title: Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do?
abstract: Defects in DNA cross-link repair 1C (DCLRE1C), protein kinase DNA activated catalytic polypeptide (PRKDC), ligase 4 (LIG4), NHEJ1, and NBS1 involving the nonhomologous end-joining (NHEJ) DNA repair pathway result in radiation-sensitive severe combined immunodeficiency (SCID). Results of hematopoietic cell transplantation for radiation-sensitive SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of preconditioning with alkylating agents is associated with a greater likelihood of full T- and B-cell reconstitution compared with no conditioning or immunosuppression alone. A reduced-intensity regimen using fludarabine and low-dose cyclophosphamide might be effective for patients with LIG4, NHEJ1, and NBS1 defects, although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose-alkylating agents without significant late effects. Until nonchemotherapy agents, such as anti-CD45 or anti-CD117, become available, options include minimizing exposure to alkylators, such as single-agent low-dose targeted busulfan, or achieving T-cell reconstitution, followed several years later with a conditioning regimen to restore B-cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and graft-versus-host disease. Prospective multicenter studies are needed to evaluate these approaches in this rare but highly vulnerable patient population.
authors.affiliation: Allergy Immunology and Blood and Marrow Transplant Division, University of California San Francisco Benioff Children's Hospital, San Francisco, Calif. Electronic address: mcowan@peds.ucsf.edu.
authors.forename: Morton J
authors.initials: MJ
authors.lastname: Cowan
authors.affiliation: Paediatric Immunology Department, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Gennery
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D051747:DNA-Activated Protein Kinase / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004720:Endonucleases; D015316:Genetic Therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007167:Immunotherapy; D009687:Nuclear Proteins / Q000235:genetics; D011827:Radiation; D011836:Radiation Tolerance / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000276:immunology* / Q000628:therapy; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; C112156:NBN protein, human; C508551:NHEJ1 protein, human; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; C426344:DCLRE1C protein, human; D004720:Endonucleases; D011088:DNA Ligases; D045643:DNA Repair Enzymes; D000072481:DNA Ligase ATP
keywords: DNA repair; Severe combined immunodeficiency; hematopoietic cell transplantation; nonhomologous end joining; radiation sensitivity