Trends of research in vitiligo

Vitiligo is a skin condition characterized by destruction of melanocytes resulting in the appearance of white patches. The cause of vitiligo is still not clearly known. In vitiligo, high infiltration of autoreactive cytotoxic T cells the perilesional margin is suggested being responsible for depigmentation.A deficiency of immunosuppressive T regulatory cells is suspected to play a key role in the breakdown in self-tolerance leading to the development of the disease. In this review article, the current trends on vitiligo research, treatment, and the role of T regulatory cells in vitiligo pathogenesis are discussed.

Introduction.

Vitiligo is a skin disorder which is caused by the loss of melanocytes. Patients with vitiligo comprise between 0.5 and 2% of total population, and a conservative estimate lays within a range of 35-140 million patients worldwide [1]. The global market for vitiligo is estimated to grow from $1.4 billion in 2011 to $2.7 billion in 2019 [2].

The main signs of vitiligo are depigmented milky-white patches on the skin. Initially, these patches occur in small sizes which frequently spread out and tend to grow by changing shapes. The rate of spreading is variable among individuals - some people report quick dispersing while in others the process is slow. In addition, patients with vitiligo often struggle with early graying of the hair [3]. Individuals with vitiligo do not report with pain or life-threatening symptoms. However, vitiligo lies under the quality of life disease category where some patients might be stigmatized for their condition and often experience depression or mood disorders [4].

Vitiligo can be diagnosed through the use of several methods: an eye exam and ultraviolet (UV). When the vitiligo skin is exposed to UV, it glows blue and healthy skin has no reaction. There are conditions with similar symptoms including pityriasis alba, tuberculoid leprosy, postinflammatory hypopigmentation, tinea versicolor, albinism, and piebaldism. Final confirmation can be obtained by performing biopsy [5].

Currently available treatments do not appear to have a significant efficacy. Therefore, it is relevant to find new approaches that induce immune tolerance towards melanocyte antigens and lead to derma depigmentation.

Currently available treatments for vitiligo.

There is no available cure for vitiligo which can fully reverse the symptoms. However, several moderate treatment options are currently available in the market [6]. Immune mediators such as glucocorticoids and calcineurin inhibitors are currently considered as first-line treatments for vitiligo. Phototherapy (exposure to UV-B lamp) is considered to be a second-line therapy for vitiligo. It has been frequently reported that combination of UV-B phototherapy with topical steroids improves repigmentation. Due to the higher risks of skin cancer or sunburn-type of reactions, UV phototherapy is suggested only when primary standard treatments are ineffective [7].

Olsson M.J. et al.proposed to transplant melanocytes to vitiligo lesions. This procedure involved a separation of melanocytes from a thin layer of pigmented skin excised from a gluteal region. Then, obtained melanocytes expanded in vitro. Affected vitiligo skin was denuded with dermabrader and melanocytes skin-graft was applied to those areas. As a result, approximately 70-85% of patients had a nearly complete repigmentation, which differed among individuals in terms of longevity. In addition, a few transplantation techniques were developed at this point using melanocyte precursors derived from hair follicles [8]. Recently, a drug Afamelanotide was passed Phase II clinical trials for vitiligo and derma related diseases. Moreover, a rheumatoid arthritis drug Tofacitinib also has been tested for vitiligo treatment [9]. Genetic predisposition.

There are many hypotheses have been suggested as potential triggers that might be the cause of vitiligo, whereas genetic susceptibility and autoimmunity are the most probable. The predisposition to vitiligo might be caused by specific genes. Analyzes of melanocytes for consistent morphologic aberrancies showed that VIT1 expression is reduced among vitiligo patients, and it is related to enhanced expression of the hMSH6 mismatch repair gene [10]. Therefore, it has been suggested that VIT1 can regulate hMSH6 expression via the formation of RNA-RNA hybrids, and this increased expression is indicative of a necessity for G/T mismatch repair. Deficient mismatch repair leaves melanocytes susceptible to UV light. Another vitiligo related gene is a gene that encodes catalase [11]. Presence of catalase in the melanocyte cultures showed that mutation in this gene or genes that are close to the gene leaves made the cells more sensitive to damage [12]. Moreover, the link of vitiligo to an autoimmune gene AIS1it was found. In addition, it was revealed that genes associated with vitiligo are involved in antigen-processing and presentation, such as LMP7, TAP1, and CTLA-4 [13].

