Development of approaches for cellular immunotherapy of vitiligo

Vitiligo is an incurable autoimmune, poorly understood skin disease that affects 0.5-1% of the world’s population. To date, there are no targeted treatments for vitiligo. the disease is not classified as a fatal or life-threatening disease and, therefore, low funding for research on the disease. Conventional therapy includes topical use of corticosteroids and UVB phototherapy. These treatments do not always achieve the desired effect and have serious side effects. In the case when the patient’s skin is affected more than 70-80%, surgical melanocyte transplantation and complete depigmentation are used. In terms of quality of life, vitiligo negatively affects the quality and well-being of patients’ life. Stigma varies across cultures, with many patients experiencing psychological stress, low self-esteem and depression, which can lead to suicide attempts. The etiology of vitiligo is not fully understood. Vitiligo is caused by stress, genetic predisposition, environmental factors, and a melanocyte-specific autoimmune response. According to recent studies, the breakdown of immune tolerance is considered the main cause of the development of the disease, in which cytotoxic T cells attack the patient’s melanocytes. Most autoimmune diseases have a similar etiology associated with dysregulation of the immune response, including deficiency or impairment of Tregs activity. When there is a problem in recognizing its own or foreign antigens, the immune system nonspecifically destroys the cells and tissues of the body and, as a result, causes autoimmune diseases. The role of Tregs in this case is to actively suppress the activation of the immune system and prevent pathological self-reactivity. In vitiligo, a systemic decrease in the proportion of CD39 + and CD44 + Tregs is observed, which determines the phenotypic characteristics and functional activity, as well as a decrease in the migration of Tregs to vitiligo foci, which correlates with the area of ​​depigmentation. It was previously shown that the adaptive transfer of Tregs to mice with vitiligo led to a temporary arrest of depigmentation. Thus, it was suggested that the use of antigen-specific Tregs as a cellular immunotherapy for vitiligo can be highly effective, restoring local immune tolerance and preventing unwanted autoimmune reactions. Correction of the microbiome, as a result of the use of antibiotics, is also considered a promising direction in the treatment of vitiligo and other autoimmune diseases. A better understanding of bacteria affecting T cell activation could reveal the effect of the microbiome on the development of vitiligo, as shown in a model of vitiligo-prone mice to assess microbiome alteration and Treg distribution. studying the phenotypic characteristics of peripheral blood Tregs in vitiligo patients and developing approaches for stimulating and generating antigen-specific Tregs based on CAR as a potential immunotherapy for vitiligo and studying the effectiveness of the approaches in vitro and in vivo, as well as the effect of antibiotics to control depigmentation in mice. Mukhataev Zh. Was the first to find that the proportion of CD39 + and CD44 + Tregs in peripheral blood is significantly reduced in vitiligo. It was also found that in patients with vitiligo who are in remission, the proportion of Tregs with the phenotype CD39 + and CD44 + FoxP3 + is also reduced in comparison with the control. The data obtained indicate dysfunction of Treg cells in vitiligo and may indicate a decrease in their immunosuppressive properties and the ability to effectively migrate to the foci of depigmentation, which can lead to uncontrolled activity of melanocyte-specific T cells and the progression of the disease. The results obtained contribute to the understanding of the mechanisms of impaired immune regulation in vitiligo and can serve as a basis for the development of new approaches to the treatment of vitiligo based on an increase in the suppressor activity of Tregs and their recruitment to the skin areas affected by vitiligo. in areas of the skin of people and mice affected by vitiligo. Increased expression of the surface antigen GD3 has been identified as an antigenic target in vitiligo. For the first time, microbial diversity after administration of antibiotics such as ampicillin and neomycin and its effect on the development of vitiligo in an experimental mouse model was investigated. It was found that ampicillin leads to increased depigmentation, while neomycin suppresses the development of the disease by indirectly affecting the infiltration of skin Tregs. The obtained data reveal the mechanisms of vitiligo development and can be used to create approaches for cell immunotherapy of vitiligo, based on the use of antigen-specific Tregs. the significance of the results obtained lies in the development new approaches to the therapy of autoimmune diseases using transgenic CAR-based TRs with antigen-specificity. The data obtained in the course of the dissertation work indicate the effectiveness of the adaptive transfer of CAR-modified Tregs for the treatment of vitiligo, which indicates the prospects of this method for further clinical trials, and the developed methods can serve as the basis for the development of immunotherapy for other autoimmune diseases, such as psoriasis, multiple sclerosis. , celiac disease, Crohn’s disease, lupus, etc. The indirect effect of neomycin on increasing the infiltration of skin areas with Tregami and reducing depigmentation in an experimental model of vitiligo can be used to develop approaches for vitiligo therapy. specific CAR. Research results Mukhataeva Zh.E. published in 13 scientific papers, including Autoimmunity reviews (IF 8.2, Q1, 94 percentile), Frontiers Immunollogy (IF 5.08, Q1, (94 percentile), Journal of Investigative Dermatology (IF 7.12, Q1, 98th Percentile) and have been reported at a number of international conferences. US Provisional Patent (Serial No. 62 / 915,945 in the US) “Materials and Methods for the Treatment of Vitiligo” has been received, and successively the US Patent and International PCT Patent (Utility & PCT, Serial No: 17 / 072,939 & PCT / US2020 / 056104) was submitted 16.10.2020 under the title “MATERIALS AND METHODS FOR TREATMENT OF VITILIGO” (internal link: NU2019-172-02 and -03). Thesis “Development of approaches to stimulation of T-regulatory cells for immunotherapy of vitiligo” was successfully defended in the dissertation council of KazNU named after al-Farabi in the specialty 6D060700 – Biology in 2020 and Mukhataev Zh.E. received the “Daryn” award for talented young scientists.