Long-term efficacy and safety of intravenous injection of clonal mesenchymal stem cells derived from bone marrow in five adults with moderate to severe atopic dermatitis
Hyun-Tae Shin
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorSi Hyub Lee
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorHee Seong Yoon
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorJi Hye Heo
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorSeon Bok Lee
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorJi Won Byun
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorJeonghyun Shin
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorYun-Kyoung Cho
SCM Lifescience Co. Ltd., Incheon, Republic of Korea
Search for more papers by this authorEunkyung Chung
SCM Lifescience Co. Ltd., Incheon, Republic of Korea
Search for more papers by this authorMyung-Shin Jeon
Program in Biomedical Science and Engineering, Graduate School, Inha University, Incheon, Republic of Korea
Search for more papers by this authorCorresponding Author
Sun U. Song
SCM Lifescience Co. Ltd., Incheon, Republic of Korea
Program in Biomedical Science and Engineering, Graduate School, Inha University, Incheon, Republic of Korea
Correspondence
Sun U. Song, Department of Integrated Biomedical Sciences, Inha University School of Medicine, Inhang-ro 27, Jung-gu, Incheon 22332, Korea.
Email: [email protected]
Gwang Seong Choi, Department of Dermatology, Inha University School of Medicine, Inhang-ro 27, Jung-gu, Incheon 22332, Korea.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Gwang Seong Choi
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Correspondence
Sun U. Song, Department of Integrated Biomedical Sciences, Inha University School of Medicine, Inhang-ro 27, Jung-gu, Incheon 22332, Korea.
Email: [email protected]
Gwang Seong Choi, Department of Dermatology, Inha University School of Medicine, Inhang-ro 27, Jung-gu, Incheon 22332, Korea.
Email: [email protected]
Search for more papers by this authorHyun-Tae Shin
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorSi Hyub Lee
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorHee Seong Yoon
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorJi Hye Heo
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorSeon Bok Lee
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorJi Won Byun
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorJeonghyun Shin
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Search for more papers by this authorYun-Kyoung Cho
SCM Lifescience Co. Ltd., Incheon, Republic of Korea
Search for more papers by this authorEunkyung Chung
SCM Lifescience Co. Ltd., Incheon, Republic of Korea
Search for more papers by this authorMyung-Shin Jeon
Program in Biomedical Science and Engineering, Graduate School, Inha University, Incheon, Republic of Korea
Search for more papers by this authorCorresponding Author
Sun U. Song
SCM Lifescience Co. Ltd., Incheon, Republic of Korea
Program in Biomedical Science and Engineering, Graduate School, Inha University, Incheon, Republic of Korea
Correspondence
Sun U. Song, Department of Integrated Biomedical Sciences, Inha University School of Medicine, Inhang-ro 27, Jung-gu, Incheon 22332, Korea.
Email: [email protected]
Gwang Seong Choi, Department of Dermatology, Inha University School of Medicine, Inhang-ro 27, Jung-gu, Incheon 22332, Korea.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Gwang Seong Choi
Department of Dermatology, Inha University School of Medicine, Incheon, Republic of Korea
Correspondence
Sun U. Song, Department of Integrated Biomedical Sciences, Inha University School of Medicine, Inhang-ro 27, Jung-gu, Incheon 22332, Korea.
Email: [email protected]
Gwang Seong Choi, Department of Dermatology, Inha University School of Medicine, Inhang-ro 27, Jung-gu, Incheon 22332, Korea.
Email: [email protected]
Search for more papers by this authorHyun-Tae Shin and Si Hyub Lee contributed equally to this work.