The link between vitiligo and autoimmunity.

It has been recently shown that vitiligo is an autoimmune disease. The first evidence of autoimmune nature of the disease was the detection of circulating antibodies towards melanocytes in vitiligo patients but not in healthy individuals. It is suggested that the production of antibodies toward melanocytes is a result of vitiligo pathogenesis rather than a direct cause. Moreover, the melanocyte antigen - melanosomal transmembrane protein (MelanA) induces cytotoxic T-cells but not humoral responses. In actively depigmenting patients perilesional margin ishighly infiltrated by T cells and macrophages. Therefore, autoimmune destruction of melanocytes is mediated by cytotoxic T-cells rather than antibodies [14]. Vitiligo is frequently can be associated with other autoimmune diseases such as psoriasis, alopecia, systemic lupus erythematosus, and scleroderma [15]. According to a latest study, T cells proliferate without antigen stimulation in the skin of vitiligo patients. In vitro, cytokine profiles, peptide specificity, and cytotoxic activity towards melanocytes has been represented, and T helper cells and cytotoxic T cells predominantly release T helper type-1 (Th1) cytokines (interferon gamma (IFN-γ), tumor necrosis factor alfa (TNF-α)) [16].

It is generally accepted that autoimmune desorders starts when antigen-presenting cells (APCs) are activated through toll-like receptors (TLRs). These APCs are activated by triggers such as cell damage, microorganisms, which leads to release of CpGoligodeoxynucleotides(CpG) and lipopolysaccharide (LPS) расшифруй [17]. In perilesional skin, TNF-related apoptosis- inducing ligand (TRAIL)-positive DCs are presented in close proximity to TRAIL receptor-expressing melanocytes [18]. These circulating TRAIL might be responsible for the death of melanocytes [19]. These dead melanocytes turn into a source of antigens for DCs, which then are presented to T cells. CD4+ and CD8+ T cells of infiltrate derma [20] and attack melanocytes in a Th1-manner [21]. This assumption is reinforced by the apparent IFN-γ-dependent depigmentation in mouse models [22,23]. CD8T cells reactive to tyrosinase or MART-1 were detected in peripheral blood of vitiligo patients [24,25]. Moreover, it has been shown that the percentage of immunosuppressive T regulatory cells (Tregs) among T cell infiltrates in vitiligo lesions is lack. Due to the paucity of Tregs in vitiligo skin, it is proposed that Treg/T effector (Teff) cell ratios are unfavorable and that uninhibited cytotoxic T cells can contribute to depigmentation [26].

A Genomewide Association study revealed approximately 10 independent susceptibility loci associated with vitiligo. In the MHC encoding region, differential genome expression was found in both class I between HLA-A and HLA-HGC9 and class II between HLA-DRB1 and HLA-DQA1 genes. Moreover, high number of vitiligo patients carry a single amino acid mutation (Leu15>His) in the NLRP1 gene that might contribute to pathogenesis. NLRP1 gene encodes for Cas1 and Cas7 that is responsible for activating IL-1β, which is overexpressed in patients with vitiligo. In addition, TYR gene, which encodes tyrosine, has a mutation TYRQ402A, whereas TYRR402Q is closely associated with melanoma. It is postulated that peptides with TYRQ402A mutation are displayed on MHC-I, while peptides containing TYRR402Q mutation may fail to be recognized by immune system. Therefore, both NLRP1 and TYR mutations in a single amino acid may play different roles in immunity[27].

A paucity of tregs in vitiligo skin.

Tregs are a subpopulation of T cells, which play a key role in regulation of the immune response. The role of Tregs for controlling the immune response to self and foreign antigens prevents autoimmune disorders [28]. In healthy skin, Tregs comprise more than 50% of all T cells, but the paucity of Tregs was observed in vitiligo skin [29]. Until recently, it was challenging to categorize two types of Tregs which were natural Tregs and inducible Tregs. When Tregs are activated, they release inhibitory cytokines. The currently known markers for Tregs include cytotoxic T lymphocyte-associated antigen (CTLA- 4), IL-2 receptor CD25, Forkhead box P3 transcription factor FoxP3, glucocorticoid-induced tumor necrosis factor (GITR), and neuropilin-1. Recently, the most reliable marker for Tregs is considered to be the FoxP3. However, it is still lack of information about antigen specificity of Tregs [30].

