Newer treatments for autoimmune disease are showing some promise, including peptide analogs that block autoantigen binding and inhibit soluble cytokines.
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Autoimmune disease affects over 50 million Americans, and millions more the world over, for an overall prevalence of about 3 percent. These are debilitating conditions, associated with significant pain, limitation of movement, and often, loss of independence.
Autoimmune disease is caused by a disruption in the central and peripheral mechanisms that operate to bring about a functional immune tolerance of self-antigens.
Thus, there is a severe and often permanent imbalance of pro- and anti-inflammatory activity underlying the autoimmune condition.
Many cells, signaling pathways, and cytokines play important roles through various mechanisms to maintain immune tolerance, such as the T regulatory cells, certain interleukins, and interferons.
This knowledge will shape possible treatments designed to restore immune tolerance. These include T cell anergy, exhaustion, and immune regulation.
Immunosuppression and Anti-Inflammatories
Conventional treatments for autoimmune diseases have focused on globally arresting the cycle of inflammation, using prostaglandin-cyclo-oxygenase pathway inhibitors, or immunosuppressive drugs for a nonspecific reduction in antibody production.
While these do mitigate the symptoms to some extent, they have potentially serious side effects. One paper comments, “The goal of ongoing research in immune tolerance is the development of autoantigen-specific treatments that allow for the specific blockade of the deleterious effects of self-reactive immune-cell function while maintaining the ability of the immune system to clear non-self antigens.”
Currently, soluble receptors, monoclonal antibodies, and molecular mimics have come into widespread use to phase out or at least reduce the dosage of conventional immunosuppressive therapy.
Induction of Immune Tolerance – Tolerizing Therapies
Currently, it is known that T cell receptors cannot differentiate self from non-self antigens. Most T cells with high-affinity receptors that react to self-antigens are eliminated during thymic development, but a few do persist in healthy individuals. These are restrained by peripheral tolerance mechanisms.
Tolerizing therapies seek to induce immune tolerance primarily due to an increase in antigen-specific Tregs relative to antigen-specific effector T cells.
One tolerizing therapy makes use of T cell or T cell peptide vaccinations, using either attenuated activated T cells to suppress the actual disease-causing T cells. T cell receptor peptides have also been used instead of the whole T cell for the same purpose. The early results have been promising but further testing is required.
Desensitization by the administration of antigens like oral collagen type II or certain disease-specific autoantigen peptides is another tolerizing therapy that is currently being tested by clinical trials.
Coupling such antigens to cells, nanoparticles, and microparticles may result in a higher induction of antigen-specific tolerance.
Monoclonal antibodies, along with engineered fusion proteins and small molecules, are called biologics and are now standard therapy in many autoimmune conditions.
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These biologics work in many ways, such as blockade of cytokine pathways, depletion of T or B cells, and enhancement of immunomodulation. This makes them suitable for the therapy of several autoimmune disorders for which inflammation is mediated via TNF, IL-1, IL-6, IL-12, and IL-23.
Monoclonal antibodies often stimulate the immune system to produce antibodies against them, limiting their usefulness. This motivated the development of humanized or chimeric monoclonal antibodies by molecular engineering. However, this can push up the already high cost of these drugs.
Secondly, the effect of these drugs is transient.
They can also produce undesirable long-term side effects on the immune system. For instance, monoclonal antibodies directed against the IL2Rα receptor could also eventually wipe out the modulatory Treg cells, causing the emergence of type-1 autoimmune disease.
Newer experimental biological drugs may block certain specific immune pathways.
One therapy involves the use of peptide analogs that disrupt the formation of the MHC-autoantigen-T cell receptor complex. These drugs inhibit the autoimmune process in four ways:
- The peptide may antagonize the T cell binding wildtype antigen, which blocks antigen presentation to the adaptive immune system. This prevents T cell activation and loss of immune response to the autoantigen.
- The peptide may inhibit the proliferation of the T cells.
- The peptide may stimulate neutral T helper cells to differentiate into Th2 cells, which are anti-inflammatory in function (immune deviation)
- The peptide may stimulate the differentiation of a specific clone of regulatory T cells that bind to the autoantigen and suppress the resulting autoimmune response – bystander immunity
As a result, such analogs can block autoimmune-triggered inflammation, inhibit the autoimmune T and B cells that are generating an adaptive immune response, or stimulate the development of tolerance by induction of modulatory responses for the autoantigen in question.
Peptide analogs can also inhibit soluble cytokines or their receptors, blocking the further onset of inflammation and tissue destruction. Thus, they are thought to hold promise for the eventual replacement of monoclonal antibodies.
Peptides are inexpensive to manufacture, have a simple synthesizing process, involve a lower risk of immune stimulation via the hyperactivation of autoimmune T cells, or even more severe side effects caused by the unwanted actions of these antibodies on the targeted cytokines, cytokine receptors or cells.
Other Experimental Techniques
T regulatory cells
An approach to personalized T regulatory (Treg) cell populations are also being developed to ensure the stable suppression of autoimmunity, but is still at a very early stage. Treg cells are CD4 T cells which express CD25, the alpha chain of the IL-2 receptor, at a high level, with the transcription factor Foxp3. These suppress self-antigen-directed autoimmune responses.
Treg cell therapy has been used in organ transplants to prevent severe acute graft-versus-host disease (aGVHD).
Cell therapy can be made very specific, can renew itself, and is regulated endogenously, but requires extensive development and testing. Other cell-based therapies include B cells, macrophages, and dendritic cells from the innate immunity compartment.
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Gene therapy involves the introduction of functional genes into the body to treat a disorder caused by defective genes, by inactivating or replacing them.
Mesenchymal stem cells
Mesenchymal stem cells are known to be multipotent as well as having strong anti-inflammatory properties and the ability to induce regeneration. With successful results from early testing, randomized clinical trials need to be carried out, so that the role of these cells in autoimmune disease can be pinpointed.
A protein called PD-1 is expressed in immune cells like B and T cells, which modulates the immune system. The impaired function of this protein plays a major role in the pathogenesis of various autoimmune conditions.
Experiments on mice show that a specific anti-PD-1 antibody can selectively ablate only the dysfunctional cells, restoring the balance of the immune system. Scientists are now looking for the human version of the antibody, which will hopefully give the same results as the mouse version does.
Inhibition of Costimulatory Pathways
One of these drugs is abatacept, which blocks the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) pathway. Abatacept is a CTLA-4–immunoglobulin (Ig), which directly prevents the binding of costimulatory ligands B7-1 and B7-2 to the T cell CD28 receptor.
Thus, it prevents costimulation mediated by CD28. This drug is used in RA and psoriasis. This modality is better at preventing disease than treating it in preclinical experiments, perhaps because it cannot block memory cells or previously activated T cells.
The future of autoimmune disease therapy
In the future, a combination of therapies for autoimmune disease will probably be preferred, exploiting the different mechanisms of action and choosing complementary methods to arrive at the most effective therapy with the least redundancy.
A sequence of approaches could be used to first achieve remission and then restore immune tolerance, thus ensuring the disease process is not reactivated. Individual variability and the possibility of unwanted synergism may complicate such combinations, which mandates careful clinical testing.
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