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Treatment of autoimmune diseases by modulation of T regulatory cells (Treg) with interleukin 2

Autoimmune diseases

Autoimmune diseases are caused by immune cells. They attack the host tissues they are supposed to protect. Recent advances suggest that maintaining balance of effector and regulatory immune function is critical to eliminating autoimmunity. New therapies, including regulatory treatment of T lymphocytes, costimulation blockade, antigen-specific immunotherapy and interleukin-2 route manipulation, attempt to restore this balance and prevent the imbalance of overall immunosuppression. [1]

T regulatory cells

Although there are several mechanisms for controlling immune responses directed to antigens, one of the most important is based on a unique T cell population called Regulatory T cell (Treg). Treg are a subset of CD4 + T cells. They express high levels of CD25 receptor for interleukin-2 (IL-2) and transcription factor Foxp3. Treg cells have clearly demonstrated that they suppress pathogenic immune responses directed to their own antigens.Both in mice and humans with dysfunctional Treg develop autoimmune disease. Foxp3-deficient mice develop de novo autoimmune thyreoiditis, gastritis, dermatitis, diabetes and inflammatory bowel disease and die at 3 to 4 weeks of age. People who have mutations in the Foxp3 gene have a similar phenotype. They develop autoimmune enteropathy and endocrinopathy that occur during the first few months of life. Without bone marrow transplantation, these patients usually die in childhood.

The role of Treg in preventing more frequent autoimmune diseases is the subject of intense current interest that has led to the emerging paradigm: The result of all immune responses, including those directed to antigens, is determined by the ratio of functional effector (or conventional) T cells to Tregs. [1]

Treg IL-2 therapy

IL-2 was originally seen only as a pro-inflammatory cytokine that promotes the proliferation and activation of naive T cells in their helper subgroups. IL-2 is also an important cytokine in regulating the transcription of growth and metabolic Treg cells. Due to high expression of high affinity IL-2R, it is believed that Treg may preferably expand under low IL-2 conditions. Treatment with low doses of IL-2 results in an increase in percentage of peripheral CD4 + CD25HighFoxp3 + T cells with increased suppressive function. In patients with graft versus host disease (GVHD) with 12-month IL-2 treatment, the researchers observed an increase in the number of CD4 + Treg cells. In patients with hepatitis C-induced vasculitis, the number of Treg cells was restored after low IL-2 dosing, and in 8 out of 10 patients there was a clinical improvement in their autoimmune disorder. It should be noted that no effect on the T effector population was observed in patients from these clinical trials. [2,3] A number of IL-2 alterations have been made that have brought IL-2 to the right target, including IL-2 fusion proteins, mutant IL-2 and IL-2 antibodies. Experimental and clinical studies using IL-2 are being extended to a variety of disease types, including solid organ transplantation. Although the efficacy and sustainability of IL-2 responsive cells in the control of disease activity are still not fully understood, the results of clinical trials will provide the basis for the most effective regimen for each disease. [4] New therapeutic approaches that prevent side effects and specifically target IL-2 to Tregs or Tfh cells will significantly improve the efficacy of therapies. One possible way to achieve this goal is to explore the potential synergistic effects of the combination of IL-2 administration with cytokine blockade. These prevent the Treg function or promote the development of Tfh cells. For example, while IL-2 signaling supports Treg's expansion and function, IL-6 suppresses Treg activity. Combined administration of IL-2 and anti-IL-6R could, in addition to increasing the activity of Treg, prevent undesired reactions of Tfh cells, thus preventing self-reactive GC B cell responses.

Conclusion

The use of IL-2 / anti-IL-2 complexes for target cells expressing CD25 and for Treg expansion is a promising strategy for promoting IL-2 mediated immunosuppression without inducing the expansion of autoreactive Teff cells. However, clinical trials have not been conducted to evaluate the clinical benefits and safety of IL-2 / anti-IL-2 complex immunotherapy in human patients. Therefore, future studies need to be conducted to further verify the results obtained on experimental animal models and to determine the appropriate dose of IL-2 / anti-human IL-2 complexes that can be safely administered to patients.[5]