BACKGROUND: Thalassemia major can be cured with allogeneic hematopoietic stem cell transplantation. Persistent mixed chimerism develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood. DESIGN AND METHODS: The presence of interleukin-10-producing T cells in the peripheral blood of eight patients with persistent mixed chimerism and five with full donor chimerism was investigated. A detailed characterization was then performed, by T-cell cloning, of the effector and regulatory T-cell repertoire of one patient with persistent mixed chimerism, who developed stable split erythroid/lymphoid chimerism after a hematopoietic stem cell transplant from an HLA-matched unrelated donor. RESULTS: Higher levels of interleukin-10 were produced by peripheral blood mononuclear cells from patients with persistent mixed chimerism than by the same cells from patients with complete donor chimerism or normal donors. T-cell clones of both host and donor origin could be isolated from the peripheral blood of one, selected patient with persistent mixed chimerism. Together with effector T-cell clones reactive against host or donor alloantigens, regulatory T-cell clones with a cytokine secretion profile typical of type 1 regulatory cells were identified at high frequencies. Type 1 regulatory cell clones, of both donor and host origin, were able to inhibit the function of effector T cells of either donor or host origin in vitro. CONCLUSIONS: Overall these results suggest that interleukin-10 and type 1 regulatory cells are associated with persistent mixed chimerism and may play an important role in sustaining long-term tolerance in vivo. These data provide new insights into the mechanisms of peripheral tolerance in chimeric patients and support the use of cellular therapy with regulatory T cells following hematopoietic stem cell transplantation.
BACKGROUND:Thalassemia major can be cured with allogeneic hematopoietic stem cell transplantation. Persistent mixed chimerism develops in around 10% of transplanted thalassemic patients, but the biological mechanisms underlying this phenomenon are poorly understood. DESIGN AND METHODS: The presence of interleukin-10-producing T cells in the peripheral blood of eight patients with persistent mixed chimerism and five with full donor chimerism was investigated. A detailed characterization was then performed, by T-cell cloning, of the effector and regulatory T-cell repertoire of one patient with persistent mixed chimerism, who developed stable split erythroid/lymphoid chimerism after a hematopoietic stem cell transplant from an HLA-matched unrelated donor. RESULTS: Higher levels of interleukin-10 were produced by peripheral blood mononuclear cells from patients with persistent mixed chimerism than by the same cells from patients with complete donor chimerism or normal donors. T-cell clones of both host and donor origin could be isolated from the peripheral blood of one, selected patient with persistent mixed chimerism. Together with effector T-cell clones reactive against host or donor alloantigens, regulatory T-cell clones with a cytokine secretion profile typical of type 1 regulatory cells were identified at high frequencies. Type 1 regulatory cell clones, of both donor and host origin, were able to inhibit the function of effector T cells of either donor or host origin in vitro. CONCLUSIONS: Overall these results suggest that interleukin-10 and type 1 regulatory cells are associated with persistent mixed chimerism and may play an important role in sustaining long-term tolerance in vivo. These data provide new insights into the mechanisms of peripheral tolerance in chimeric patients and support the use of cellular therapy with regulatory T cells following hematopoietic stem cell transplantation.
Authors: J Kapelushnik; R Or; D Filon; A Nagler; G Cividalli; M Aker; E Naparstek; S Slavin; A Oppenheim Journal: Blood Date: 1995-10-15 Impact factor: 22.113
Authors: M Andreani; M Manna; G Lucarelli; P Tonucci; F Agostinelli; M Ripalti; S Rapa; N Talevi; M Galimberti; S Nesci Journal: Blood Date: 1996-04-15 Impact factor: 22.113
Authors: G Lucarelli; R A Clift; M Galimberti; E Angelucci; C Giardini; D Baronciani; P Polchi; M Andreani; D Gaziev; B Erer; A Ciaroni; F D'Adamo; F Albertini; P Muretto Journal: Blood Date: 1999-02-15 Impact factor: 22.113
Authors: Nicola Gagliani; Chiara F Magnani; Samuel Huber; Monica E Gianolini; Mauro Pala; Paula Licona-Limon; Binggege Guo; De'Broski R Herbert; Alessandro Bulfone; Filippo Trentini; Clelia Di Serio; Rosa Bacchetta; Marco Andreani; Leonie Brockmann; Silvia Gregori; Richard A Flavell; Maria-Grazia Roncarolo Journal: Nat Med Date: 2013-04-28 Impact factor: 53.440