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1
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Freeman AF, Gonzalez CE, Yates B, Cole K, Little L, Flannelly E, Steinberg SM, Mo G, Piette N, Hughes TE, Cuellar-Rodriguez J, Gea-Banacloche J, Heller T, Hammoud DA, Holland SM, Kong HH, Young FD, Jing H, Kayaoglu B, Su HC, Pai SY, Hickstein DD, Shah NN. Hematopoietic cell transplantation for DOCK8 deficiency: Results from a prospective clinical trial. J Allergy Clin Immunol 2025; 155:176-187. [PMID: 39233015 DOI: 10.1016/j.jaci.2024.08.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/06/2024]
Abstract
BACKGROUND DOCK8 deficiency is a primary immunodeficiency in which allogeneic hematopoietic cell transplantation (HCT) represents the only known cure. We tested the ability of a busulfan-based regimen to achieve reliable engraftment and high levels of donor chimerism with acceptable toxicity in a prospective clinical trial in DOCK8 deficiency. OBJECTIVES To both evaluate the ability of HCT to reverse the clinical phenotype and to correct the immunologic abnormalities by 1 year post HCT. METHODS We conducted a prospective HCT trial for recipients with DOCK8 deficiency. Subjects were recruited from October 5, 2010, to December 30, 2022. Donor sources included fully matched related and unrelated donors and haploidentical donors. The reduced toxicity, myeloablative conditioning regimen contained no serotherapy. Graft-versus-host disease (GVHD) prophylaxis included either a calcineurin inhibitor with methotrexate or post-HCT cyclophosphamide (PT/Cy) followed by tacrolimus and mycophenolate mofetil. The trial was later amended to study PT/Cy in all patients. (Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 [NCT01176006].) RESULTS: Thirty-six subjects, both children and adults (median age 16.4 years), underwent HCT for DOCK8 deficiency. Most patients, 33 of 36 (92%), achieved full (≥98%) donor chimerism in whole blood as early as day +30. With a median potential follow-up of 7.4 years, 29 (80.6%) were alive with no evidence of new DOCK8 deficiency-related complications. PT/Cy was effective in reducing the risk of acute GVHD in patients who had received matched unrelated donor and haploidentical transplants, but it was associated with transient delays in immune-reconstitution and hemorrhagic cystitis. CONCLUSIONS A busulfan-based HCT regimen using PT/Cy for GVHD prophylaxis and a broad range of donor types and hematopoietic cell sources were well tolerated, leading to the reversal of the clinical immunophenotype.
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Affiliation(s)
- Alexandra F Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Corina E Gonzalez
- Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md.
| | - Bonnie Yates
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md
| | - Kristen Cole
- Transplant and Cell Therapy Program, Clinical Center, Bethesda, Md
| | - Lauren Little
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md
| | - Erin Flannelly
- Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md
| | - Seth M Steinberg
- Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Md
| | - George Mo
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md
| | | | | | - Jennifer Cuellar-Rodriguez
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Juan Gea-Banacloche
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md
| | - Dima A Hammoud
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, Bethesda, Md
| | - Steve M Holland
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Heidi H Kong
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - Fernanda D Young
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Huie Jing
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Basak Kayaoglu
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Helen C Su
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Sung-Yun Pai
- Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md
| | - Dennis D Hickstein
- Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md
| | - Nirali N Shah
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md
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2
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Kono A, Wakamatsu M, Umezawa Y, Muramatsu H, Fujiwara H, Tomomasa D, Inoue K, Hattori K, Mitsui T, Takada H, Minegishi Y, Takahashi Y, Yamamoto M, Mori T, Kanegane H. Successful treatment of DOCK8 deficiency by allogeneic hematopoietic cell transplantation from alternative donors. Int J Hematol 2023; 118:519-525. [PMID: 37131080 DOI: 10.1007/s12185-023-03613-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 05/04/2023]
Abstract
Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by eczematous dermatitis, elevated serum IgE, and recurrent infections, comprising a seemingly hyper-IgE syndrome (HIES). DOCK8 deficiency is only curable with allogeneic hematopoietic cell transplantation (HCT), but the outcome of HCT from alternative donors is not fully understood. Here, we describe the cases of two Japanese patients with DOCK8 deficiency who were successfully treated by allogeneic HCT from alternative donors. Patient 1 underwent cord blood transplantation at the age of 16 years, and Patient 2 underwent haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide at the age of 22 years. Each patient received a fludarabine-based conditioning regimen. Their clinical manifestations, including refractory molluscum contagiosum, promptly improved post-HCT. They achieved successful engraftment and immune reconstitution without serious complications. Alternative donor sources such as cord blood and haploidentical donors can be options for allogeneic HCT for DOCK8 deficiency.
