Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

Durkin, Emily T.; Jones, Kelly A.; Rajesh, Deepika; Shaaban, Aimen F.

doi:10.1182/blood-2007-12-128116

Cited by 54 publications

(81 citation statements)

References 66 publications

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“…Our findings of transfer of maternal alloantibodies would suggest that a possible mechanism for this observation is activation of donor MHC class I-specific NK cells by maternal alloantibody via an ADCC mechanism in a milieu of low frequencies of donor cells. Levels of chimerism in our model of intravascular injection far exceed the threshold level of initial chimerism postulated to be required for host NK cell tolerance and subsequent durable engraftment (53). The fact that 100% of our foster-reared pups maintained stable engraftment demonstrates that fetal NK cells are not a barrier to the levels of engraftment seen in this study and supports previous data (54,55) suggesting that the milieu of high levels of donor cells during NK cell development may modify their receptor profile and reduce the frequency of donor-reactive NK cells, negating their effect.…”

Section: Discussionmentioning

confidence: 81%

Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice

Merianos¹,

Tiblad²,

Santore³

et al. 2009

J. Clin. Invest.

114

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The lack of fetal immune responses to foreign antigens, i.e., fetal immunologic tolerance, is the most compelling rationale for prenatal stem cell and gene therapy. However, the frequency of engraftment following in utero hematopoietic cell transplantation (IUHCT) in the murine model is reduced in allogeneic, compared with congenic, recipients. This observation supports the existence of an immune barrier to fetal transplantation and challenges the classic assumptions of fetal tolerance. Here, we present evidence that supports the presence of an adaptive immune response in murine recipients of IUHCT that failed to maintain engraftment. However, when IUHCT recipients were fostered by surrogate mothers, they all maintained long-term chimerism. Furthermore, we have demonstrated that the cells responsible for rejection of the graft were recipient in origin. Our observations suggest a mechanism by which IUHCT-dependent sensitization of the maternal immune system and the subsequent transmission of maternal alloantibodies to pups through breast milk induces a postnatal adaptive immune response in the recipient, which, in turn, results in the ablation of engraftment after IUHCT. Finally, we showed that non-fostered pups that maintained their chimerism had higher levels of Tregs as well as a more suppressive Treg phenotype than their non-chimeric, non-fostered siblings. This study resolves the apparent contradiction of induction of an adaptive immune response in the pre-immune fetus and confirms the potential of actively acquired tolerance to facilitate prenatal therapeutic applications.

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Section: Discussionmentioning

confidence: 81%

Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice

Merianos¹,

Tiblad²,

Santore³

et al. 2009

J. Clin. Invest.

114

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“…18 In addition to T-cell and DC interactions, other mechanisms such as NK-cell tolerance likely contribute to this threshold. 14 The surprisingly high rate of fetal loss after transplantation of alloantigen into TCR75 fetuses suggests that there is a particularly robust early indirect response in these animals. Because T cells mature earlier in TCR-Tg animals, they may be present early after transplantation to induce an immune response, until thymic antigen presentation and tolerance may be established.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8] Natural killer (NK) cell-mediated tolerance has also been described. 14 However, although chimeric animals reportedly have donor-specific Tregs, 7,15 whether these cells are critical for establishing or maintaining chimerism remains an open question.…”

Section: Introductionmentioning

confidence: 99%

Direct and indirect antigen presentation lead to deletion of donor-specific T cells after in utero hematopoietic cell transplantation in mice

Nijagal

Derderian

et al. 2013

Blood

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• Tolerance induction after in utero hematopoietic cell transplantation involves both direct and indirect antigen presentation.• Tolerance is achieved by deletion of effector T cells, which results in Treg enrichment without de novo Treg induction.In utero hematopoietic cell transplantation (IUHCTx) is a promising method to induce donor-specific tolerance but the mechanisms of antigen presentation that educate host T cells and the relative importance of deletion vs regulation in this setting are unknown. We studied the roles of direct and indirect antigen presentation (mediated by donorand host-derived antigen-presenting cells [APCs], respectively) in a mouse model of IUHCTx. We found that IUHCTx leads to precocious maturation of neonatal host dendritic cells (DCs) and that there is early differentiation of donor-derived DCs, even after transplantation of a stem cell source without mature APCs. We next performed allogeneic IUHCTx into donor-specific T-cell receptor transgenic mice and confirmed that both direct and indirect antigen presentation lead to clonal deletion of effector T cells in chimeras. Deletion did not persist when chimerism was lost. Importantly, although the percentage of regulatory T cells (Tregs) after IUHCTx increased, there was no expansion in Treg numbers. In wild-type mice, there was a similar deletion of effector cells without expansion of donor-specific Tregs. Thus, tolerance induction after IUHCTx depends on both direct and indirect antigen presentation and is secondary to thymic deletion, without de novo Treg induction. (Blood. 2013;121(22):4595-4602)

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“…In this instance, the frequency of engraftment of B6 FL in Rag1 -/-recipients was 89% (Figure 2A, n = 9, c 2 test, P = 0.83 compared with congenic controls), indicating that the barrier to IUHCTx in our model was likely due to an adaptive alloimmune response. While NK cells have been shown to be important in engraftment after IUHCTx (22,23), their effect can be overcome using high-cell doses, as we are doing in this model (24). As expected, the overall levels of chimerism in these animals were much higher (59.2% ± 7.2% compared with 22.2% ± 4.5% for allogeneic wild-type recipients, P = 0.0001), likely secondary to the competitive advantage of transplanted cells in the Rag1 -/-hosts (ref.…”

Section: Figurementioning

confidence: 99%

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

Nijagal¹,

Wegorzewska²,

Jarvis³

et al. 2011

J. Clin. Invest.

125

133

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Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we hypothesized that maternal cells trafficking into the fetus may pose the true barrier to effective IUHCTx. Here, we have demonstrated that there is macrochimerism of maternal leukocytes in the blood of unmanipulated mouse fetuses, with substantial increases in T cell trafficking after IUHCTx. To determine the contribution of these maternal lymphocytes to rejection after IUHCTx, we bred T and/or B cell-deficient mothers to wild-type fathers and performed allogeneic IUHCTx into the immunocompetent fetuses. There was a marked improvement in engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to engraftment. Furthermore, when the graft was matched to the mother, there was no difference in engraftment between syngeneic and allogeneic fetal recipients. Our study suggests that the clinical success of IUHCTx may be improved by transplanting cells matched to the mother.

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Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras

Cited by 54 publications

References 66 publications

Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice

Maternal alloantibodies induce a postnatal immune response that limits engraftment following in utero hematopoietic cell transplantation in mice

Direct and indirect antigen presentation lead to deletion of donor-specific T cells after in utero hematopoietic cell transplantation in mice

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

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