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

Abstract

Background: Severe combined immunodeficiency (SCID) can be cured by using allogeneic hematopoietic stem cell transplantation, and the absence of host immunity often obviates the need for preconditioning. Depending on the underlying genetic defect and when blocks in differentiation occur during lymphocyte ontogeny, infants with SCID have absent or greatly reduced numbers of functional T cells. Natural killer (NK) cell populations are usually absent in the SCID-X1 and Janus kinase 3 forms of SCID and greatly reduced in adenosine deaminase deficiency SCID but often present in other forms of the disorder.

Objective: To determine if SCID phenotypes indicate host permissiveness to donor cell engraftment.

Methods: A retrospective data analysis considered whether host NK cells influenced donor T-cell engraftment, immune reconstitution, and long-term outcomes in children who had undergone nonconditioned allogeneic stem cell transplantation between 1990 and 2011 in the United Kingdom. Detailed analysis of T- and B-cell immune reconstitution and donor chimerism was compared between the NK(+) (n = 24) and NK(-) (n = 53) forms of SCID.

Results: Overall, 77 children underwent transplantation, with survival of 90% in matched sibling donor/matched family donor transplants compared with 60% when alternative donors were used. Infants with NK(-)SCID were more likely to survive than NK(+) recipients (87% vs 62%, P < .01) and had high-level donor T-cell chimerism with superior long-term recovery of CD4 T-cell immunity. Notably, 33% of children with NK(+)SCID required additional transplantation procedures compared with only 8% of children with NK(-)SCID (P < .005).

Conclusions: NK(-)SCID disorders are highly permissive for donor T-cell engraftment without preconditioning, whereas the presence of NK cells is a strong indicator that preparative conditioning is required for engraftment of T-cell precursors capable of supporting robust T-cell reconstitution.

Keywords: Severe combined immunodeficiency; adenosine deaminase deficiency; chimerism; conditioning; engraftment; natural killer cells.

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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%.

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⁻.

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⁻.

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⁻.

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⁻.

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.