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Affiliation(s)
- Asuka Kono
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Manabu Wakamatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiro Umezawa
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
| | - Hideki Muramatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Fujiwara
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Dan Tomomasa
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kento Inoue
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Keiichiro Hattori
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Tetsuo Mitsui
- Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hidetoshi Takada
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yoshiyuki Minegishi
- Division of Molecular Medicine, Institute of Advanced Enzyme Research, Tokushima University, Tokushima, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahide Yamamoto
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Takehiko Mori
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
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3
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Yang W, Ma Y, Jin J, Ren P, Zhou H, Xu S, Zhang Y, Hu Z, Rong Y, Dai Y, Zhang Y, Zhang S. Cyclophosphamide Exposure Causes Long-Term Detrimental Effect of Oocytes Developmental Competence Through Affecting the Epigenetic Modification and Maternal Factors' Transcription During Oocyte Growth. Front Cell Dev Biol 2021; 9:682060. [PMID: 34164401 PMCID: PMC8215553 DOI: 10.3389/fcell.2021.682060] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 05/12/2021] [Indexed: 12/19/2022] Open
Abstract
Cyclophosphamide (CTX) is widely used in various cancer therapies and in immunosuppression, and patients can still have babies after CTX chemotherapy. CTX directly causes primordial follicle loss with overactivation and DNA damage-induced apoptosis. Previous studies have shown that maternal exposure to CTX before conception increases the incidence of birth abnormalities and alters the methylation of genes in the oocytes of offspring. Mice were treated with a single dose of CTX (100 mg/kg) at post-natal day 21 and sacrificed 47 days later when primordial follicles surviving chemotherapy developed to the antral stage. Acute DNA damage and acceleration of the activation of primordial follicles after CTX treatment were repaired within several days, but the remaining follicle numbers remarkably decrease. Although partial surviving primordial follicle were developed to mature oocyte, oocyte quality hemostasis was impaired exhibiting aberrant meiosis progression, abnormal spindle and aneuploidy, mitochondrial dysfunction and increased endoplasmic reticulum stress. Thereafter, embryo development competency significantly decreased with fewer blastocyst formation after CTX exposure. CTX treatment resulted in alteration of DNA methylations and histone modifications in fully grown GV oocytes. Single-cell RNA-seq revealed CTX treatment suppressed multiple maternal genes’ transcription including many methyltransferases and maternal factor YAP1, which probably accounts for low quality of CTX-repaired oocyte. In vitro addition of lysophosphatidic acid (LPA) to embryo culture media to promote YAP1 nuclear localization improved CTX-repaired embryo developmental competence. This study provides evidence for the consistent toxic effect of CTX exposure during follicle development, and provide a new mechanism and new insights into future clinical interventions for fertility preservation.
