diseases are lacking, mitigation of symptoms is the most common treatment option. Most autoimmune diseases have a rhythmic pattern of flare-ups and subsequent remission. Immune-suppressing drugs are frequently used to decrease the body’s overactive immune response, as happens in autoimmune diseases. However, a major downside of using immunosuppressants is increased susceptibility to contracting various infections and a subdued immune response to infectious pathogens.
Glucocorticoids and nonsteroidal anti-inflammatory drugs (NSAIDs) are administered to curb the body’s inflammatory response. Dehydroepiandrosterone (DHEA), an endocrine hormone, is also administered for certain patients with systemic lupus erythematosus (SLE). Although DHEA was found to reduce flare-ups, it comes with a plethora of side effects. Certain drugs like methotrexate and cyclophosphamide, which are used frequently in chemotherapy, have also been repurposed in aid of autoimmune patients, as they suppress the immune system.
The administration of immune-suppressing drugs for autoimmune disease is a tightrope walk that seeks to ensure a fragile balance of inflammatory responses of the immune system — the goal being enough immune response to guard the body against pathogenic invaders and yet not destroy the body’s own cells.
What are recent developments to treat autoimmune diseases?
As Nicolas Poirier, the chief scientific officer of OSE Immunotherapeutics, explains, “Not all immune cells are pathogenic. There are ‘bad guys’ of course, but there are also ‘good guys’ in the immune system, which help to fight or control autoimmune attacks.”
The fight against the “bad guys” for autoimmune diseases has involved the exploration of diverse therapeutic routes. All these approaches involve selectively activating or inhibiting a specific type of immune cell or immune pathway, without suppressing the complete immune system and compromising the patient’s health against infections. In this article we summarise current and emerging modalities used to treat autoimmune diseases, along with examples of key approaches that have been used.
Monoclonal antibodies:
Monoclonal antibodies (mAbs) are used as an immunotherapy against multiple cancers. These lab-generated antibodies, much like those generated by our immune system, are used in a number of ways ranging from neutralization of self-antigens, interleukin (IL) inhibitors, antibody-dependent depletion of B and T cells, and also as activation of costimulatory receptors. Key approaches that have been used include:
- Inhibition of cytokine signaling
- Inhibition of co-stimulatory pathways
- Prevention of tissue homing
The below table summarizes some of the more successful mAbs being used as a therapy for autoimmune diseases.
Inhibition of cytokine signaling
Cytokines function as molecular soldiers of the immune system, initiating a pro-inflammatory or anti-inflammatory response. Tissue damage as a result of chronic inflammatory response can be minimized by specific cytokine blockers that induce pro-inflammatory responses.
Inhibition of tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, has proved to be a beneficial therapy for juvenile idiopathic arthritis (JIA), psoriasis, and Crohn’s disease. This has led to generation of various molecules targeting TNF-α, with five such drugs gaining approval for clinical use: infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol. However, inhibition of TNF-α is not beneficial for multiple sclerosis (MS) patients, proving that a one-size-fits-all therapy will not work for this diverse family of diseases.
Inhibition of co-stimulatory pathways
A coordinated orchestration of events culminates in activation of T cells to elicit an immune response. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4-Ig) is a fusion protein that is used as a therapeutic tool in inhibiting CD28-B7 mediated T cell activation and subsequent immune response. Thus, CTLA-4–Ig became a candidate to be tested as a therapeutic for autoimmune diseases.
Abatacept and alefacept are two such drug derivatives of CTLA-4-Ig. CTLA-4-Ig was first tested for psoriasis vulgaris, an inflammatory skin disease. With extensive clinical trials for other autoimmune conditions, abatacept (Orencia), developed by Bristol-Myers-Squibb, is now used as a drug for rheumatoid arthritis (RA). Abatacept also slows the progression of type 1 diabetes mellitus. Presently, abatacept is being assessed for benefits against autoimmune hepatitis.