Abstract
Atopic dermatitis is a chronic and relapsing inflammatory skin disease that is treated with immunosuppressants. However, long-term use of immunosuppressants may cause toxicity and severe side-effects. To confirm the long-term efficacy and safety of clonal mesenchymal stem cell therapy, we performed investigator-initiated clinical trials and long-term observation in five adult patients with moderate to severe atopic dermatitis that was refractory to conventional treatments. The clinical response assessment values such as Eczema Area and Severity Index (EASI) improved significantly at 16 weeks, and 80% (4/5) of the patients achieved EASI-50 after one or two treatment cycles. Patients were observed for long-term efficacy and safety for an average of 38 weeks (range, 16–86) and showed no serious side-effects. Among the cytokines tested, CCL-17, interleukin (IL)-13, and IL-22 significantly decreased at the end-point of the five participants, two patients who maintained good clinical response over 84 weeks showed increased IL-17 cytokine levels in the blood.
CONFLICT OF INTEREST
None declared.
Supporting Information
| Filename | Description |
|---|---|
| jde15928-sup-0001-FigS1.pdfPDF document, 29.7 KB | Fig S1 |
| jde15928-sup-0002-FigS2.pdfPDF document, 24.6 MB | Fig S2 |
| jde15928-sup-0003-FigS3.pdfPDF document, 20.7 MB | Fig S3 |
| jde15928-sup-0004-FigS4.pdfPDF document, 18.4 MB | Fig S4 |
| jde15928-sup-0005-TableS1-S4.xlsxapplication/excel, 30.5 KB | Table S1-S4 |
| jde15928-sup-0006-Supinfo.pdfPDF document, 149.2 KB | Supplementary Material |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Chamlin SL. The psychosocial burden of childhood atopic dermatitis. Dermatol Ther. 2006; 19(2): 104–7. https://doi.org/10.1111/j.1529-8019.2006.00060.x
- 2Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016; 375(24): 2335–48. https://doi.org/10.1056/NEJMoa1610020
- 3Kantor R, Thyssen JP, Paller AS, Silverberg JI. Atopic dermatitis, atopic eczema, or eczema? A systematic review, meta-analysis, and recommendation for uniform use of ‘atopic dermatitis’. Allergy. 2016; 71(10): 1480–5. https://doi.org/10.1111/all.12982
- 4Bergmann KC, Heinrich J, Niemann H. Current status of allergy prevalence in Germany: position paper of the Environmental Medicine Commission of the Robert Koch Institute. Allergo journal international. 2016; 25: 6–10. https://doi.org/10.1007/s40629-016-0092-6
- 5Saeki H, Tsunemi Y, Fujita H, Kagami S, Sasaki K, Ohmatsu H, et al. Prevalence of atopic dermatitis determined by clinical examination in Japanese adults. J Dermatol. 2006; 33(11): 817–9. https://doi.org/10.1111/j.1346-8138.2006.00187.x
- 6Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol. 2013; 132(5): 1132–8. https://doi.org/10.1016/j.jaci.2013.08.031
- 7Sidbury R, Davis DM, Cohen DE, Cordoro KM, Berger TG, Bergman JN, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014; 71(2): 327–49. https://doi.org/10.1016/j.jaad.2014.03.030
- 8Deleuran M, Thaçi D, Beck LA, de Bruin-Weller M, Blauvelt A, Forman S, et al. Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study. J Am Acad Dermatol. 2020; 82(2): 377–88. https://doi.org/10.1016/j.jaad.2019.07.074
- 9Ruzicka T, Hanifin JM, Furue M, Pulka G, Mlynarczyk I, Wollenberg A, et al. Anti-interleukin-31 receptor A antibody for atopic dermatitis. N Engl J Med. 2017; 376(9): 826–35. https://doi.org/10.1056/NEJMoa1606490
- 10Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005; 105(4): 1815–22. https://doi.org/10.1182/blood-2004-04-1559
- 11Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol. 2003; 57(1): 11–20. https://doi.org/10.1046/j.1365-3083.2003.01176.x
- 12Figueroa FE, Carrion F, Villanueva S, Khoury M. Mesenchymal stem cell treatment for autoimmune diseases: a critical review. Biol Res. 2012; 45(3): 269–77. https://doi.org/10.4067/S0716-97602012000300008