In the absence of Tregs, as it is observed in patients with FoxP3 mutations, autoreactive T cells can persistently attack healthy cells. It has been reported that lack of Tregs was observed in several autoimmune diseases such as rheumatoid arthritis, alopecia areata, multiple necrosis, and vitiligo. Also, reduced Treg infiltration has been observed in depigmented lesions [31].

Approaches to enhance the activity of tregs.

To restore the number of Tregs in patients with autoimmune diseases the Treg transfer approach was developed. To restore the Treg number, autologous cells were amplified in vitro and reintroduced to the patient. However, safety concerns were not fully addressed in this technique [32]. It has been demonstrated that mice with graft-versus-host disease (GVHD) had benefited formTreg transfer by halting the expansion of T cells [33]. In addition, genetically modified T cells have been tested clinically, and off-target effects can be handled using suicide genes or applying corticosteroids to suppress autoimmune response. A group of scientists (Chatterjee S., et al.) developed traceable Tregs and injected them into h3TA2 mice that developed spontaneous vitiligo and then measured the effects on depigmentation. It was found that the injection of 200,000 cells is sufficient to maintain elevated Treg/Teff ratios in mice for 6 weeks. As a result, treated mice had increased Treg number and reduced depigmentation [34]. Application of antigen-specific Treg purified on the basis of latency-associated peptide (LAP) or glycoprotein A repetitions predominant (GARP) surface expression increased the specificity of adoptive Treg transfers [35]. Moreover, antigen-specific Tregs were generated for the treatment of other autoimmune diseases with known target antigens. For example, HSP70-specific Tregs were tested for autoimmune arthritis. For vitiligo, tyrosinase-reactive Tregs were developed by TCR gene transfer into in vitro expanded Tregs. Obtained Tregs expressed FoxP3, functional TCRs and effectively suppressed antigen-specific Teff in a murine tumor model [36]. It has been difficult to maintain a functionally stable inducible Tregs from antigen-specific T cells, however, abovementioned studies provided the principles for adoptive Treg transfer in vitiligo [37].

Another approach of Treg cell generation in vivo has been developed. Treg development can be encouraged in thymus by soluble factors such as IL-2, where IL-2 activates effector T cells as well [38]. This controversy is widely accepted, and competition for IL-2 between effector T cells and Tregs determines the therapeutic result [39]. Another cytokine that plays a key roleduring Treg development is transforming growth factor-beta (TGFβ). TGFβ is applied during the expantion of Tregs in vitro in the presence of IL-2, but this can also recruit T helper 17 cell development, when accompanied with IL-6. Also, rapamycin can promote Tregs development via protein kinase B with subsequent mTOR activation [40]. It has been performed that rapamycin administeration on alternate days for 2 weeks at 5 mg/kg of body weight results in remarkable vitiligo inhibition and prolonged Treg skin infiltration in h3TA2 mice [41]. Rapamycin can also benefit in reduced effector T cell and increased Treg abundance in several autoimmune disorders including autoimmune myositis, rheumatic disease, pancreatitis, psoriasis, and keloid formation from [42-45]. Moreover, vitamin D supplementation to patients with autoimmune thyroiditis was beneficial in restoring expression FoxP3 by Tregs and its derivatives can augment Treg activity and reduce the levels of IL- 17-producing T cells, [46, 47]. Of note, effective therapeutics for vitiligo narrow-band UVB light can increase vitamin D levels and promote pigmentation. Thus, enhanced Treg induction may explain the observed correlation between these parameters.