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Affiliation(s)
- Weijie Yang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Yerong Ma
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Jiamin Jin
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Peipei Ren
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Hanjing Zhou
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Shiqian Xu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Yingyi Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Zhanhong Hu
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Yan Rong
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Yongdong Dai
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Yinli Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
| | - Songying Zhang
- Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Department of Obstetrics and Gynecology, Hangzhou, China
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4
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Parta M, Hilligoss D, Kelly C, Kwatemaa N, Theobald N, Zerbe CS, Holland SM, Malech HL, Kang EM. Failure to Prevent Severe Graft-Versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in Chronic Granulomatous Disease. J Clin Immunol 2020; 40:619-624. [PMID: 32314173 PMCID: PMC7507116 DOI: 10.1007/s10875-020-00772-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/20/2020] [Indexed: 10/24/2022]
Abstract
PURPOSE Haploidentical related donor (HRD) transplantation was performed in 7 recipients with chronic granulomatous disease (CGD) who had no matched-related or unrelated donor. METHODS Peripheral blood cell (PBC) products were used with a conditioning regimen consisting of low-dose cyclophosphamide, fludarabine, total body irradiation, and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of high-dose post-transplant cyclophosphamide and sirolimus. Recipients were ages 14-26 years, and 3 had severe infections active at transplant. RESULTS All 7 recipients achieved full engraftment with complete donor chimerism early in the post-transplant period. Acute GVHD occurred in all cases and was grade 3 or steroid refractory in 3. Two patients with steroid-refractory GVHD died. Three patients with severe infectious complications active at transplant, 1 Nocardia pneumonia and 2 extensive invasive fungal infections), survived and were cured of their infection at last follow-up. Bacterial disease occurred post-transplant in all recipients, and viral infections/reactivation were common, including 4 cases of BK virus-associated hemorrhagic cystitis. CONCLUSIONS Seven patients with CGD achieved rapid and full-donor engraftment from HRDs utilizing PBCs and a conditioning regimen with PTCy and sirolimus GVHD prophylaxis. However, the incidence of grade 3 and steroid-refractory GVHD was high and led to 2 deaths. Patients with active infections at transplant had successful transplant courses and were cured of their disease. Although there was an initial success with this regimen, the cumulative experience does not support its use in CGD due to an unacceptable rate of severe GVHD.
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Affiliation(s)
- Mark Parta
- Clinical Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA.
| | - Dianne Hilligoss
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA
| | - Corin Kelly
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA
| | - Nana Kwatemaa
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA
| | - Narda Theobald
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA
| | - Christa S Zerbe
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA
| | - Steven M Holland
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA
| | - Harry L Malech
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA
| | - Elizabeth M Kang
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Dr., Rm. 6-3754, MSC 1763, Bethesda, MD, 20892-1456, USA
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5
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Freeman AF, Yazigi N, Shah NN, Kleiner DE, Parta M, Atkinson P, Heller T, Holland SM, Kaufman SS, Khan KM, Hickstein DD. Tandem Orthotopic Living Donor Liver Transplantation Followed by Same Donor Haploidentical Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency. Transplantation 2019; 103:2144-2149. [PMID: 30720689 PMCID: PMC6667308 DOI: 10.1097/tp.0000000000002649] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND An 11-year-old girl with dedicator of cytokinesis 8 (DOCK8) deficiency was proposed for potentially curative hematopoietic stem cell transplantation (HSCT), the donor being her haploidentical mother. However, end-stage liver disease caused by chronic Cryptosporidium infection required liver transplantation before HSCT. METHODS Consequently, a staged approach of a sequential liver transplant followed by a HSCT was planned with her mother as the donor for both liver and HSCT. RESULTS The patient successfully underwent a left-lobe orthotopic liver transplant; however, she developed a biliary leak delaying the HSCT. Notably, the recipient demonstrated 3% donor lymphocyte chimerism in her peripheral blood immediately before HSCT. Haploidentical-related donor HSCT performed 2 months after liver transplantation was complicated by the development of acyclovir-resistant herpes simplex virus viremia, primary graft failure, and sinusoidal obstruction syndrome. The patient died from sinusoidal obstruction syndrome-associated multiorgan failure with Candida sepsis on day +40 following HSCT. CONCLUSIONS We discuss the many considerations inherent to planning for HSCT preceded by liver transplant in patients with primary immunodeficiencies, including the role of prolonged immunosuppression and the risk of infection before immune reconstitution. We also discuss the implications of potential recipient sensitization against donor stem cells precipitated by exposure of the recipient to the donor lymphocytes from the transplanted organ.
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Affiliation(s)
- Alexandra F. Freeman
- Laboratory of Clinical Immunology and Microbiology,
National Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD
| | - Nada Yazigi
- Pediatric Liver Transplantation, Department of Pediatrics,
MedStar Georgetown University Hospital, Washington DC
| | - Nirali N. Shah
- Pediatric Oncology Branch, National Cancer Institute,
National Institutes of Health, Bethesda, MD
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute,
National Institutes of Health, Bethesda, MD
| | - Mark Parta
- Clinical Monitoring Research Program Directorate, Frederick
National Laboratory for Cancer Research sponsored by the National Cancer
Institute
| | - Prescott Atkinson
- Division of Pediatric Allergy, Asthma and Immunology,
University of Alabama at Birmingham, Birmingham, AL
| | - Theo Heller
- Liver Diseases Branch, National Institute of Digestive,
Diabetes, and Kidney Disease Institute, National Institutes of Health, Bethesda,
MD
| | - Steven M. Holland
- Laboratory of Clinical Immunology and Microbiology,
National Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD
| | - Stuart S. Kaufman
- Pediatric Liver Transplantation, Department of Pediatrics,
MedStar Georgetown University Hospital, Washington DC
| | - Khalid M. Khan
- Pediatric Liver Transplantation, Department of Pediatrics,
MedStar Georgetown University Hospital, Washington DC
| | - Dennis D. Hickstein
- Experimental Transplantation and Immunology Branch,
National Cancer Institute, National Institutes of Health, Bethesda, MD
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6
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Gavrilova T. Considerations for hematopoietic stem cell transplantation in primary immunodeficiency disorders. World J Transplant 2019; 9:48-57. [PMID: 31392129 PMCID: PMC6682495 DOI: 10.5500/wjt.v9.i3.48] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 07/10/2019] [Accepted: 07/17/2019] [Indexed: 02/05/2023] Open
Abstract
Primary immunodeficiency disorders (PIDs) result from inborn errors in immunity. Susceptibility to infections and oftentimes severe autoimmunity pose life-threatening risks to patients with these disorders. Hematopoietic cell transplant (HCT) remains the only curative option for many. Severe combined immunodeficiency disorders (SCID) most commonly present at the time of birth and typically require emergent HCT in the first few weeks of life. HCT poses an unusual challenge for PIDs. Donor source and conditioning regimen often impact the outcome of immune reconstitution after HCT in PIDs. The use of matched or unmatched, as well as related versus unrelated donor has resulted in variable outcomes for different subsets of PIDs. Additionally, there is significant variability in the success of engraftment even for a single patient’s lymphocyte subpopulations. While certain cell lines do well without a conditioning regimen, others will not reconstitute unless conditioning is used. The decision to proceed with a conditioning regimen in an already immunocompromised host is further complicated by the fact that alkylating agents should be avoided in radiosensitive PIDs. This manuscript reviews some of the unique elements of HCT in PIDs and evidence-based approaches to transplant in patients with these rare and challenging disorders.
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Affiliation(s)
- Tatyana Gavrilova
- Division of Allergy and Immunology, Montefiore Medical Center, Bronx, NY 10461, United States
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7
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Pillay BA, Avery DT, Smart JM, Cole T, Choo S, Chan D, Gray PE, Frith K, Mitchell R, Phan TG, Wong M, Campbell DE, Hsu P, Ziegler JB, Peake J, Alvaro F, Picard C, Bustamante J, Neven B, Cant AJ, Uzel G, Arkwright PD, Casanova JL, Su HC, Freeman AF, Shah N, Hickstein DD, Tangye SG, Ma CS. Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients. JCI Insight 2019; 5:127527. [PMID: 31021819 DOI: 10.1172/jci.insight.127527] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αβ T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.
