FOXP3 expression following bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning

• Published in: Immunologic research 2009-07, Vol.44 (1-3), p.179-184
• Main Authors: Dorsey, Morna J., Petrovic, A., Morrow, M. R., Dishaw, L. J., Sleasman, J. W.
• Format: Article
• Language: English
• Subjects: Alemtuzumab; Allergology; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm - administration & dosage; Antibodies, Neoplasm - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - therapeutic use; Autoimmune diseases; Autoimmune Diseases - drug therapy; Autoimmune Diseases - genetics; Autoimmune Diseases - surgery; Biomedical and Life Sciences; Biomedicine; Blood products; Bone Marrow Transplantation; Forkhead Transcription Factors - biosynthesis; Forkhead Transcription Factors - genetics; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin E - blood; Immunology; Infant; Interleukin-7 Receptor alpha Subunit - immunology; Interleukin-7 Receptor alpha Subunit - metabolism; Internal Medicine; Male; Medicine/Public Health; Melphalan - administration & dosage; Melphalan - therapeutic use; Stem cells; T cell receptors; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Transplantation Conditioning; Transplants & implants; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives; Vidarabine - therapeutic use; X-Linked Combined Immunodeficiency Diseases - drug therapy; X-Linked Combined Immunodeficiency Diseases - genetics; X-Linked Combined Immunodeficiency Diseases - surgery
• ISSN: 0257-277X; 1559-0755
• DOI: 10.1007/s12026-009-8112-y

The objective of this study is to determine if immune reconstitution of FOXP3+ T regulatory cells correlates with clinical improvement of IPEX syndrome following allogeneic hematopoietic stem cell transplant. An 8-months-old male infant with a mutation in the polyadenylation site of FOXP3 gene, absence of FOXP3 protein expression and clinical manifestations of IPEX syndrome, including eczema, colitis, failure to thrive, TPN requirement, and elevated serum IgE, underwent matched unrelated hematopoietic stem cell transplant. After reduced-intensity conditioning with alemtuzumab followed by fludarabine and melphalan the patient’s neutrophils engrafted day +15 and platelets day +29. Patient was a full donor chimera day +28 and +60. Intracellular FOXP3 protein expression in CD4+ T cells was absent pre-HSCT. After transplantation, percentage CD4+ T cells expressing FOXP3+CD25 bright phenotype quickly increased from 4.5 (day +29) to 23% (day +90) and continued in this trend. Foxp3 mRNA expression confirmed flow cytometry data. Serum IgE levels decreased from 5,000 IU/ml pre-transplant to 6 IU/ml on day +90, eczema resolved, and secretory diarrhea and feeding intolerance improved. T regulatory cell reconstitution is evident soon after HSCT following reduced-intensity conditioning correlating with development of full donor chimerism. Increased FOXP3 expression correlates with correction of clinical and laboratory manifestations of IPEX syndrome providing direct evidence that HSCT is a curative procedure for this disorder.