Effective homing of Tregs to the skin is another approach to stimulate repigmentation in vitiligo. Tregs are populated in tissues where an ongoing immune response occurring and chemokines and their receptors are presented [48]. Because of the decreased number of Tregs in vitiligo skin tissues, this tendency was evaluated through comparison with healthy skin. As a result, no difference was observed between the expression of homing receptors including cutaneous lymphocyte antigen, CCR4, and CCR8 in vitiligo derma [29]. However, a significant reduction in the number of CCL22-expressing cells in vitiligo skin was observed. Macrophages and DCs normally express cutaneous CCL22, which is not known to be reduced in vitiligo skin [29, 49, 50]. It is known that reduced CCL22 expression extends to the unaffected skin suggesting that a paucity of Tregs can set the cytotoxic T cells to attack. The existence of melanocyte-reactive CD8+ T cells is not specific for vitiligo patients. Therefore, a shortage of Tregs might help to determine vitiligo progress [51]. The paucity of Tregs among an affected skin from h3TA2 and wild-type mice was dissociated and Tregs were identified by CD3 and FoxP3 co-expression. Moreover, cutaneous Ccl22 overexpression can restore Tregs and prevent vitiligo, and some other chemokines might reinforce thehoming of Tregs into skin. However, CCL22 and possibly CCL17 are expected to be superior chemo-attractants given the high percentage of Tregs which express CCR4 [52, 53]. Promoting Treg homing might intensify the inhibition of effector T-cell homing incorporating blockade the antibodies toward CXCR3, and repopulating vitiligo skin with a healthy Tregs might be helpful for normalizing off-balance immune response in patients skin overall [54].

Future of Treg therapy for vitiligo.

Among autoimmune disorders, vitiligo is one of the first diseases where target antigens have been identified, thus enabling the generation of antigen-specific Tregs is very promising [56]. Treatment options with antigen-specific Tregs may not be fully effective as to maintain their function requires periodically application. Thus, local treatment supported by chemokines or immunosuppressive agents might be necessary for an effective

therapy. According to the above-mentioned studies, Treg-based treatment for vitiligo.

therapeutics holds great promise and can be a potential

 