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Affiliation(s)
- Bethany A Pillay
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia
| | - Danielle T Avery
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia
| | - Joanne M Smart
- Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Theresa Cole
- Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Sharon Choo
- Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Damien Chan
- Women and Children's Hosp==ital, Adelaide, South Australia, Australia
| | - Paul E Gray
- Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, New South Wales, Australia.,School of Women's and Children's Health, UNSW Sydney, Sydney, New South Wales, Australia.,Clinical Immunogenomics Research Consortium of Australia (CIRCA), Sydney, New South Wales, Australia
| | - Katie Frith
- Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, New South Wales, Australia.,School of Women's and Children's Health, UNSW Sydney, Sydney, New South Wales, Australia
| | - Richard Mitchell
- School of Women's and Children's Health, UNSW Sydney, Sydney, New South Wales, Australia.,Kids Cancer Centre, Sydney Children's Hospital, Randwick, New South Wales Australia
| | - Tri Giang Phan
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.,Clinical Immunogenomics Research Consortium of Australia (CIRCA), Sydney, New South Wales, Australia
| | - Melanie Wong
- Clinical Immunogenomics Research Consortium of Australia (CIRCA), Sydney, New South Wales, Australia.,Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Dianne E Campbell
- Clinical Immunogenomics Research Consortium of Australia (CIRCA), Sydney, New South Wales, Australia.,Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - Peter Hsu
- Clinical Immunogenomics Research Consortium of Australia (CIRCA), Sydney, New South Wales, Australia.,Children's Hospital at Westmead, Westmead, New South Wales, Australia
| | - John B Ziegler
- Department of Immunology and Infectious Diseases, Sydney Children's Hospital, Sydney, New South Wales, Australia.,School of Women's and Children's Health, UNSW Sydney, Sydney, New South Wales, Australia.,Clinical Immunogenomics Research Consortium of Australia (CIRCA), Sydney, New South Wales, Australia
| | - Jane Peake
- Queensland Children's Hospital, South Brisbane, Queensland, Australia
| | - Frank Alvaro
- Pediatric Hematology, John Hunter Hospital, New Lambton, New South Wales, Australia
| | - Capucine Picard
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine institut, Paris, France.,Study Center for Primary Immunodeficiencies, Assistance Publique-Hôpitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France.,Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
| | - Jacinta Bustamante
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine institut, Paris, France.,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes Paris, France.,St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA
| | - Benedicte Neven
- Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France
| | - Andrew J Cant
- Great North Children's Hospital, Newcastle upon Tyne Hospitals, NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.,Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle upon Tyne University, Newcastle upon Tyne, United Kingdom
| | - Gulbu Uzel
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Peter D Arkwright
- Lydia Becker Institute of Immunology & Inflammation, University of Manchester, Manchester, United Kingdom
| | - Jean-Laurent Casanova
- Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.,Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Institut IMAGINE, Necker Medical School, University Paris Descartes Paris, France.,St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, New York, USA.,Howard Hughes Medical Institute, New York, New York, USA
| | - Helen C Su
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Alexandra F Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | | | - Dennis D Hickstein
- Experimental Transplantation and Immunology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Stuart G Tangye
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.,Clinical Immunogenomics Research Consortium of Australia (CIRCA), Sydney, New South Wales, Australia
| | - Cindy S Ma
- Garvan Institute of Medical Research, Sydney, New South Wales, Australia.,St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, New South Wales, Australia.,Clinical Immunogenomics Research Consortium of Australia (CIRCA), Sydney, New South Wales, Australia
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8
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Gernez Y, Baker MG, Maglione PJ. Humoral immunodeficiencies: conferred risk of infections and benefits of immunoglobulin replacement therapy. Transfusion 2019; 58 Suppl 3:3056-3064. [PMID: 30536429 PMCID: PMC6939302 DOI: 10.1111/trf.15020] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023]
Abstract
Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper‐IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal‐dominant hyper‐IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy.
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Affiliation(s)
- Yael Gernez
- Division of Allergy and Immunology, Department of Pediatrics, Stanford School of Medicine, Stanford, California
| | - Mary Grace Baker
- Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Paul J Maglione
- Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
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9
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Castagnoli R, Delmonte OM, Calzoni E, Notarangelo LD. Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Diseases: Current Status and Future Perspectives. Front Pediatr 2019; 7:295. [PMID: 31440487 PMCID: PMC6694735 DOI: 10.3389/fped.2019.00295] [Citation(s) in RCA: 129] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 07/03/2019] [Indexed: 12/29/2022] Open
Abstract
