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BMC Medicine
Published in: BMC Medicine 1/2015

Open Access 01-12-2015 | Research article

Hair regrowth in alopecia areata patients following Stem Cell Educator therapy

Authors: Yanjia Li, Baoyong Yan, Hepeng Wang, Heng Li, Quanhai Li, Dong Zhao, Yana Chen, Ye Zhang, Wenxia Li, Jun Zhang, Shanfeng Wang, Jie Shen, Yunxiang Li, Edward Guindi, Yong Zhao

Published in: BMC Medicine | Issue 1/2015

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Abstract

Background

Alopecia areata (AA) is one of the most common autoimmune diseases and targets the hair follicles, with high impact on the quality of life and self-esteem of patients due to hair loss. Clinical management and outcomes are challenged by current limited immunosuppressive and immunomodulating regimens.

Methods

We have developed a Stem Cell Educator therapy in which a patient’s blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, allows the cells to briefly interact with adherent human cord blood-derived multipotent stem cells (CB-SC), and returns the “educated” autologous cells to the patient’s circulation. In an open-label, phase 1/phase 2 study, patients (N = 9) with severe AA received one treatment with the Stem Cell Educator therapy. The median age was 20 years (median alopecic duration, 5 years).

Results

Clinical data demonstrated that patients with severe AA achieved improved hair regrowth and quality of life after receiving Stem Cell Educator therapy. Flow cytometry revealed the up-regulation of Th2 cytokines and restoration of balancing Th1/Th2/Th3 cytokine production in the peripheral blood of AA subjects. Immunohistochemistry indicated the formation of a “ring of transforming growth factor beta 1 (TGF-β1)” around the hair follicles, leading to the restoration of immune privilege of hair follicles and the protection of newly generated hair follicles against autoimmune destruction. Mechanistic studies revealed that co-culture with CB-SC may up-regulate the expression of coinhibitory molecules B and T lymphocyte attenuator (BTLA) and programmed death-1 receptor (PD-1) on CD8β+NKG2D+ effector T cells and suppress their proliferation via herpesvirus entry mediator (HVEM) ligands and programmed death-1 ligand (PD-L1) on CB-SCs.

Conclusions

Current clinical data demonstrated the safety and efficacy of the Stem Cell Educator therapy for the treatment of AA. This innovative approach produced lasting improvement in hair regrowth in subjects with moderate or severe AA.

