Treatment of X-Linked Severe Combined Immunodeficiency by in Utero Transplantation of Paternal Bone Marrow

Flake, Alan W.; Roncarolo, Maria Grazia; Puck, Jennifer M.; Almeida-Porada, Graça; Evans, Mark I.; Johnson, Mark P.; Abella, Estaban M.; Harrison, Duane D.; Zanjani, Esmail D.

doi:10.1056/nejm199612123352404

Cited by 334 publications

(180 citation statements)

References 24 publications

(17 reference statements)

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“…In spite of the results from animal models, the clinical success of IUHCTx for congenital disorders has been hampered by poor donor cell engraftment except in severe combined immunodeficiency (8,9), in which there is a clear survival advantage for transplanted cells without a host adaptive immune response. While there are many potential barriers to engraftment, such as cell dose, technique of transplantation, and lack of competitive advantage of transplanted cells (10), the host immune system, even in the fetus, may be an important barrier to consider.…”

Section: Introductionmentioning

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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Section: Introductionmentioning

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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“…14 Indeed, introduction of foreign substances, such as hematopoietic stem cells, results in engraftment in human fetuses only if transplantation is initiated before 16-20 weeks of gestation or if the recipient is immunocompromised. 15,16 It is not known whether adenovirus-mediated gene therapy initiated before immune development in species other than the mouse can result in prolonged gene expression.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary inflammation associated with repeated, prenatal exposure to an E1, E3-deleted adenoviral vector in sheep

et al. 1999

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Fetal gene therapy may prove useful in treating diseases electively killed and 13 died in utero. The incidence of morthat manifest in the perinatal or early postnatal period.tality was higher than the р10% we have experienced with Adenoviruses effectively transfer gene expression to a varother fetal sheep studies and was not likely related to comiety of tissues but also stimulate inflammatory and immune plications arising from surgical or anesthetic procedures. responses. The purpose of this study was to test the Inflammatory and fibrotic responses were observed in the hypothesis that exposure of fetal sheep to a first generation lungs and may represent untoward long-term conseadenovirus vector encoding bacterial ␤-galactosidase, quences of in utero adenoviral gene therapy. Tolerance to Av1nBg, before the development of the immune system, is Av1nBg was not established, and repeated exposure to safe, minimizes inflammatory and immune responses and Av1nBg before birth was associated with significant patholinduces tolerance. A total of 22 fetal sheep was studied; of ogy and mortality. these, two were born with respiratory distress, seven were

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“…[11][12][13] Indeed, gene therapy has been performed by transfecting HUCB in ADA-deficient SCID patients using fresh cord blood cells 14 and cryopreserved HUCB. 15 The fact that related cord blood reconstitutes the lymphoid functions in non-myeloablated SCID children is potentially very important for two reasons: first, related cord blood banking programs have been initiated all over the world but it is not clear yet what the cost-benefits ratio of these programs will be; second, up to now, lymphoid functions have been reconstituted best in non-ablated SCID patients when the children had been transplanted in utero. 16,17 As opposed to in utero transplantation after the 16th week of gestation that is generally unsuccessful in human beings, SCID is an ideal disease for this treatment because graft rejection is unlikely.…”

Section: Discussionmentioning

confidence: 99%

Successful human umbilical cord blood stem cell transplantation without conditioning in severe combined immune deficiency

Toren

Nagler

Amariglio

et al. 1999

Bone Marrow Transplant

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Summary:A 2-month-old girl with severe combined immunodeficiency (SCID), presented with mild staphylococcal skin infection, lymphopenia, low T cell number, absence of B cells, high number of NK cells, and a negligible response to mitogens. Since her older brother died as a result of SCID 2 years earlier, cord blood was harvested from a sister born 2. years earlier, who was normal and fully matched both by serology and molecular typing. In view of her clinical condition and in spite of a high number of NK cells with normal activity, HUCBT without preparative conditioning was performed. No G-CSF was administered. Engraftment with mixed chimerism was evident 3 weeks post transplantation. There were no peritransplantation complications. Eighteen months post transplantation, the girl is in excellent condition, blood counts are normal, T cell engraftment is complete, B cell engraftment is proceeding gradually, and the mitogen stimulation tests are normal. Due to the unique nature of HUCB hematopoietic cells, engraftment without conditioning may be possible in patients with SCID with fully matched donors. This is the first HUCBT performed without conditioning. Keywords: severe combined immunodeficiency (SCID); human umbilical cord blood transplantation (HUCBT); microsatellite sequences; mixed chimerism Severe combined immunodeficiency (SCID) is a heterogenous, lethal, congenital disorder of lymphoid progenitors resulting in the failure of T cells to respond to mitogens and specific antigens, and the inability of B cells to produce specific antibodies. SCID immunophenotypes can be classified according to the presence (B+ SCID) or absence (BϪ SCID) of B cells in the peripheral blood of the patients. 1 There are several causes for the more common B+ SCID

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Treatment of X-Linked Severe Combined Immunodeficiency by in Utero Transplantation of Paternal Bone Marrow

Cited by 334 publications

References 24 publications

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

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

Pulmonary inflammation associated with repeated, prenatal exposure to an E1, E3-deleted adenoviral vector in sheep

Successful human umbilical cord blood stem cell transplantation without conditioning in severe combined immune deficiency

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