Published online 16 July 2009
Haematologica, Vol 94, Issue 10, 1415-1426 doi:10.3324/haematol.2008.003129
Copyright © 2009 by Ferrata Storti Foundation

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Stem Cell Transplantation

Type 1 regulatory T cells are associated with persistent split erythroid/lymphoid chimerism after allogeneic hematopoietic stem cell transplantation for thalassemia

Giorgia Serafini^1,2, Marco Andreani¹, Manuela Testi¹, MariaRosa Battarra¹, Andrea Bontadini³, Eika Biral^4,5, Katharina Fleischhauer², Sarah Marktel⁴, Guido Lucarelli¹, Maria Grazia Roncarolo^2,5, Rosa Bacchetta^2,4

¹ Mediterranean Institute of Hematology (IME Foundation), Policlinico di Tor Vergata, Rome
² San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Milan
³ Blood Transfusion Service, Ospedale S. Orsola-Malpighi, Bologna
⁴ Pediatric Immunology and Hematology Unit, San Raffaele Scientific Institute, Milan
⁵ Vita-Salute San Raffaele University, Milan, Italy

Correspondence: Maria Grazia Roncarolo, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Via Olgettina 58, 20132, Milan, Italy. E-mail:roncarolo.mariagrazia{at}hsr.it

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.

Key words: thalassemia, hematopoietic stem cell transplantation, persistent mixed chimerism, tolerance, type 1 regulatory T (Tr1) cells.

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