REFERENCES

  1. Krüger C., Schallreuter K.U. A review of the worldwide prevalence of vitiligo in children/adolescents and adults. //Int. J. Dermatol. - 2012. -Vol 51. -P.1206-1212.
  2. Global Data. Vitiligo therapeutics - pipeline assessment and market forecasts to 2019. //New York: Market Publishers. -2012. P. 7-9.
  3. Halder R.M., Wolff K., Freedberg I.M., Fitzpatrick TB. Fitzpatrick's dermatology in general medicine. //New York: McGraw-Hill Professional. -2007. -Vol 7. P.12-17.
  4. Picardi A., Pasquini P., Cattaruzza M.S., Gaetano P., Melchi C.F., Baliva G., Camaioni D., Tiago A., Abeni D., Biondi M. Stressful life events, social support, attachment security and alexithymia in vitiligo. A case-control study. //Psychotherapy and Psychosomatics. -2003. -Vol 72 (3). - P.150-8.
  5. Schallreuter K.U., Wood J.M., Lemke K.R., Levenig C. Treatment of vitiligo with a topical application of pseudo- catalase and calcium in combination with short-term UVB exposure: a case study on 33 patients. //Dermatology -1995. Vol 190(3). -P.223-9.
  6. Ezzedine K., Eleftheriadou V., Whitton M., van Geel N. Vitiligo. // Lancet. -2015. -Vol. 386 (9988). -P. 74-84.
  7. Scherschun L., Kim J.J., Lim H.W. Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo. //Journal of the American Academy of Dermatology. -2001. -Vol 44 (6). -P. 999-1003.
  8. Olsson M.J., Juhlin L. Melanocyte transplantation in vitiligo. //Lancet. -1992. -Vol340 (8825). - P. 981-988.
  9. Fabrikant J., Touloei K., Brown S.M. A review and update on melanocyte stimulating hormone therapy: afamelanotide. //J. Drugs. Dermatol. -2013. Vol 12 (7). -P. 775-9.
  10. Le Poole I.C., Sarangarajan R., Zhaoy R., Stennett LS, Brown TL, Sheth P, Miki T, Boissy RE. 'VIT1', a novel gene associated with vitiligo. //Pigment. Cell. Res. -2001. -Vol 14. -P.475-484.
  11. Casp C.B., She J.X., McCormack W.T. Genetic association of the catalase gene (CAT) with vitiligo susceptibility.// Pigment. Cell. Res.-2002. -Vol 15. P. 62-66.
  12. Medrano E.E., Nordlund J.J. Successful culture of adult human melanocytes obtaines from normal and vitiligo donors. // J. Invest. Dermatol. -1990. -Vol 95. -P.441-445.
  13. Alkhateeb A., Stetler G.L., Old W., Old W., Talbert J., Uhlhorn C., Taylor M., Fox A., Miller C., Dills G., Chester Ridgway E., Bennett D.C., Fain P. R., Spritz R.A. Mapping of an autoimmunity susceptibility locus (AIS1) to chromosome 1p31.3-P32.2. //Hum. Mol. Genet. -2002. - Vol.11. - P.661-667.
  14. Spritz R.A. Modern vitiligo genetics sheds new light on an ancient disease. //The Journal of Dermatology. - 2013. -Vol 40 (5). - P.310318.
  15. Ezzedine K., Eleftheriadou V., Whitton M., van Geel N. Vitiligo. //Lancet. -2015. -Vol. 386 (9988). -P.74-84.
  16. Le Poole I. C.,Mehrotra S.Replenishing Regulatory T Cells to Halt Depigmentation in Vitiligo. //Journal of Investigative Dermatology Symposium Proceedings. - 2017. - Vol 18(2) P.38-45.
  17. Ganju P., Nagpal S., Mohammed M.H., Nishal Kumar P., Pandey R., Natarajan V.T., Sharmila S., Mande R., Gokhale S. Microbial community profiling shows dysbiosis in the lesional skin of Vitiligo subjects. //Sci. Rep. - 2016. Vol 6. -e.18761
  18. Kroll T.M., Bommiasamy H., Boissy R.E., Hernandez C., Nickoloff B.J., Mestril R., Le Poole I.C. 4-Tertiary butyl phenol exposure sensitizes human melanocytes to dendritic cell-mediated killing: relevance to vitiligo. //J. Invest. Dermatol. - 2005. - Vol 124 (4). -P. 798-806.
  19. Edgunlu T., SolakTekin N., OzelTurkcu U¨., Karakas C, elik S., Urhan-Kucuk M. Evaluation of serum trail level and DR4 gene variants as biomarkers for vitiligo patients.//J.Eur.Acad.Derm.Venereol.-2016.-Vol 30(10).-P.97 98.
  20. van den Wijngaard R., Wankowicz-Kalinska A., Le Poole C., Tigges B., Westerhof W., Das P. Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA+T cells at the perilesional site.//Lab Invest.-2000.-Vol 83(5). P.683-95.
