Successful Correction of Immune Defects in a Patient with NEMO Mutation by Allogeneic Transplantation Uncovers Intrinsic Epithelial Basis for Colitis

Abstract

RationaleMutations in critical components of the nuclear factor-κB (NF-κB) signaling pathway, such as NF-κB essential modulator (NEMO), result in primary immunodeficiency. Whether both the immune defects and other manifestations, such as colitis, seen in boys with NEMO mutation are correctable by allogeneic transplantation is not known.MethodsWe report a patient with NEMO mutation, immunodeficiency and corticosteroid-dependent colitis. An HLA-matched unaffected sibling was born after in vitro fertilization and preimplantation genetic diagnosis. The patient underwent sibling matched hematopoietic stem cell transplantation (HSCT) after myeloablative conditioning. Responses to Toll-like receptor (TLR) agonists, natural killer cell cytotoxicity and CD40-mediated responses were assessed pre and post-HSCT. The clinical course of colitis and corticosteroid use post-HSCT were also examined.ResultsThe patient tolerated conditioning and had 98-100% donor chimerism in all immune cells tested. Defects in responses to TLR agonists, natural killer cell cytotoxicity, and CD40-mediated proliferation were all corrected following allogeneic HSCT. However, the patient continued to have flares of colitis, often precipitated by bacterial infection, requiring treatment with corticosteroids.ConclusionsPreimplantation genetic diagnosis was used successfully in conjunction with allogeneic HSCT to correct the immune defects in a patient with NEMO mutation. However, the patient's colitis persisted. Our data strongly suggest that lack of NEMO function and NF-κB signaling in intestinal epithelium is sufficient to drive susceptibility to colitis. RationaleMutations in critical components of the nuclear factor-κB (NF-κB) signaling pathway, such as NF-κB essential modulator (NEMO), result in primary immunodeficiency. Whether both the immune defects and other manifestations, such as colitis, seen in boys with NEMO mutation are correctable by allogeneic transplantation is not known. Mutations in critical components of the nuclear factor-κB (NF-κB) signaling pathway, such as NF-κB essential modulator (NEMO), result in primary immunodeficiency. Whether both the immune defects and other manifestations, such as colitis, seen in boys with NEMO mutation are correctable by allogeneic transplantation is not known. MethodsWe report a patient with NEMO mutation, immunodeficiency and corticosteroid-dependent colitis. An HLA-matched unaffected sibling was born after in vitro fertilization and preimplantation genetic diagnosis. The patient underwent sibling matched hematopoietic stem cell transplantation (HSCT) after myeloablative conditioning. Responses to Toll-like receptor (TLR) agonists, natural killer cell cytotoxicity and CD40-mediated responses were assessed pre and post-HSCT. The clinical course of colitis and corticosteroid use post-HSCT were also examined. We report a patient with NEMO mutation, immunodeficiency and corticosteroid-dependent colitis. An HLA-matched unaffected sibling was born after in vitro fertilization and preimplantation genetic diagnosis. The patient underwent sibling matched hematopoietic stem cell transplantation (HSCT) after myeloablative conditioning. Responses to Toll-like receptor (TLR) agonists, natural killer cell cytotoxicity and CD40-mediated responses were assessed pre and post-HSCT. The clinical course of colitis and corticosteroid use post-HSCT were also examined. ResultsThe patient tolerated conditioning and had 98-100% donor chimerism in all immune cells tested. Defects in responses to TLR agonists, natural killer cell cytotoxicity, and CD40-mediated proliferation were all corrected following allogeneic HSCT. However, the patient continued to have flares of colitis, often precipitated by bacterial infection, requiring treatment with corticosteroids. The patient tolerated conditioning and had 98-100% donor chimerism in all immune cells tested. Defects in responses to TLR agonists, natural killer cell cytotoxicity, and CD40-mediated proliferation were all corrected following allogeneic HSCT. However, the patient continued to have flares of colitis, often precipitated by bacterial infection, requiring treatment with corticosteroids. ConclusionsPreimplantation genetic diagnosis was used successfully in conjunction with allogeneic HSCT to correct the immune defects in a patient with NEMO mutation. However, the patient's colitis persisted. Our data strongly suggest that lack of NEMO function and NF-κB signaling in intestinal epithelium is sufficient to drive susceptibility to colitis. Preimplantation genetic diagnosis was used successfully in conjunction with allogeneic HSCT to correct the immune defects in a patient with NEMO mutation. However, the patient's colitis persisted. Our data strongly suggest that lack of NEMO function and NF-κB signaling in intestinal epithelium is sufficient to drive susceptibility to colitis.