Fabien Touzot1, Bénédicte Neven2, Liliane Dal-Cortivo3, Aurélie Gabrion3, Despina Moshous2, Guilhem Cros4, Maryline Chomton4, Jean-Marc Luby3, Brigitte Terniaux3, Jérémy Magalon5, Capucine Picard6, Stéphane Blanche4, Alain Fischer7, Marina Cavazzana8. 1. Département de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France. Electronic address: fabien.touzot@nck.aphp.fr. 2. Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie-Hématologie et Rhumatologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France; INSERM UMR1163, Paris, France. 3. Département de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. 4. Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie-Hématologie et Rhumatologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. 5. Département de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France. 6. Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Centre d'étude des déficits immunitaires (CEDI), Hôpital Necker-Enfants Malades, AP-HP, Paris, France; INSERM UMR1163, Paris, France. 7. Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; Unité d'Immunologie-Hématologie et Rhumatologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France; INSERM UMR1163, Paris, France; College de France, Paris, France. 8. Département de Biothérapie, Centre d'Investigation Clinique intégré en Biothérapies, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Paris, France; INSERM UMR1163, Paris, France.
Abstract
BACKGROUND: Combined immunodeficiencies (CIDs) form a heterogeneous group of inherited conditions that affect the development, function, or both of T cells. The treatment of CIDs with allogeneic hematopoietic stem cell transplantation (HSCT) is complicated by a high incidence of life-threatening infections and an increased risk of graft-versus-host disease (GVHD). OBJECTIVE: In view of the growing evidence that alloreactivity is mainly derived from human naive T cells, the selective depletion of naive T cells from allografts might constitute a way of reducing alloreactivity while maintaining memory T-cell responsiveness to pathogens. METHODS: Five consecutive patients with CIDs and chronic viral infections underwent an allogeneic, HLA-mismatched HSCT. Given the patients' infection status and the potential risk of severe GVHD in the mismatched setting, the CD34(-) fraction of the allograft was depleted of naive T cells by using magnetic CD45RA beads. RESULTS: Engraftment occurred in 4 of the 5 patients. No severe GVHD occurred. In the 4 engrafted patients viral infections were cleared within 2 months of the HSCT, and both cellular and humoral immunity were re-established within a year of the HSCT. An early T-cell response against viral pathogens was documented in 2 patients. CONCLUSION: The present pilot study shows that clinical-grade depletion of naive T cells from an allograft through the use of magnetic CD45RA beads seems to be a feasible and efficacious option for the treatment of patients with CIDs at high risk of GVHD, infection, or both in an HLA-mismatched setting.
BACKGROUND: Combined immunodeficiencies (CIDs) form a heterogeneous group of inherited conditions that affect the development, function, or both of T cells. The treatment of CIDs with allogeneic hematopoietic stem cell transplantation (HSCT) is complicated by a high incidence of life-threatening infections and an increased risk of graft-versus-host disease (GVHD). OBJECTIVE: In view of the growing evidence that alloreactivity is mainly derived from human naive T cells, the selective depletion of naive T cells from allografts might constitute a way of reducing alloreactivity while maintaining memory T-cell responsiveness to pathogens. METHODS: Five consecutive patients with CIDs and chronic viral infections underwent an allogeneic, HLA-mismatched HSCT. Given the patients' infection status and the potential risk of severe GVHD in the mismatched setting, the CD34(-) fraction of the allograft was depleted of naive T cells by using magnetic CD45RA beads. RESULTS: Engraftment occurred in 4 of the 5 patients. No severe GVHD occurred. In the 4 engrafted patientsviral infections were cleared within 2 months of the HSCT, and both cellular and humoral immunity were re-established within a year of the HSCT. An early T-cell response against viral pathogens was documented in 2 patients. CONCLUSION: The present pilot study shows that clinical-grade depletion of naive T cells from an allograft through the use of magnetic CD45RA beads seems to be a feasible and efficacious option for the treatment of patients with CIDs at high risk of GVHD, infection, or both in an HLA-mismatched setting.
Authors: Lori Muffly; Kevin Sheehan; Randall Armstrong; Kent Jensen; Keri Tate; Andrew R Rezvani; David Miklos; Sally Arai; Judith Shizuru; Laura Johnston; Everett Meyer; Wen-Kai Weng; Ginna G Laport; Robert S Negrin; Sam Strober; Robert Lowsky Journal: Blood Adv Date: 2018-03-27
Authors: Patrick M Brauer; Jastaranpreet Singh; Sintia Xhiku; Juan Carlos Zúñiga-Pflücker Journal: Trends Immunol Date: 2016-10-24 Impact factor: 16.687
Authors: Dongrui Wang; Brenda Aguilar; Renate Starr; Darya Alizadeh; Alfonso Brito; Aniee Sarkissian; Julie R Ostberg; Stephen J Forman; Christine E Brown Journal: JCI Insight Date: 2018-05-17
Authors: Marie Bleakley; Shelly Heimfeld; Keith R Loeb; Lori A Jones; Colette Chaney; Stuart Seropian; Ted A Gooley; Franziska Sommermeyer; Stanley R Riddell; Warren D Shlomchik Journal: J Clin Invest Date: 2015-06-08 Impact factor: 14.808