Hematopoietic Stem Cell Transplantation in Patients with Heterozygous STAT1 Gain-of-Function Mutation

• Published in: Journal of clinical immunology Vol. 39; no. 1; pp. 37 - 44
• Main Authors: Kiykim, Ayca, Charbonnier, Louis Marie, Akcay, Arzu, Karakoc-Aydiner, Elif, Ozen, Ahmet, Ozturk, Gulyuz, Chatila, Talal A., Baris, Safa
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-01-2019; Springer Nature B.V
• Subjects: Autoimmunity; Autoimmunity - genetics; Biomedical and Life Sciences; Biomedicine; Bone marrow; Bone marrow transplantation; Candidiasis; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; Child, Preschool; Chimerism; Chronic mucocutaneous candidiasis; Cord blood; Enumeration; Female; Gain of Function Mutation - genetics; Graft vs Host Disease - genetics; Graft-versus-host reaction; Grafts; Hematopoietic Stem Cell Transplantation - methods; Hemorrhage; Heterozygote; Histocompatibility antigen HLA; Humans; Immunodeficiency; Immunology; Infectious Diseases; Interleukin 17; Internal Medicine; Lymphocytes; Lymphocytes T; Male; Medical Microbiology; Mimicry; Morbidity; Mutation; Original Article; Phosphorylation; Prophylaxis; STAT1 Transcription Factor - genetics; Stem cells; Toxicity; Transcription; Transplantation Conditioning - methods; Transplants & implants; β-Interferon; γ-Interferon; hematopoietic stem cell transplantation; gain-of function mutation; autoimmunity; STAT1; mucocutaneous candidiasis
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-018-0575-y

Purpose
Human signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations present with a broad range of manifestations ranging from chronic mucocutaneous candidiasis and autoimmunity to combined immunodeficiency (CID). So far, there is very limited experience with hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disorder. Here, we describe two patients with heterozygous
STAT1
GOF mutations mimicking CID who were treated with HSCT.
Methods
Data on the HSC sources, conditioning regimen, graft-versus-host disease (GvHD) and antimicrobial prophylaxis, and the post-transplant course including engraftment, GvHD, transplant-related complications, infections, chimerism, and survival were evaluated. Pre- and post-transplant immunological studies included enumeration of circulating interferon gamma (IFN-γ)- and interleukin 17 (IL-17)-expressing CD4
+
T cells and analysis of IFN-β-induced STAT1 phosphorylation in patient 1 (P1)’s T cells.
Results
P1 was transplanted with cord blood from an HLA-identical sibling, and P2 with bone marrow from a fully matched unrelated donor using a reduced toxicity conditioning regimen. While P1 completely recovered from her disease, P2 suffered from systemic CMV disease and secondary graft failure and died due to severe pulmonary involvement and hemorrhage. The dysregulated IFN-γ production, suppressed IL-17 response, and enhanced STAT1 phosphorylation previously found in the CD4
+
T cells of P1 were normalized following transplantation.
Conclusion
HSCT could be an alternative and curative therapeutic option for selected
STAT1
GOF mutant patients with progressive life-threatening disease unresponsive to conventional therapy. Morbidity and mortality-causing complications included secondary graft failure, infections, and bleeding.