  21. Wankowicz-Kalinska A., van den Wijngaard R.M., Tigges B.J., Westerhof W., Ogg G.S., Cerundolo V. Immunopolarization of CD4+ and CD8T cells to Type-1-like is associated with melanocyte loss in human vitiligo. //Lab Invest -2003. -Vol 7(1) -P. 237-241.
  22. Gregg R.K., Nichols L., Chen Y., Lu B., Engelhard V.H. Mechanisms of spatial and temporal development of autoimmune vitiligo in tyrosinase-specific TCR transgenic mice. //J. Immunol. -2010. -Vol 184(4) -P.1909-17.
  23. Harris J.E., Harris T.H., Weninger W., Wherry E.J., Hunter C.A., Turka L.A. A mouse model of vitiligo with focused epidermal depigmentation requires IFN-g for autoreactive CD8 T-cell accumulation in the skin. //J. Invest. Dermatol. -2012. -Vol 132(7). -P.186976
  24. van den Boorn J.G., Konijnenberg D., Dellemijn T.A., van der Veen J.P., Bos J.D., Melief C.J. Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients. //J. Invest. Dermatol. - 2009. Vol 129(9): P. 2220-32.
  25. Ogg G.S., Rod Dunbar P., Romero P., Chen J.L., Cerundolo V. High frequency of skin-homing melanocyte-specific cytotoxic T lymphocytes in autoimmune vitiligo. //J. Exp. Med. -1998. -Vol 188(6) -P.1203-8.
  26. Klarquist J., Denman C.J., Hernandez C., Wainwright D.A., Strickland F.M., Overbeck A., Mehrotra S., Nishimura M.I., Le Poole I.C. Reduced skin homing by functional Treg in vitiligo. //Pigment. Cell. Melanoma. - Res 2010.-Vol 23(2). - P.276-86.
  27. Levandowski C.B., Mailloux C.M., Ferrara T.M., Gowan K., Ben S., Jin Y., McFann K.K., Holland P.J., Fain P.R., Dinarello C.A., Spritz R.A. NLRP1 haplotypes associated with vitiligo and autoimmunity increase interleukin-1beta processing via the NLRP1 inflammasome. // Proc. Natl. Acad. Sci. U S A. - 2013. -Vol 110.-P.2952-2956.
  28. Chen W. Tregs in immunotherapy: opportunities and challenges. //Immunotherapy. - 2013. -Vol 8- P. 911-4.
  29. Klarquist J., Denman C.J., Hernandez C., Wainwright D.A., Strickland F.M., Overbeck A. Reduced skin homing by functional Treg in vitiligo. //Pigment Cell Melanoma. - 2010. -Vol 23(2). - P.276-86.
  30. Chen W., Jin W., Hardegen N., Lei KJ, Li L, Marinos N. Conversion of peripheral CD4+CD25- naive T cells to CD4flCD25fl regulatory T cells by TGF-beta induction of transcription factor Foxp3. //J.Exp.Med. -2003. -Vol 198(12). -P.1875-86.
  31. Le Poole I.C. and Mehrotra S. Replenishing Regulatory T Cells to Halt Depigmentation in Vitiligo //Journal of Investigative Dermatology Symposium Proceedings. - 2017.-Vol 8(2) -P. 38-45.
  32. Gattinoni L. Adoptive T cell transfer: imagining the next generation of cancer immunotherapies. // Seminars Immunol. -2016.-Vol 28(1). -P. 1-2.
  33. Mutis T., van Rijn R.S., Simonetti E.R., Aarts-Riemens T., Emmelot M.E., van Bloois L. Human regulatory T cells control xenogeneic graft- versushost disease induced by autologous T cells in RAG2-/- gc-/-immunodeficient mice. //Clin Cancer Res. - 2006.- Vol 12(18). - P.5520-5.
  34. Chatterjee S., Eby J.M., Al-Khami A.A., Soloshchenko M., Kang H.K., Kaur N. A quantitative increase in regulatory T cells controls development of vitiligo. //J. Invest. Dermatol. - 2014.-Vol34(5). - P. 1285-1294.
  35. Noyan F., Lee Y.S., Zimmermann K., Hardtke-Wolenski M., Taubert R., Warnecke G. Isolation of human antigen-specific regulatory T cells with high suppressive function. // Eur. J. Immunol. -2014.-Vol 44(9). P.2592-602.
  36. Brusko T.M., Koya R.C., Zhu S., Lee M.R., Putnam A.L., McClymont S.A., Nishimura M.I., Han S., Chang L.J., Atkinson M.A., Ribas A., Bluestone J.A. Human antigen-specific regulatory T cells generated by T cell receptor gene transfer. //PLoS One. -2010. - Vol. 5(7). -e. 11726.
  37. Sarikonda G., Fousteri G., Sachithanantham S., Miller J.F., Dave A., Juntti T., Coppieters K.T., von Herrath M. BDC12-4.1 T-cell receptor transgenic insulin-specific CD4 T cells are resistant to in vitro differentiation into functional Foxp3+ T regulatory cells. //PLoS One. - 2014. Vol 9(11). -e112242.
  38. Lio C.W., Hsieh C.S. A two-step process for thymic regulatory T cell development. //Immunity. -2008. -Vol 28 (1). -P. 100-11.