Prevention of tissue homing
Inflammation and tissue damage can only occur if specific immune cells (effector T cells) can reach the concerned tissue and accumulate there. This process is called tissue homing. Molecules that can prevent tissue homing of effector T cells work by one of two modes: a) inhibition of T cell activation or b) prevention of the migration of effector T cells to the inflammatory site.
Natalizumab is the first such inhibitor molecule that proved to be therapeutic for multiple sclerosis patients, decreasing the rate of relapse. It is also used in treating Crohn’s disease. Multiple drugs are being developed that work by this mode of action for different autoimmune diseases. One caveat of this category of molecules, however, is that they still function as immunosuppressants.
Peptide analogs and peptidomimetics:
Peptide-based immunotherapy for autoimmune diseases work in a multitude of ways, including:
- Mimicking naturally processed antigens
- Suppressing pro-inflammatory cytokine production
- Upregulating anti-inflammatory cytokines like IL-10
- Inhibiting proliferation of specific T cells
- Inducing bystander effect by stimulating specific regulatory T cells, and thereby suppressing the resultant autoimmune response
- Inducing production of neutral T helper cells (Th2 cells), which assists in inducing peripheral tolerance
Among the most popular synthetic peptides, glatiramer acetate (Copaxone) tops the list, being a standard drug now for relapsing MS patients. Much like Copaxone, a copolymer called poly (Y, F, A, K) (YFAK) is another synthetic peptide found to decrease relapses in MS patients. Another peptide analog that holds tremendous promise in ongoing clinical trials is phosphopeptide P140 (Lupuzor) for the treatment of SLE.
Peptide analogs have gained favor, as they are inexpensive to produce, have few to no side effects, and entail lower overall risk. Peptide analogs are all the more promising, as they are stable molecules, can be delivered to the site of action via nanoparticles, and can also be administered by noninvasive routes like nasal or oral ingestion.
Cell-based therapies:
Just as specific molecules (be it monoclonal antibodies or peptidomimetics) are being engineered as drugs for a multitude of disease conditions, another emerging technology has shown immense promise in the last few years. This therapy utilizes the concept of tinkering with the body’s immune system so that it helps manage the condition. It relies on taking the patient’s immune cells and modifying them in a certain way, then transplanting them back into the patient. These cell-based therapies can be imagined as “living drugs” that can specifically remove the rogue cells of the immune system that attack the body and cause autoimmune diseases.
Two key arms of cell-based therapy for autoimmune diseases are:
- Chimeric antigen receptor T (CAR T): In many autoimmune diseases, a T cell goes rogue and secretes pro-inflammatory cytokines like interferon gamma (IFN-γ) and TNF-α and also induces cellular apoptosis. To address these conditions, CAR T cell–derived immunotherapy, whereby CAR T cells can release immunosuppressive cytokines like transforming growth factor β1 (TGF-β1) and interleukin 10 (IL-10), is being investigated. Clinical trials involving CAR T cell–based therapy are currently ongoing for myasthenia gravis and SLE.
- Chimeric autoantibody receptor T (CAAR T): Some autoimmune diseases result from autoantibody-mediated tissue destruction, as in the case of Sjögren’s syndrome. CAAR T cell therapies are being investigated for these types of autoimmune diseases. CAAR T cell–based therapy for pemphigus vulgaris as well as for myasthenia gravis are in preclinical development.
One major caveat of such cell-based therapies is that they can be prohibitively expensive due to their complex, time-consuming, and personalized nature.
Conclusion:
Autoimmune diseases are chronic conditions that affect roughly one in every 20 people. Living with any autoimmune disease can be mentally and physically challenging. For some patients, the financial burden of living with a debilitating disease is astronomical and provides a challenge in itself. At present, there is no treatment for the underlying causes of autoimmune diseases, only the symptoms. In this article, we have highlighted both current treatment options as well as promising new approaches under development. It lies in the interest of society at large to find actual cures for autoimmune diseases.
