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.

Keywords: DNA repair; Severe combined immunodeficiency; hematopoietic cell transplantation; nonhomologous end joining; radiation sensitivity.

Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

A. A. DNA is uncoiled at transcription “factories” within the cell, where the associated recombination and repair proteins co-localize. B. The lymphoid specific recombinase activating gene 1 and 2 (RAG1/2) proteins recognize and bind the recombination signal sequences (RSS) that flank the V(D)J gene segments, and introduce site-specific DNA-DSBs. C. The phosphorylated blunt signal ends and the covalently sealed hairpin intermediate of the coding end are held together by the RAG complex. B. D. The MRN complex binds the broken DNA ends and activates ATM which initiates cell cycle arrest and attraction of the repair proteins. H2AX, 53BP1 and RNF168, and with other proteins stabilize the damaged chromatin. Ei. Ku70/Ku80 heterodimer binds the coding ends and recruits DNA-PKcs and Artemis, which is required to open the hairpin intermediates. The covalently sealed hairpin intermediate is randomly nicked by the DNA-Pkcs/Artemis complex, which generates a single stranded break with 3’ or 5’ overhangs. Eii. XRCC4, DNA ligase 4 and cernunnos-XLF (C-XLF) co-associate and are recruited to the ends. The signal ends are directly ligated by the XRCC4/DNALIG4/ C-XLF complex. The opened hairpin intermediate is modified by polymerases, exonucleases and the lymphoid-specific terminal deoxynucleotidyl transferase (TdT), before Eiii. being repaired and ligated by the XRCC4/DNA-LIG4/C-XLF complex

Figure 1

A. A. DNA is uncoiled at transcription “factories” within the cell, where the associated recombination and repair proteins co-localize. B. The lymphoid specific recombinase activating gene 1 and 2 (RAG1/2) proteins recognize and bind the recombination signal sequences (RSS) that flank the V(D)J gene segments, and introduce site-specific DNA-DSBs. C. The phosphorylated blunt signal ends and the covalently sealed hairpin intermediate of the coding end are held together by the RAG complex. B. D. The MRN complex binds the broken DNA ends and activates ATM which initiates cell cycle arrest and attraction of the repair proteins. H2AX, 53BP1 and RNF168, and with other proteins stabilize the damaged chromatin. Ei. Ku70/Ku80 heterodimer binds the coding ends and recruits DNA-PKcs and Artemis, which is required to open the hairpin intermediates. The covalently sealed hairpin intermediate is randomly nicked by the DNA-Pkcs/Artemis complex, which generates a single stranded break with 3’ or 5’ overhangs. Eii. XRCC4, DNA ligase 4 and cernunnos-XLF (C-XLF) co-associate and are recruited to the ends. The signal ends are directly ligated by the XRCC4/DNALIG4/ C-XLF complex. The opened hairpin intermediate is modified by polymerases, exonucleases and the lymphoid-specific terminal deoxynucleotidyl transferase (TdT), before Eiii. being repaired and ligated by the XRCC4/DNA-LIG4/C-XLF complex