Autoimmune Diseases: An Alternative Application for Immunotherapy
Introduction
Autoimmune diseases are chronic conditions that result from aberrant immune function, where cells of the immune system target self- or autoantigens.1 This leads to the destruction of healthy cells or tissues affecting one or several organs. There are approximately 100 known autoimmune diseases, such as lupus, rheumatoid arthritis, type I diabetes, multiple sclerosis, and psoriasis. Collectively, these disorders affect approximately 12.5% of the world’s population, with women accounting for 78% of cases.2,3 However, researchers forecast that their incidence rate will continue to rise over the coming years. Physicians often prescribe immunosuppressant or anti-inflammatory drugs, such as corticosteroids, to patients with autoimmune diseases.4 Although these treatments can reduce symptoms, their general mechanisms also increase a patient’s susceptibility to infections and can produce several side effects including cancer.
Below this information is an illustration of the female anatomy with labels connecting common autoimmune diseases with the organs they afflict including multiple sclerosis and nerve cells, Graves’ disease and the thyroid gland, rheumatic fever and the heart, diabetes and the pancreas, psoriasis and the skin, Guillain-Barre syndrome and the muscles in the legs, Hashimoto's thyroiditis and the thyroid gland, vasculitis and the blood vessels, Addison's disease and the adrenal glands, IBD or celiac disease and the intestines, rheumatoid arthritis and the joints, and lupus and the skin, joints, and brain.
The Link between Autoimmune Disease and Cancer
To maintain health, the body must delicately balance immune function.5 While overactivity leads to autoimmune diseases, too little activity promotes pathogen and cancer growth. As a result, scientists frequently think of autoimmune disease and cancer as opposite ends of a scale, and treatment for either disease can tip the scale too far in the other direction. Consequently, scientists develop antigen- and disease-specific therapies for autoimmune diseases and look to existing cancer treatments, such as immunotherapy, for inspiration.6
Below this text is an illustration of a double-pan balance with healthy immune function represented by a balanced scale and autoimmune disease and cancer represented by an unbalanced scale.
Generating Immunotherapies for Autoimmune Disease Treatment
Immunotherapies are drugs or cell-based therapies that alter immune activity to help treat diseases. While scientists employ cancer immunotherapies to boost immune function, autoimmune disease immunotherapies dampen immune responses and include tolerogenic vaccines, nanoparticle-based treatments, therapeutic antibodies, and adoptive cell therapies.
Tolerogenic vaccines
Tolerogenic vaccines train the immune system to stop responding to a specific autoantigen through repetitive exposure and thus generate immune tolerance.7 Scientists have developed several inverse vaccine platforms including those employing DNA, mRNA, protein, and peptides.8 Recently, researchers designed new tolerogenic protein vaccines by conjugating autoantigens with a glycosylated polymer.9 This tag mimics the natural marks that the liver adds to molecules derived from aged cells to prevent the body from reacting to them. Scientists have successfully used this approach to reduce the symptoms of a multiple sclerosis mouse model.
Next to this information is an illustration of an ampoule and a syringe.
Nanoparticle-based treatments
Researchers often use nanoparticles as vehicles for tolerogenic vaccines to increase the delivery of autoantigens or their encoding nucleic acids to tissues.7 Additionally, they can also coat nanoparticles with autoantigen-carrying major histocompatibility complex (MHC) class II molecules to induce helper T cells with receptors for these proteins to differentiate into regulatory T cells, which ultimately reduces autoimmune activity.10,11 Scientists have engineered these MHC class II molecule-coated nanoparticles to display peptides derived from collagen and showed that this therapy reduces joint inflammation in a mouse model of rheumatoid arthritis.
Next to this text is an illustration of a liposome carrying autoantigens.
Therapeutic antibodies
Scientists have used monoclonal antibodies for decades to treat patients with autoimmune diseases.12 These antibodies deplete immune cells, such as B cells, monocytes, or T cells, by binding to antigens present on their surfaces and inhibiting downstream signaling pathways leading to cell death. For instance, clinicians have established that teplizumab, which is a monoclonal antibody against the T cell marker CD3, delays the onset of type I diabetes in young patients.13 Researchers have also started designing bispecific antibodies that can bind to two antigens simultaneously to improve the efficacy of these treatments.14
Next to this information are illustrations of antibodies.
Adoptive cell therapies
Scientists have devised numerous types of adoptive cell therapies for the treatment of autoimmune diseases, such as repurposed chimeric antibody receptor (CAR) T cells, chimeric autoantibody receptor (CAAR) T cells, mesenchymal stromal cells (MSCs) with CARs (called CAR-MSCs), or CAR regulatory T (Treg) cells.
Adoptive Cell Therapy | Mechanism of Action | Preclinical Application |
Repurposed CAR T cells | Binds to disease-associated epitopes present on the surface of autoreactive immune cells to induce their death15 | Prevented type I diabetes development in a non-obese diabetic mouse model16 |
CAAR T cells | Binds to autoantigen-specific B cell receptors on the surface of autoreactive B cells leading to their death15 | Reduced skin blistering in a pemphigus vulgaris mouse model17,18 |
CAR-MSCs | Upon binding to the autoantigen, the cells increase immunosuppressive receptor expression and immunosuppressive cytokine production19 | Displayed improved localization and immunosuppressive activity in a mouse model of graft-versus-host disease compared to MSCs19 |
CAR Treg cells | Binds to autoantigen-expressing cells and secretes anti-inflammatory cytokines to help protect the cells from autoimmune activity15 | Decreased inflammation and disease symptoms in a mouse model of multiple sclerosis20 |
Above the table is an illustration of a CAR T cell.
References
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