Host natural killer immunity is a key indicator of permissiveness for donor cell engraftment in patients with severe combined immunodeficiency Amel Hassan,

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Presentation transcript:

Host natural killer immunity is a key indicator of permissiveness for donor cell engraftment in patients with severe combined immunodeficiency Amel Hassan, MD, Pamela Lee, MD, Paraskevi Maggina, MD, Jin Hua Xu, BSc, Diana Moreira, MD, Mary Slatter, MBBS, Zohreh Nademi, PhD, Austen Worth, BMBCh, Stuart Adams, PhD, Alison Jones, MBBCh, Catherine Cale, MBBS, Zoe Allwood, MPH, Kanchan Rao, MBBS, Robert Chiesa, MD, Persis Amrolia, MBBS, Hubert Gaspar, MBBS, E. Graham Davies, MBBChir, Paul Veys, MBBS, Andrew Gennery, MBBS, Waseem Qasim, MBBS Journal of Allergy and Clinical Immunology Volume 133, Issue 6, Pages 1660-1666 (June 2014) DOI: 10.1016/j.jaci.2014.02.042 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 On the basis of donor type, overall survival of infants with SCID after nonconditioned allo-SCT with MSD or MFD donors (49/77 infusions) was 90%, and that after matched unrelated grafts (MUD) and haploidentical (Haplo) transplantations (28/77 infusions) was 62%. Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, Primary NK deficiency was defined as less than 100 × 106/L, and NK cell counts were low in children with T−B+ SCID (SCID-X1 and Jak3 deficiency) and ADA deficiency. SCID disorders with normal NK cell numbers (mean, 538 × 106/L) were heterogeneous and included both T−B+ SCID and T−B− SCID disorders. B, On the basis of the absence or presence of NK cells, overall survival after nonconditioned transplantations for NK−SCID was 87% compared with 62% for NK+SCID (P < .01). C, Event-free survival, which was defined as survival without the need for a subsequent procedure, was 81% for patients with NK−SCID compared with 42% in the NK+ group (P < .005). NK+ve, NK+; NK-ve, NK−. Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 CD3 T-cell recovery was superior for patients with NK−SCID, with normalization of counts in most children, in contrast to those with NK+SCID disorders. NK+ve, NK+; NK-ve, NK−. Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 A, CD4 T-cell count recovery for NK+SCID was poorer than for NK−SCID or ADA-SCID. The source of the donor graft is highlighted. F, MFD; H, haploidentical; S, MSD; U, matched unrelated donor. B, Naive CD4 T-cell recovery provided an indication of thymopoiesis, and recovery was greatest in patients with NK−SCID, intermediate in patients with ADA-SCID, and low in patients with NK+SCID. NK+ve, NK+; NK-ve, NK−. Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 High levels of donor T-cell (CD3) engraftment were achieved in patients with NK−SCID and ADA-SCID, but a number of children with NK+SCID had mixed T-cell chimerism. NK+ve, NK+; NK-ve, NK−. Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Phenotypic classifications of SCID are based on the presence or absence of T, B, and NK cells. The genetic basis of SCID disorders can now be elucidated in the majority of infants, although historically, transplantation has often proceeded before mutations could be identified. T−B+NK− disorders arise after blocks in T and NK cell development, and we speculate that in these infants vacant and receptive bone marrow niches are receptive and permissive for engraftment of donor-derived precursors without conditioning. The presence of circulating NK cells is strongly indicative that common T/NK niches are occupied, and this might result in engraftment competition with donor precursors. Certain disorders with a T−B+NK+ phenotype (eg, IL-7 receptor deficiency and CD3 signaling defects) might be more permissive than T−B−NK+ disorders, perhaps reflecting an intermediate stage of T-cell (but not NK cell) developmental arrest. Here transplantation without conditioning might well be successful, but in other NK+ conditions, including defects of VDJ recombination, conditioning is likely to be required to clear niches and secure precursor engraftment. In the case of ADA-SCID, accumulation of toxic metabolites compromises all lymphoid lineages as shown, but detoxification after nonconditioned transplantation can be sufficient to ensure engraftment of long-term multilineage progenitors. CIITA, Class II transactivator; CLP, common lymphoid progenitor; DNA-PK, DNA protein kinases; DP-T, double positive T cells; IL7Rα, IL-7 receptor α; RAG, recombination-activating gene; RFX5, regulatory factor X5; RFXANK, regulatory factor X ankyrin repeat containing; RFXAP, regulatory factor X5 associated protein RMRP, mitochondrial RNA-processing endoribonuclease; Stim1, stromal interaction molecule 1; TAP, transporter associated with antigen processing; ZAP70, ζ chain–associated protein of 70 kDa. Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2014 133, 1660-1666DOI: (10.1016/j.jaci.2014.02.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions