title: Therapeutic in vivo selection of thymic-derived natural T regulatory cells following non-myeloablative hematopoietic stem cell transplant for IPEX.
abstract: FOXP3 is critical for the development and function of CD4(+)CD25(bright) natural regulatory T cells (nTreg). Individuals harboring mutations in FOXP3 develop immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). We describe a child diagnosed with IPEX who underwent a reduced intensity, T and B cell depleted, matched unrelated donor bone marrow transplant followed by clinical resolution. Using lineage-specific donor chimerism studies, we demonstrate that non-myeloablative HSCT resolves disease in the context of low level donor hematopoietic stem cell (HSC) engraftment. Despite low-levels of donor HSC, thymically-derived nTreg and to a lesser extent CD4(+) and CD8(+) T cells, exhibit a selective in vivo growth advantage for populations containing a functional FOXP3 gene. Moreover, nTreg from this patient show regulatory function directly ex vivo. These results have implications for improving clinical therapy for patients with IPEX and provide mechanistic insight into the in vivo development of human nTreg and unexpectedly, non-regulatory T cells.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Kasow
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Morales-Tirado
authors.forename: David
authors.initials: D
authors.lastname: Wichlan
authors.forename: Sheila A
authors.initials: SA
authors.lastname: Shurtleff
authors.forename: Allistair
authors.initials: A
authors.lastname: Abraham
authors.forename: Derek A
authors.initials: DA
authors.lastname: Persons
authors.forename: Janice M
authors.initials: JM
authors.lastname: Riberdy
mesh_terms: D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D016026:Bone Marrow Transplantation; D002470:Cell Survival; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000601:surgery*; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000601:surgery*; D007223:Infant; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008212:Lymphocyte Depletion; D008297:Male; D008558:Melphalan; D017354:Point Mutation; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D013852:Thiotepa; D013950:Thymus Gland / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D000074323:Alemtuzumab; D013852:Thiotepa; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan