Tolerogenic effect of mesenchymal stromal cells on gliadin-specific T lymphocytes in celiac disease.
OBJECTIVE
Celiac disease is caused by a dysregulated immune response toward dietary gluten, whose only treatment is a lifelong gluten-free diet. We investigated the effects of mesenchymal stromal cells (MSCs) on gliadin-specific T cells, which are known to induce intestinal lesions, in view of a possible use as new therapy.


METHODS
Bone marrow-derived MSCs and gliadin-specific T-cell lines were obtained from allogeneic donors and mucosal specimens of celiac patients, respectively. The immunosuppressant effect of MSCs was evaluated in terms of proliferative response and interferon (IFN)-γ production upon gliadin stimulation of long-term T-cell lines; the immunomodulant effect was assessed in terms of apoptotic rate, immunophenotype and cytokine profile of short-term T-cell lines generated in the presence of MSCs. Different MSC:T-cell ratios were applied, and statistics were performed as appropriate.


RESULTS
MSCs inhibited both proliferative response and IFN-γ production of long-term T-cell lines in a dose-dependent manner while limiting the expansion of short-term T-cell lines by increasing the apoptotic rate. Moreover, a reduction of the CD4(+) population and expansion of the regulatory FoxP3+ subset were found in T-cell lines cultured with MSCs, in which a significant decrease of interleukin (IL)-21, IFN-γ and IL-10 paralleled by an upregulation of transforming growth factor-β1, IL-6 and IL-8 were observed. Finally, an increase of the indoleamine 2,3-dioxygenase activity was found, possibly playing a key role in mediating these effects.


CONCLUSIONS
MSCs exert potent immunomodulant effects on gliadin-specific T cells, which may be exploited for future therapeutic application in celiac disease.
Clinica Medica I, Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy. Electronic address: rachele.ciccocioppo@unipv.it.
Rachele
R
Ciccocioppo
Istituto Scienze dell'Alimentazione, CNR Avellino, Italy.
Alessandra
A
Camarca
Clinica Medica I, Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy.
Giuseppina Cristina
GC
Cangemi
Istituto Scienze dell'Alimentazione, CNR Avellino, Italy.
Giorgia
G
Radano
Istituto Scienze dell'Alimentazione, CNR Avellino, Italy.
Serena
S
Vitale
Clinica Medica I, Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy.
Elena
E
Betti
Dipartimento di Bioscienze, Università di Parma, Italy (currently affiliated with Dipartimento di Biochimica e Biologia Molecolare, Università di Parma, Italy; Dipartimento di Medicina Occupazionale, Ergonomia e Disabilità, Laboratorio di Nanotecnologia, Fondazione IRCCS Salvatore Maugeri, Università di Pavia, Italy).
Davide
D
Ferrari
Laboratorio di Nanotecnologia, Fondazione IRCCS Salvatore Maugeri, Università di Pavia, Italy (currently affiliated with Dipartimento di Medicina Occupazionale, Ergonomia e Disabilità, Laboratorio di Nanotecnologia, Fondazione IRCCS Salvatore Maugeri, Università di Pavia, Italy; Dipartimento di Medicina Molecolare, Centro di Ingegneria Tissutale, INSTM UdR Pavia, Università di Pavia, Italy).
Livia
L
Visai
Servizio di Endoscopia Digestiva, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Elena
E
Strada
Servizio di Immunogenetica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Carla
C
Badulli
Dipartimento di Onco-Ematologia Pediatrica e Medicina Trasfusionale, Ospedale Bambino Gesù, Roma e Università degli Studi di Pavia, Pavia, Italy.
Franco
F
Locatelli
Servizio di Biometria e Statistica, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
Catherine
C
Klersy
Istituto Scienze dell'Alimentazione, CNR Avellino, Italy.
Carmen
C
Gianfrani
Clinica Medica I, Fondazione IRCCS Policlinico San Matteo, Università di Pavia, Pavia, Italy.
Gino Roberto
GR
Corazza
D000293:Adolescent; D000328:Adult; D000368:Aged; D002446:Celiac Disease / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D005260:Female; D005903:Gliadin / Q000276:immunology; D005983:Glutens / Q000633:toxicity; D006801:Humans; D007108:Immune Tolerance; D007165:Immunosuppression Therapy / Q000379:methods; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology
D005983:Glutens; D007371:Interferon-gamma; D005903:Gliadin
T lymphocytes; celiac disease; immune tolerance; mesenchymal stromal cells