1. In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency
- Author
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Alessia Scarselli, Sarah Marktel, Francesca Ferrua, Barbara Cappelli, Immacolata Brigida, Shimon Slavin, Caterina Cancrini, Barbara Cassani, Miriam Casiraghi, Memet Aker, Alessandro Aiuti, Maria Grazia Roncarolo, Samantha Scaramuzza, Silvia Selleri, Selleri, S, Brigida, I, Casiraghi, M, Scaramuzza, S, Cappelli, B, Cassani, B, Ferrua, F, Aker, M, Slavin, S, Scarselli, A, Cancrini, C, Marktel, S, Roncarolo, MARIA GRAZIA, and Aiuti, Alessandro
- Subjects
Adult ,Adenosine Deaminase ,Lymphocyte ,T cell ,Genetic enhancement ,Immunology ,CD34 ,Biology ,Transplantation, Autologous ,03 medical and health sciences ,0302 clinical medicine ,Agammaglobulinemia ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Humans ,Transplantation, Homologous ,Child ,Cellular Senescence ,030304 developmental biology ,Bone Marrow Transplantation ,0303 health sciences ,Cell Cycle ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell ,Receptors, Antigen, T-Cell, gamma-delta ,Genetic Therapy ,Telomere ,3. Good health ,Haematopoiesis ,medicine.anatomical_structure ,Retroviridae ,Case-Control Studies ,Severe Combined Immunodeficiency ,Bone marrow ,Stem cell ,Immunologic Memory ,030215 immunology ,Granulocytes - 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. (J Allergy Clin Immunol 2011;127:1368-75.) 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.
- Published
- 2010