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 language | English |
|---|---|
| Journal | Journal of Allergy and Clinical Immunology |
| Volume | 127 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 2011 |
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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 journal › Article
}
TY - JOUR
T1 - In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency
AU - Selleri, Silvia
AU - Brigida, Immacolata
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
AU - Grazia Roncarolo, Maria
AU - Aiuti, Alessandro
PY - 2011/6
Y1 - 2011/6
N2 - 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.
AB - 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.
KW - ADA-SCID
KW - cell cycle
KW - Gene therapy
KW - immune reconstitution
KW - senescence
UR - http://www.scopus.com/inward/record.url?scp=79957838337&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79957838337&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2011.03.004
DO - 10.1016/j.jaci.2011.03.004
M3 - Article
C2 - 21477850
AN - SCOPUS:79957838337
VL - 127
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 6
ER -