Trial registration

ClinicalTrials.gov, NCT01673789, 21 August 2012
Literature
1.
2.
Huang KP, Mullangi S, Guo Y, Qureshi AA. Autoimmune, atopic, and mental health comorbid conditions associated with alopecia areata in the United States. JAMA Dermatol. 2013;149:789–94.CrossRefPubMed
3.
Galan-Gutierrez M, Rodriguez-Bujaldon A, Moreno-Gimenez JC. Update on the treatment of alopecia areata. Actas Dermosifiliogr. 2009;100:266–76.CrossRefPubMed
4.
Gilhar A, Landau M, Assy B, Shalaginov R, Serafimovich S, Kalish RS. Mediation of alopecia areata by cooperation between CD4+ and CD8+ T lymphocytes: transfer to human scalp explants on Prkdc(scid) mice. Arch Dermatol. 2002;138:916–22.CrossRefPubMed
5.
Ito T, Ito N, Saatoff M, Hashizume H, Fukamizu H, Nickoloff BJ, et al. Maintenance of hair follicle immune privilege is linked to prevention of NK cell attack. J Invest Dermatol. 2008;128:1196–206.CrossRefPubMed
6.
Ito T, Meyer KC, Ito N, Paus R. Immune privilege and the skin. Curr Dir Autoimmun. 2008;10:27–52.CrossRefPubMed
7.
Paus R, Ito N, Takigawa M, Ito T. The hair follicle and immune privilege. J Investig Dermatol Symp Proc. 2003;8:188–94.CrossRefPubMed
8.
Ito N, Ito T, Betterman A, Paus R. The human hair bulb is a source and target of CRH. J Invest Dermatol. 2004;122:235–7.CrossRefPubMed
9.
Ito N, Ito T, Kromminga A, Bettermann A, Takigawa M, Kees F, et al. Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol. FASEB J. 2005;19:1332–4.PubMed
10.
Ito T, Ito N, Bettermann A, Tokura Y, Takigawa M, Paus R. Collapse and restoration of MHC class-I-dependent immune privilege: exploiting the human hair follicle as a model. Am J Pathol. 2004;164:623–34.CrossRefPubMedPubMedCentral
11.
Gilhar A, Ullmann Y, Berkutzki T, Assy B, Kalish RS. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest. 1998;101:62–7.CrossRefPubMedPubMedCentral
12.
13.
McElwee KJ, Freyschmidt-Paul P, Hoffmann R, Kissling S, Hummel S, Vitacolonna M, et al. Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)/CD25(-) cells promote systemic alopecia areata and CD4(+)/CD25(+) cells blockade disease onset in the C3H/HeJ mouse model. J Invest Dermatol. 2005;124:947–57.CrossRefPubMed
14.
15.
16.
Mathieu C, Gillard P. Arresting type 1 diabetes after diagnosis: GAD is not enough. Lancet. 2011;378:291–2.CrossRefPubMed
17.
Wherrett DK, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet. 2011;378:319–27.CrossRefPubMedPubMedCentral
18.
Zhao Y, Wang H, Mazzone T. Identification of stem cells from human umbilical cord blood with embryonic and hematopoietic characteristics. Exp Cell Res. 2006;312:2454–64.CrossRefPubMed
19.
Zhao Y, Mazzone T. Human cord blood stem cells and the journey to a cure for type 1 diabetes. Autoimmun Rev. 2010;10:103–7.CrossRefPubMed
20.
Zhao Y. Stem cell educator therapy and induction of immune balance. Curr Diab Rep. 2012;12:517–23.CrossRefPubMed
21.
Zhao Y, Glesne D, Huberman E. A human peripheral blood monocyte-derived subset acts as pluripotent stem cells. Proc Natl Acad Sci U S A. 2003;100:2426–31.CrossRefPubMedPubMedCentral
22.
Zhao Y, Mazzone T. Human umbilical cord blood-derived f-macrophages retain pluripotentiality after thrombopoietin expansion. Exp Cell Res. 2005;310:311–8.CrossRefPubMed
23.
Zhao Y, Lin B, Darflinger R, Zhang Y, Holterman MJ, Skidgel RA. Human cord blood stem cell-modulated regulatory T lymphocytes reverse the autoimmune-caused type 1 diabetes in nonobese diabetic (NOD) mice. PLoS One. 2009;4, e4226.CrossRefPubMedPubMedCentral
24.
Zhao Y, Jiang Z, Zhao T, Ye M, Hu C, Yin Z, et al. Reversal of type 1 diabetes via islet beta cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Med. 2012;10:3.CrossRefPubMedPubMedCentral
25.
Zhao Y, Jiang Z, Zhao T, Ye M, Hu C, Zhou H, et al. Targeting insulin resistance in type 2 diabetes via immune modulation of cord blood-derived multipotent stem cells (CB-SCs) in stem cell educator therapy: phase I/II clinical trial. BMC Med. 2013;11:160.CrossRefPubMedPubMedCentral
26.
Zhao Y, Jiang Z, Guo C. New hope for type 2 diabetics: Targeting insulin resistance through the immune modulation of stem cells. Autoimmun Rev. 2011;11:137–42.CrossRefPubMed
27.
Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014;20:1043–9.CrossRefPubMedPubMedCentral
28.
Zhao Y, Huang Z, Qi M, Lazzarini P, Mazzone T. Immune regulation of T lymphocyte by a newly characterized human umbilical cord blood stem cell. Immunol Lett. 2007;108:78–87.CrossRefPubMed
29.
30.
Foitzik K, Lindner G, Mueller-Roever S, Maurer M, Botchkareva N, Botchkarev V, et al. Control of murine hair follicle regression (catagen) by TGF-beta1 in vivo. FASEB J. 2000;14:752–60.PubMed
31.
Gilhar A, Landau M, Assy B, Ullmann Y, Shalaginov R, Serafimovich S, et al. Transfer of alopecia areata in the human scalp graft/Prkdc(scid) (SCID) mouse system is characterized by a TH1 response. Clin Immunol. 2003;106:181–7.CrossRefPubMed
32.
Skapenko A, Niedobitek GU, Kalden JR, Lipsky PE, Schulze-Koops H. Generation and regulation of human Th1-biased immune responses in vivo: a critical role for IL-4 and IL-10. J Immunol. 2004;172:6427–34.CrossRefPubMed
33.
Webb LM, Feldmann M. Critical role of CD28/B7 costimulation in the development of human Th2 cytokine-producing cells. Blood. 1995;86:3479–86.PubMed
34.
King CL, Stupi RJ, Craighead N, June CH, Thyphronitis G. CD28 activation promotes Th2 subset differentiation by human CD4+ cells. Eur J Immunol. 1995;25:587–95.CrossRefPubMed
35.
Rulifson IC, Sperling AI, Fields PE, Fitch FW, Bluestone JA. CD28 costimulation promotes the production of Th2 cytokines. J Immunol. 1997;158:658–65.PubMed
36.
Skapenko A, Lipsky PE, Kraetsch HG, Kalden JR, Schulze-Koops H. Antigen-independent Th2 cell differentiation by stimulation of CD28: regulation via IL-4 gene expression and mitogen-activated protein kinase activation. J Immunol. 2001;166:4283–92.CrossRefPubMed
37.
Soma T, Dohrmann CE, Hibino T, Raftery LA. Profile of transforming growth factor-beta responses during the murine hair cycle. J Invest Dermatol. 2003;121:969–75.CrossRefPubMed
38.
Welker P, Foitzik K, Bulfone-Paus S, Henz BM, Paus R. Hair cycle-dependent changes in the gene expression and protein content of transforming factor beta 1 and beta 3 in murine skin. Arch Dermatol Res. 1997;289:554–7.CrossRefPubMed
39.
40.
41.
42.
Ito T, Hashizume H, Shimauchi T, Funakoshi A, Ito N, Fukamizu H, et al. CXCL10 produced from hair follicles induces Th1 and Tc1 cell infiltration in the acute phase of alopecia areata followed by sustained Tc1 accumulation in the chronic phase. J Dermatol Sci. 2012;69:140–7.CrossRefPubMed
43.
Barahmani N, Lopez A, Babu D, Hernandez M, Donley SE, Duvic M. Serum T helper 1 cytokine levels are greater in patients with alopecia areata regardless of severity or atopy. Clin Exp Dermatol. 2010;35:409–16.CrossRefPubMed
44.
Katagiri K, Arakawa S, Hatano Y. In vivo levels of IL-4, IL-10, TGF-beta1 and IFN-gamma mRNA of the peripheral blood mononuclear cells in patients with alopecia areata in comparison to those in patients with atopic dermatitis. Arch Dermatol Res. 2007;298:397–401.CrossRefPubMed
45.
Kubo R, Nakamura M, Tokura Y. Alopecia universalis following two sequential traffic accidents: possible association with increased Th1 and Th17 cells and decreased Th2 cells. J UOEH. 2011;33:313–7.PubMed
46.
Lanier LL, Corliss B, Wu J, Phillips JH. Association of DAP12 with activating CD94/NKG2C NK cell receptors. Immunity. 1998;8:693–701.CrossRefPubMed
47.
Bellone G, Aste-Amezaga M, Trinchieri G, Rodeck U. Regulation of NK cell functions by TGF-beta 1. J Immunol. 1995;155:1066–73.PubMed
48.
Schmierer B, Hill CS. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007;8:970–82.CrossRefPubMed
49.
Nishimura EK, Suzuki M, Igras V, Du J, Lonning S, Miyachi Y, et al. Key roles for transforming growth factor beta in melanocyte stem cell maintenance. Cell Stem Cell. 2010;6:130–40.CrossRefPubMedPubMedCentral
Metadata
Title
Hair regrowth in alopecia areata patients following Stem Cell Educator therapy
Authors
Yanjia Li
Baoyong Yan
Hepeng Wang
Heng Li
Quanhai Li
Dong Zhao
Yana Chen
Ye Zhang
Wenxia Li
Jun Zhang
Shanfeng Wang
Jie Shen
Yunxiang Li
Edward Guindi
Yong Zhao
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2015
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-015-0331-6

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