Publications
Publications
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The rise of haplo: a quest for the perfect graft.
Blood
2024; 143 (3): 193-195
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View details for DOI 10.1182/blood.2023022428
View details for PubMedID 38236615
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Accelerating Immune Reconstitution in HSCT Patients through iPSC-Derived Thymic Epithelial Cells
AMER SOC HEMATOLOGY. 2023
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View details for DOI 10.1182/blood-2023-186901
View details for Web of Science ID 001159306701217
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Loss of Metabolic Control Beyond the Promyelocyte Stage Resolves Myeloid Maturation Arrest in Reticular Dysgenesis
AMER SOC HEMATOLOGY. 2023
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View details for DOI 10.1182/blood-2023-185497
View details for Web of Science ID 001159900802188
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Precision Delivery of Steroids as a Rescue Therapy for Gastrointestinal Graft-versus-Host Disease in Pediatric Stem Cell Transplant Recipients.
Journal of clinical medicine
2023; 12 (13)
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Abstract
Graft versus host disease (GVHD) is one of the most serious complications following stem cell transplant in children and is a major cause of morbidity and mortality. Corticosteroids remain the mainstay of treatment, and although a majority of children respond to systemic steroids, those refractory to or dependent upon corticosteroids suffer from complications secondary to long-term steroid administration. This problem has prompted consideration of steroid-sparing treatment strategies, although the time to clinical remission can be variable. Intraarterial corticosteroid delivery has been used in adults as a rescue therapy in steroid-resistant patients, but its use in children has been limited. We investigated the feasibility of intraarterial steroid administration into the bowel and/or liver in a cohort of six pediatric patients with acute GVHD. All patients successfully underwent treatment with no serious adverse effects. Five of five (100%) patients with gastrointestinal bleeding due to GVHD had rapid symptom improvement by 48 h, which was durable up to three weeks. Three of four (75%) patients with hepatic GVHD had improved cholestasis following intraarterial steroid administration. Our experience with this small cohort preliminarily demonstrated the feasibility and safety of intraarterial steroid administration in children with acute GVHD. This approach warrants consideration as a rescue therapy in steroid-refractory cases and as a "bridge" therapy for children with severe acute GVHD who are transitioning to steroid-sparing regimens.
View details for DOI 10.3390/jcm12134229
View details for PubMedID 37445274
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Case report: Refractory Evans syndrome in two patients with spondyloenchondrodysplasia with immune dysregulation treated successfully with JAK1/JAK2 inhibition.
Frontiers in immunology
2023; 14: 1328005
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Abstract
Biallelic mutations in the ACP5 gene cause spondyloenchondrodysplasia with immune dysregulation (SPENCDI). SPENCDI is characterized by the phenotypic triad of skeletal dysplasia, innate and adaptive immune dysfunction, and variable neurologic findings ranging from asymptomatic brain calcifications to severe developmental delay with spasticity. Immune dysregulation in SPENCDI is often refractory to standard immunosuppressive treatments. Here, we present the cases of two patients with SPENCDI and recalcitrant autoimmune cytopenias who demonstrated a favorable clinical response to targeted JAK inhibition over a period of more than 3 years. One of the patients exhibited steadily rising IgG levels and a bone marrow biopsy revealed smoldering multiple myeloma. A review of the literature uncovered that approximately half of the SPENCDI patients reported to date exhibited increased IgG levels. Screening for multiple myeloma in SPENCDI patients with rising IgG levels should therefore be considered.
View details for DOI 10.3389/fimmu.2023.1328005
View details for PubMedID 38347954
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Precision Delivery of Steroids as a Rescue Therapy for Gastrointestinal Graft-versus-Host Disease in Pediatric Stem Cell Transplant Recipients
Journal of Clinical Medicine
2023; 12 (4229)
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View details for DOI 10.3390/jcm12134229
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Human JAK1 gain of function causes dysregulated myelopoeisis and severe allergic inflammation.
JCI insight
2022; 7 (24)
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Abstract
Primary atopic disorders are a group of inborn errors of immunity that skew the immune system toward severe allergic disease. Defining the biology underlying these extreme monogenic phenotypes reveals shared mechanisms underlying common polygenic allergic disease and identifies potential drug targets. Germline gain-of-function (GOF) variants in JAK1 are a cause of severe atopy and eosinophilia. Modeling the JAK1GOF (p.A634D) variant in both zebrafish and human induced pluripotent stem cells (iPSCs) revealed enhanced myelopoiesis. RNA-Seq of JAK1GOF human whole blood, iPSCs, and transgenic zebrafish revealed a shared core set of dysregulated genes involved in IL-4, IL-13, and IFN signaling. Immunophenotypic and transcriptomic analysis of patients carrying a JAK1GOF variant revealed marked Th cell skewing. Moreover, long-term ruxolitinib treatment of 2 children carrying the JAK1GOF (p.A634D) variant remarkably improved their growth, eosinophilia, and clinical features of allergic inflammation. This work highlights the role of JAK1 signaling in atopic immune dysregulation and the clinical impact of JAK1/2 inhibition in treating eosinophilic and allergic disease.
View details for DOI 10.1172/jci.insight.150849
View details for PubMedID 36546480
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Functional Human iPSC-Derived Thymic Epithelial Progenitor Cells Reconstitute T Cell Development and Function in an In Vivo Model of Thymic Aplasia
AMER SOC HEMATOLOGY. 2022: 7340-7341
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View details for DOI 10.1182/blood-2022-171133
View details for Web of Science ID 000893230300154
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Epigenetic and Immunological Indicators of IPEX Disease in subjects with FOXP3 gene mutation.
The Journal of allergy and clinical immunology
2022
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Abstract
Forkhead-Box-Protein-3 (FOXP3) is the master transcription factor in CD4+CD25hiCD127lo regulatory T (Treg) cells. Mutations in FOXP3 result in IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. Clinical presentation of IPEX syndrome is broader than initially described, challenging the understanding of the disease, its evolution and treatment choice.To study the type and extent of immunological abnormalities which remain ill-defined in IPEX, across genetic and clinical heterogeneity.We performed Treg-specific epigenetic quantification and immunological characterization of severe "typical" (n=6) and "atypical" or asymptomatic (n=9) IPEX patients.Increased number of cells with Treg-Specific Demethylated Region (TSDR) demethylation in FOXP3 is a consistent feature in IPEX patients, with i) highest values in those with typical IPEX, ii) increased values in subjects with pathogenic FOXP3 but still no symptoms, and iii) gradual increase over the course of disease progression. Large scale profiling using Luminex identified plasma inflammatory signature of macrophage activation and Th2 polarization, with cytokines previously not associated with IPEX pathology, including CCL22, CCL17, CCL15, and IL-13, and the inflammatory markers TNFα, IL-1A, IL-8, sFasL, and CXCL9. Similarly, both Treg and Teff compartments, studied by CyTOF, were skewed towards the Th2 compartment, especially in typical IPEX.Elevated TSDR demethylated cells, combined with elevation of plasmatic and cellular markers of a polarized Type 2 inflammatory immune response extends our understanding of IPEX diagnosis and heterogeneity.IPEX-specific epigenetic and immunologic changes provide invaluable tools that, complementing the genetic diagnosis, allow monitoring disease progression and enable early treatment interventions.
View details for DOI 10.1016/j.jaci.2022.09.013
View details for PubMedID 36152823
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A case of Spondyloenchondrodysplasia with immune dysregulation presenting as Systemic Lupus Erythematous
SPRINGER/PLENUM PUBLISHERS. 2021: S18–S19
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View details for Web of Science ID 000639851600028