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In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency
In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 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, M. G., Aiuti, A. 2011; 127 (6): 1368-U95Abstract
Gene therapy (GT) with hematopoietic stem cells is a promising treatment for inherited immunodeficiencies.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.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).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.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.
View details for DOI 10.1016/j.jaci.2011.03.004
View details for Web of Science ID 000291048500007
View details for PubMedID 21477850