Primary immunodeficiencies (PID) are disorders that for the most part result from mutations in genes involved in immune host defense and immunoregulation. These conditions are characterized by various combinations of recurrent infections, autoimmunity, lymphoproliferation, inflammatory manifestations, atopy, and malignancy. Most PID are due to genetic defects that are intrinsic to hematopoietic cells. Therefore, replacement of mutant cells by healthy donor hematopoietic stem cells (HSC) represents a rational therapeutic approach. Full or partial ablation of the recipient's marrow with chemotherapy is often used to allow stable engraftment of donor-derived HSCs, and serotherapy may be added to the conditioning regimen to reduce the risks of graft rejection and graft versus host disease (GVHD). Initially, hematopoietic stem cell transplantation (HSCT) was attempted in patients with severe combined immunodeficiency (SCID) as the only available curative treatment. It was a challenging procedure, associated with elevated rates of morbidity and mortality. Overtime, outcome of HSCT for PID has significantly improved due to availability of high-resolution HLA typing, increased use of alternative donors and new stem cell sources, development of less toxic, reduced-intensity conditioning (RIC) regimens, and cellular engineering techniques for graft manipulation. Early identification of infants affected by SCID, prior to infectious complication, through newborn screening (NBS) programs and prompt genetic diagnosis with Next Generation Sequencing (NGS) techniques, have also ameliorated the outcome of HSCT. In addition, HSCT has been applied to treat a broader range of PID, including disorders of immune dysregulation. Yet, the broad spectrum of clinical and immunological phenotypes associated with PID makes it difficult to define a universal transplant regimen. As such, integration of knowledge between immunologists and transplant specialists is necessary for the development of innovative transplant protocols and to monitor their results during follow-up. Despite the improved outcome observed after HSCT, patients with severe forms of PID still face significant challenges of short and long-term transplant-related complications. To address this issue, novel HSCT strategies are being implemented aiming to improve both survival and long-term quality of life. This article will discuss the current status and latest developments in HSCT for PID, and present data regarding approach and outcome of HSCT in recently described PID, including disorders associated with immune dysregulation.
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Affiliation(s)
- Riccardo Castagnoli
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.,Department of Pediatrics, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Ottavia Maria Delmonte
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Enrica Calzoni
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.,Department of Molecular and Translational Medicine, A. Nocivelli Institute for Molecular Medicine, University of Brescia, Brescia, Italy
| | - Luigi Daniele Notarangelo
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
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10
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Su HC, Jing H, Angelus P, Freeman AF. Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome. Immunol Rev 2019; 287:9-19. [PMID: 30565250 PMCID: PMC6350515 DOI: 10.1111/imr.12723] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 10/15/2018] [Indexed: 12/29/2022]
Abstract
DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and (b) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered the roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.
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Affiliation(s)
- Helen C. Su
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
| | - Huie Jing
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
| | - Pam Angelus
- Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health
| | - Alexandra F. Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health
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11
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Aydin SE, Freeman AF, Al-Herz W, Al-Mousa HA, Arnaout RK, Aydin RC, Barlogis V, Belohradsky BH, Bonfim C, Bredius RG, Chu JI, Ciocarlie OC, Doğu F, Gaspar HB, Geha RS, Gennery AR, Hauck F, Hawwari A, Hickstein DD, Hoenig M, Ikinciogullari A, Klein C, Kumar A, Ifversen MRS, Matthes S, Metin A, Neven B, Pai SY, Parikh SH, Picard C, Renner ED, Sanal Ö, Schulz AS, Schuster F, Shah NN, Shereck EB, Slatter MA, Su HC, van Montfrans J, Woessmann W, Ziegler JB, Albert MH. Hematopoietic Stem Cell Transplantation as Treatment for Patients with DOCK8 Deficiency. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2018; 7:848-855. [PMID: 30391550 DOI: 10.1016/j.jaip.2018.10.035] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/21/2018] [Accepted: 10/22/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Biallelic variations in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency with eczema, recurrent bacterial and viral infections, and malignancy. Natural disease outcome is dismal, but allogeneic hematopoietic stem cell transplantation (HSCT) can cure the disease. OBJECTIVE To determine outcome of HSCT for DOCK8 deficiency and define possible outcome variables. METHODS We performed a retrospective study of the results of HSCT in a large international cohort of DOCK8-deficient patients. RESULTS We identified 81 patients from 22 centers transplanted at a median age of 9.7 years (range, 0.7-27.2 years) between 1995 and 2015. After median follow-up of 26 months (range, 3-135 months), 68 (84%) patients are alive. Severe acute (III-IV) or chronic graft versus host disease occurred in 11% and 10%, respectively. Causes of death were infections (n = 5), graft versus host disease (5), multiorgan failure (2), and preexistent lymphoma (1). Survival after matched related (n = 40) or unrelated (35) HSCT was 89% and 81%, respectively. Reduced-toxicity conditioning based on either treosulfan or reduced-dose busulfan resulted in superior survival compared with fully myeloablative busulfan-based regimens (97% vs 78%; P = .049). Ninety-six percent of patients younger than 8 years at HSCT survived, compared with 78% of those 8 years and older (P = .06). Of the 73 patients with chimerism data available, 65 (89%) had more than 90% donor T-cell chimerism at last follow-up. Not all disease manifestations responded equally well to HSCT: eczema, infections, and mollusca resolved quicker than food allergies or failure to thrive. CONCLUSIONS HSCT is curative in most DOCK8-deficient patients, confirming this approach as the treatment of choice. HSCT using a reduced-toxicity regimen may offer the best chance for survival.