- 13Kim HS, Lee JH, Roh KH, Jun HJ, Kang KS, Kim TY. Clinical trial of human umbilical cord blood-derived stem cells for the treatment of moderate-to-severe atopic dermatitis: phase I/IIa studies. Stem Cells. 2017; 35(1): 248–55. https://doi.org/10.1002/stem.2401
- 14Shin TH, Kim HS, Choi SW, Kang KS. Mesenchymal stem cell therapy for inflammatory skin diseases: clinical potential and mode of action. Int J Mol Sci. 2017; 18(2): 244. https://doi.org/10.3390/ijms18020244
- 15Rong X, Li J, Yang Y, Shi L, Jiang T. Human fetal skin-derived stem cell secretome enhances radiation-induced skin injury therapeutic effects by promoting angiogenesis. Stem Cell Res Ther. 2019; 10(1): 383. https://doi.org/10.1186/s13287-019-1456-x
- 16Song SU, Kim CS, Yoon SP, Kim SK, Lee MH, Kang JS, et al. Variations of clonal marrow stem cell lines established from human bone marrow in surface epitopes, differentiation potential, gene expression, and cytokine secretion. Stem Cells Dev. 2008; 17(3): 451–61. https://doi.org/10.1089/scd.2007.0167
- 17Yi TG, Kim S-N, Lee H-J, Kim J, Cho Y-K, Shin D-H, et al. Manufacture of clinical-grade human clonal mesenchymal stem cell products from single colony forming unit-derived colonies based on the subfractionation culturing method. Tissue Eng Part C Methods. 2015; 21(12): 1251–62. https://doi.org/10.1089/ten.TEC.2015.0017
- 18Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl. 1980; 59: 44–7.
- 19Zhao T, Sun F, Liu J, Ding T, She J, Mao F, et al. Emerging role of mesenchymal stem cell-derived exosomes in regenerative medicine. Curr Stem Cell Res Ther. 2019; 14(6): 482–94. https://doi.org/10.2174/1574888X14666190228103230
- 20Eggenhofer E, Luk F, Dahlke MH, Hoogduijn MJ. The life and fate of mesenchymal stem cells. Front Immunol. 2014; 5: 148. https://doi.org/10.3389/fimmu.2014.00148
- 21von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012; 30(7): 1575–8. https://doi.org/10.1002/stem.1118
- 22Na K, Yoo HS, Zhang YX, Choi M-S, Lee K, Yi TG, et al. Bone marrow-derived clonal mesenchymal stem cells inhibit ovalbumin-induced atopic dermatitis. Cell Death Dis. 2014; 5:e1345. https://doi.org/10.1038/cddis.2014.299
- 23Guttman-Yassky E, Brunner PM, Neumann AU, Khattri S, Pavel AB, Malik K, et al. Efficacy and safety of fezakinumab (an IL-22 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by conventional treatments: a randomized, double-blind, phase 2a trial. J Am Acad Dermatol. 2018; 78(5): 872–81.e876. https://doi.org/10.1016/j.jaad.2018.01.016
- 24Guttman-Yassky E, Krueger JG, Lebwohl MG. Systemic immune mechanisms in atopic dermatitis and psoriasis with implications for treatment. Exp Dermatol. 2018; 27(4): 409–17. https://doi.org/10.1111/exd.13336
- 25Esaki H, Brunner PM, Renert-Yuval Y, Czarnowicki T, Huynh T, Tran G, et al. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J Allergy Clin Immunol. 2016; 138(6): 1639–51. https://doi.org/10.1016/j.jaci.2016.07.013
- 26Noda S, Suárez-Fariñas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol. 2015; 136(5): 1254–64. https://doi.org/10.1016/j.jaci.2015.08.015
- 27Suárez-Fariñas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de Guzman Strong C, et al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J Allergy Clin Immunol. 2013; 132(2): 361–70. https://doi.org/10.1016/j.jaci.2013.04.046
- 28Xiang T, Long H, He L, Han X, Lin K, Liang Z, et al. Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer. Oncogene. 2015; 34(2): 165–76. https://doi.org/10.1038/onc.2013.537
- 29Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, et al. Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 2013; 210(13): 2851–72. https://doi.org/10.1084/jem.20131195
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