RESUMEN
Introduction: Severe Combined Immunodeficiency (SCID) is a life-threatening immunodeficiency caused by several pathogenic genetic variants, and it is characterized by profound defects in T-cell numbers and immune function. First performed in the late 1960's, hematopoietic stem cell transplantation remains the standard treatment for most cases of SCID. There is a growing number of post-transplant SCID patients, and it is imperative to assess the long-term outcomes of these patients. We have reported here the longest follow-up of a post-transplant SCID patient who, to our knowledge, bears the first gamma chain (γc) variant to show intact IL-21 signaling. Case Presentation: The patient presented at 5 months of age with recurrent thrush and Pneumocystis jiroveci pneumonia. In 1971, at the age of 11 months, he received an unconditioned, matched, related donor transplant comprising whole, unprocessed bone marrow. He is now 48 years old without significant illness and has never required immunoglobulin replacement. He exhibits T-dependent vaccine responses. He does suffer from chronic warts and bacterial infections that have worsened in recent years. We confirmed a known pathogenic variant in the IL2RG gene showing a hemizygous variant NM_000206.2:c.675C>A, resulting in p.Ser225Arg. His chimerism studies revealed donor T cells, host B cells, host myeloid cells, and mixed NK cells. Lymphocyte enumeration revealed normal numbers and distribution of B cells. The host B cells carry the pathogenic variant in IL2RG, but, when stimulated with IL-21, they demonstrated intact, γc-dependent signaling. Conclusions: Even with host B cells, reconstitution with donor T cells can be sufficient to allow over four decades of survival when B-cell function is intact. Our case demonstrates that satisfactory B-cell function can arise as a consequence of both intact IL-21 signaling due to a hypomorphic γc variant, and close HLA matching with the donor to allow for effective T-cell help.
Asunto(s)
Linfocitos B/inmunología , Trasplante de Médula Ósea , Supervivencia de Injerto/inmunología , Reconstitución Inmune , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/cirugía , Aloinjertos , Cromosomas Humanos X/genética , Trasplante de Córnea , Femenino , Genes Ligados a X , Rechazo de Injerto , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Humanos , Infecciones/etiología , Subunidad gamma Común de Receptores de Interleucina/genética , Donadores Vivos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Mutación Missense , Mutación Puntual , Recurrencia , Hermanos , Verrugas/etiología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunologíaAsunto(s)
Diarrea Infantil/inmunología , Trasplante de Células Madre Hematopoyéticas , Huésped Inmunocomprometido , Janus Quinasa 3/genética , Mutación , Infecciones por Rotavirus/inmunología , Rotavirus/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/cirugía , Antibacterianos/administración & dosificación , Preescolar , Análisis Mutacional de ADN , Diarrea Infantil/diagnóstico , Diarrea Infantil/prevención & control , Diarrea Infantil/virología , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Inmunoglobulinas/administración & dosificación , Lactante , Masculino , Linaje , Fenotipo , Infecciones por Rotavirus/diagnóstico , Infecciones por Rotavirus/prevención & control , Infecciones por Rotavirus/virología , Vacunas contra Rotavirus/efectos adversos , Vacunas contra Rotavirus/inmunología , Vacunas Atenuadas/efectos adversos , Vacunas Atenuadas/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/diagnóstico , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/enzimología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunologíaRESUMEN
Hematopoietic stem cell (HSC)-targeted gene transfer is an attractive approach for the treatment of a number of hematopoietic disorders caused by single gene defects. Indeed, in a series of gene transfer trials for two different primary immunodeficiencies beginning early in this decade, outstanding success has been achieved. Despite generally low levels of engrafted, genetically modified HSCs, these trials were successful because of the marked selective advantage of gene-corrected lymphoid precursors that allowed reconstitution of the immune system. Unlike the immunodeficiencies, this robust level of in vivo selection is not available to hematopoietic repopulating cells or early progenitor cells following gene transfer of a therapeutic globin gene in the setting of beta-thalassemia and sickle cell disease. Both preclinical and clinical transplant studies involving bone marrow chimeras suggest that 20% or higher levels of engraftment of genetically modified HSCs will be needed for clinical success in the most severe of these disorders. Encouragingly, gene transfer levels in this range have recently been reported in a lentiviral vector gene transfer clinical trial for children with adrenoleukodystrophy. A clinical gene transfer trial for beta-thalassemia has begun in France, and one patient with transfusion-dependent HbE/beta-thalassemia has demonstrated a therapeutic effect after transplantation with autologous CD34(+) cells genetically modified with a beta-globin lentiviral vector. Here, the development and recent progress of gene therapy for the hemoglobin disorders is reviewed.
Asunto(s)
Terapia Genética , Trasplante de Células Madre Hematopoyéticas , Hemoglobinopatías/terapia , Adrenoleucodistrofia/cirugía , Adrenoleucodistrofia/terapia , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/cirugía , Anemia de Células Falciformes/terapia , Animales , Células Cultivadas/trasplante , Niño , Ensayos Clínicos como Asunto , Células Clonales/patología , Virus Defectuosos/genética , Modelos Animales de Enfermedad , Terapia Genética/efectos adversos , Vectores Genéticos/efectos adversos , Vectores Genéticos/uso terapéutico , Hemoglobinopatías/genética , Hemoglobinopatías/cirugía , Humanos , Lentivirus/genética , Virus de la Leucemia Murina/genética , Ratones , Mutagénesis Insercional , Trasplante de Células Madre de Sangre Periférica , Trasplante Autólogo , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/cirugía , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/terapia , Globinas beta/genética , Talasemia beta/genética , Talasemia beta/cirugía , Talasemia beta/terapiaRESUMEN
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.