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Affiliation(s)
- Susanne E Aydin
- Dr von Hauner University Children's Hospital, Ludwig Maximilians Universität, Munich, Germany
| | - Alexandra F Freeman
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Waleed Al-Herz
- Department of Pediatrics, Al-Sabah Hospital, Kuwait, Kuwait
| | - Hamoud A Al-Mousa
- Department of Pediatrics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Rand K Arnaout
- Department of Medicine, Allergy & Immunology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Roland C Aydin
- Dr von Hauner University Children's Hospital, Ludwig Maximilians Universität, Munich, Germany
| | - Vincent Barlogis
- Pediatric Hematology, Assistance publique des Hopitaux de Marseille, Marseille, France
| | | | - Carmem Bonfim
- Pediatric Blood and Marrow Transplantation Program, Hospital de Clinicas, Federal University of Parana, Curitiba, Brazil
| | | | - Julia I Chu
- Department of Pediatrics, Stanford University School of Medicine, Stanford, Calif
| | - Oana C Ciocarlie
- Department of Bone Marrow Transplantation, Great Ormond Street Hospital NHS Trust, London, United Kingdom
| | - Figen Doğu
- Department of Pediatric Immunology & Allergy, Ankara University School of Medicine, Ankara, Turkey
| | - Hubert B Gaspar
- Molecular Immunology Unit, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Raif S Geha
- Department of Immunology, Boston Children's Hospital, Boston, Mass
| | - Andrew R Gennery
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Fabian Hauck
- Dr von Hauner University Children's Hospital, Ludwig Maximilians Universität, Munich, Germany
| | - Abbas Hawwari
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | | | - Manfred Hoenig
- Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
| | - Aydan Ikinciogullari
- Department of Pediatric Immunology & Allergy, Ankara University School of Medicine, Ankara, Turkey
| | - Christoph Klein
- Dr von Hauner University Children's Hospital, Ludwig Maximilians Universität, Munich, Germany
| | - Ashish Kumar
- BMT/Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Marianne R S Ifversen
- Department for Children and Adolescents, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Susanne Matthes
- Stem Cell Transplantation, St Anna Children's Hospital, Vienna, Austria
| | - Ayse Metin
- Pediatric Immunology, Ankara Children's Hematology Oncology Training and Research Hospital, Ankara, Turkey
| | - Benedicte Neven
- Department for Pediatric Immuno-Hematology and Rheumatology, Necker Hospital, Paris, France
| | - Sung-Yun Pai
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, Mass
| | - Suhag H Parikh
- Pediatric Blood and Marrow Transplant Program, Duke University Medical Center, Durham, NC
| | - Capucine Picard
- Study Center of Primary Immunodeficiency, Necker Children's Hospital, Paris, France
| | | | - Özden Sanal
- Department of Pediatrics, Hacettepe University, Ankara, Turkey
| | - Ansgar S Schulz
- Department of Pediatrics, University Medical Center Ulm, Ulm, Germany
| | - Friedhelm Schuster
- Department of Pediatrics, Düsseldorf University Hospital, Düsseldorf, Germany
| | - Nirali N Shah
- Pediatric Oncology Branch, National Cancer Institute, Bethesda, Md
| | - Evan B Shereck
- Pediatric Hematology/Oncology, Oregon & Health Science University, Portland, Ore
| | - Mary A Slatter
- Paediatric BMT, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom
| | - Helen C Su
- Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, Md
| | - Joris van Montfrans
- Pediatric Immunology and Infectious Diseases, UMC Utrecht, Utrecht, The Netherlands
| | - Wilhelm Woessmann
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - John B Ziegler
- Immunology & Infectious Diseases, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Michael H Albert
- Dr von Hauner University Children's Hospital, Ludwig Maximilians Universität, Munich, Germany.