  39. Jaberi-Douraki M., Pietropaolo M., Khadra A. Continuum model of T-cell acidity: understanding autoreactive and regulatory T-cell responses in type 1 diabetes. //J.Theor.Biol. -2015. -Vol 383. -P. 93-105.
  40. Sauer S., Bruno L., Hertweck A., Finlay D., Leleu M., Spivakov M., Knight Z.A., Cobb B.S., Cantrell D., O'Connor E., Shokat K.M., Fisher A.G., Merkenschlager M. T cell receptor signaling controls Foxp3 expression via PI3K AktmTOR. //Proc. Natl.Acad.Sci. - 2008.- Vol 105(22). P. 7797-802.
  41. Prevel N., Allenbach Y., Klatzmann D., Salomon B., Benveniste O. Beneficial role of rapamycin in experimental autoimmune myositis. //PLoS One. -2013.-Vol 8(11). -e74450.
  42. Schwaiger T., van den Brandt C., Fitzner B., Zaatreh S., Kraatz F., Dummer A., Nizze H., Evert M., Bröker B.M., Brunner-Weinzierl M.C., Wartmann T., Salem T., Lerch M.M., Jaster R., Mayerle J. Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment. //Gut. -2014.-Vol 63(3). -P.494-505.
  43. Wong V.W., You F., Januszyk M., Gurtner G.C., Kuang A.A. Transcriptionalprofiling of rapamycin-treated fibroblasts from hypertrophic and keloidscars. //Ann.Plast.Surg. -2014. -Vol 72(6). -P.711-9.
  44. Wei K.C., Lai P.C. Combination of everolimus and tacrolimus: a potentially
  45. effective regimen for recalcitrant psoriasis. //Dermatol.Ther. -2015. -Vol 28(1) -P.25-7
  46. Sıklar Z., Karatas D., Dogu F., Hacıhamdioglu B., Ikincio_gulları A., Berberoglu M. Investigation the effects of functions of regulatory T cells and vitamin D in children with chronic autoimmune thyroiditis. //J.Clin.Res.Pediatr.Endocrinol. - 2016. -Vol 8(3). -P.276-281.
  47. Gonza´lez-Mateo G.T., Ferna´ndez-Mı´llara V., Bello´n T., Liappas G., Ruiz Ortega M., Lo´pez-Cabrera M., Rafael Selgas., Luiz S. AroeiraParicalcitol reduces peritoneal fibrosis in mice through the activation of regulatory T cells and reduction in IL-17 production. //PLoS One. -2014. -Vol 9(10). -e108477
  48. Yi H., Zhao Y. Chemokines, chemokine receptors and CD4flCD2+ regulatory T cells. //Expert. Rev. Clin. Immunol. - 2007.-Vol 3(3). -P.3439.
  49. Vulcano M., Albanesi C., Stoppacciaro A., Bagnati R., D'Amico G., Struyf S., Transidico P., Bonecchi R., Del Prete A., Allavena P., Ruco LP., Chiabrando C., Girolomoni G., Mantovani A., Sozzani S. Dendritic cells as a major source of macrophage-derived chemokine/ CCL22 in vitro and in vivo. //Eur. J. Immunol. -2001.- Vol 31 (3) -P.812-22.
  50. Le Poole I.C., van den Wijngaard R.M., Westerhof W., Das PK. Presence of T cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. //Am. J. Pathol. - 1996. - Vol 148(4). - P.1219-28.
  51. Ho W.Y., Nguyen H.N., Wolfl M., Kuball J., Greenberg PD. In vitro methods for generating CD8+ T-cell clones for immunotherapy from the naive repertoire. //J.Immunol. Methods. - 2006. -Vol 310(1-2). -P.40-52
  52. Eby J.M., Kang H.K., Tully S.T., Bindeman W.E., Peiffer D.S., Chatterjee S., Peiffer D.S., Chatterjee S., Mehrotra S., Le Poole I.C. CCL22 to activate Treg migration and suppress depigmentation in vitiligo. //J. Invest. Dermatol. - 2015.-Vol 135(6). -P.1574-1580.
  53. Wang Z., Pratts S.G., Zhang H., Spencer P.J., Yu R., Tonsho M., Shah J.A., Tanabe T., Powell H.R., Huang C.A., Madsen J.C., Sachs D.H., Wang Z. Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin. //MolOncol. -2016.-Vol 10(4). P. 553-65.
  54. Rashighi M., Agarwal P., Richmond J.M., Harris T.H., Dresser K., Su M.W., Zhou Y., Deng A., Hunter C.A., Luster A.D., Harris J.E. CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. //Sci. Transl. Med. - 2014. - Vol 6(223). P. 223ra23.
  55. Kakadia P.G., Conway B.R. Lipid nanoparticles for dermal drug delivery. //Curr. Pharm. Des -2015. -Vol 21(20). P.2823-9.
  56. Dwivedi M., Kemp E.H., Laddha N.C., Mansuri M.S., Weetman A.P., Begum R. Regulatory T cells in vitiligo: implications for pathogenesis and therapeutics. //Autoimmun Rev -2015. -Vol 14(1). -P.49-56.
  57. 2Ж.Е. Мухатаев, 1Е.О. Остапчук
Year: 2018
City: Almaty
Category: Medicine