In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency

Silvia Selleri, Immacolata Brigida, Miriam Casiraghi, Samantha Scaramuzza, Barbara Cappelli, Barbara Cassani, Francesca Ferrua, Memet Aker, Shimon Slavin, Alessia Scarselli, Caterina Cancrini, Sarah Marktel, Maria Grazia Roncarolo, Alessandro Aiuti

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Gene therapy (GT) with hematopoietic stem cells is a promising treatment for inherited immunodeficiencies. Objectives: Limited information is available on the relative contribution of de novo thymopoiesis and peripheral expansion to T-cell reconstitution after GT as well as on the potential effects of gene transfer on hematopoietic stem cells and lymphocyte replicative lifespan. We studied these issues in patients affected by adenosine deaminase severe combined immune deficiency after low-intensity conditioning and reinfusion of retrovirally transduced autologous CD34+ cells. Methods: Immunophenotype, proliferative status, telomere length, and T-cell receptor excision circles were investigated at early and late time points (up to 9 years) after GT treatment. Control groups consisted of pediatric healthy donors and patients undergoing allogeneic bone marrow transplantation (BMT). Results: We observed no telomere shortening in the bone marrow compartment and in granulocytes, whereas peripheral blood naive T cells from both GT and BMT patients showed a significant reduction in telomere length compared with healthy controls. This was in agreement with the presence of a high fraction of actively cycling naive and memory T cells and lower T-cell receptor excision circles. Conclusion: These data indicate that T-cell homeostatic expansion contributes substantially to immune reconstitution, like BMT, and is not associated with senescence in the stem cell compartment.

Original languageEnglish
JournalJournal of Allergy and Clinical Immunology
Volume127
Issue number6
DOIs
Publication statusPublished - Jun 2011

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Severe Combined Immunodeficiency
Adenosine Deaminase
Cell- and Tissue-Based Therapy
Hematopoietic Stem Cells
Genetic Therapy
Bone Marrow Transplantation
T-Lymphocytes
Telomere
T-Cell Antigen Receptor
Telomere Shortening
Homologous Transplantation
Granulocytes
Stem Cells
Bone Marrow
Tissue Donors
Lymphocytes
Pediatrics
Control Groups
Therapeutics
Genes

Keywords

  • ADA-SCID
  • cell cycle
  • Gene therapy
  • immune reconstitution
  • senescence

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency. / Selleri, Silvia; Brigida, Immacolata; Casiraghi, Miriam; Scaramuzza, Samantha; Cappelli, Barbara; Cassani, Barbara; Ferrua, Francesca; Aker, Memet; Slavin, Shimon; Scarselli, Alessia; Cancrini, Caterina; Marktel, Sarah; Grazia Roncarolo, Maria; Aiuti, Alessandro.

In: Journal of Allergy and Clinical Immunology, Vol. 127, No. 6, 06.2011.

Research output: Contribution to journalArticle

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AU - Casiraghi, Miriam

AU - Scaramuzza, Samantha

AU - Cappelli, Barbara

AU - Cassani, Barbara

AU - Ferrua, Francesca

AU - Aker, Memet

AU - Slavin, Shimon

AU - Scarselli, Alessia

AU - Cancrini, Caterina

AU - Marktel, Sarah

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AU - Aiuti, Alessandro

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