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12
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Slatter MA, Gennery AR. Hematopoietic cell transplantation in primary immunodeficiency - conventional and emerging indications. Expert Rev Clin Immunol 2018; 14:103-114. [PMID: 29300535 DOI: 10.1080/1744666x.2018.1424627] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
INTRODUCTION Hematopoietic stem cell transplantation (HSCT) is an established curative treatment for many primary immunodeficiencies. Advances in donor selection, graft manipulation, conditioning and treatment of complications, mean that survival for many conditions is now around 90%. Next generation sequencing is identifying new immunodeficiencies, many of which are treatable with HSCT. Challenges remain however with short and long-term sequalae. This article reviews latest developments in HSCT for conventional primary immunodeficiencies and presents data on outcome for emerging diseases, Areas covered: This article reviews recently published literature detailing advances, particularly in conditioning regimens and new methods of T-lymphocyte depletion, as well as new information regarding approach and out come of transplanting patients with conventional primary immunodeficiencies. The article reviews data regarding transplant outcomes for newly described primary immunodeficiencies, particularly those associated with gain-of-function mutations. Expert commentary: New methods of graft manipulation have had significant impact on HSCT outcomes, with the range of PIDs treated using T-lymphocyte depletion significantly expanded. Outcomes for newly described diseases with variable phenotypes and clinical features, transplanted when the diagnosis was unknown are beginning to be described, and will improve as patients are identified earlier, and targeted therapies such as JAK inhibitors are used as a bridge to transplantation.
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Affiliation(s)
- Mary A Slatter
- a Institute of Cellular Medicine , Newcastle University , Newcastle Upon Tyne , UK.,b Paediatric Immunology and HSCT , Great North Children's Hospital , Newcastle Upon Tyne , UK
| | - Andrew R Gennery
- a Institute of Cellular Medicine , Newcastle University , Newcastle Upon Tyne , UK.,b Paediatric Immunology and HSCT , Great North Children's Hospital , Newcastle Upon Tyne , UK
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13
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Uygun DFK, Uygun V, Reisli İ, Keleş S, Özen A, Yılmaz M, Sayar EH, Daloğlu H, Öztürkmen SI, Çakı S, Karasu GT, Yeşilipek A. Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency. Pediatr Transplant 2017; 21. [PMID: 28664550 DOI: 10.1111/petr.13015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/02/2017] [Indexed: 01/01/2023]
Abstract
DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile.
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Affiliation(s)
- Dilara Fatma K Uygun
- Department of Pediatric Immunology, Antalya Training and Research Hospital, Antalya, Turkey
| | - Vedat Uygun
- Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Antalya Hospital, Bahçeşehir University, Antalya, Turkey
| | - İsmail Reisli
- Meram Medical Faculty, Division of Pediatric Immunology and Allergy, Necmettin Erbakan University, Konya, Turkey
| | - Sevgi Keleş
- Meram Medical Faculty, Division of Pediatric Immunology and Allergy, Necmettin Erbakan University, Konya, Turkey
| | - Ahmet Özen
- Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, İstanbul, Turkey
| | - Mustafa Yılmaz
- Faculty of Medicine, Division of Pediatric Allergy and Immunology, Cukurova University, Adana, Turkey
| | - Esra H Sayar
- Meram Medical Faculty, Division of Pediatric Immunology and Allergy, Necmettin Erbakan University, Konya, Turkey
| | - Hayriye Daloğlu
- Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Antalya Hospital, Bahçeşehir University, Antalya, Turkey
| | - Seda I Öztürkmen
- Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Antalya Hospital, Bahçeşehir University, Antalya, Turkey
| | - Suar Çakı
- Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Göztepe Hospital, Bahçeşehir University, İstanbul, Turkey
| | - Gülsün T Karasu
- Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Göztepe Hospital, Bahçeşehir University, İstanbul, Turkey
| | - Akif Yeşilipek
- Faculty of Medicine, Department of Pediatric Bone Marrow Transplantation Unit, MedicalPark Antalya Hospital, Bahçeşehir University, Antalya, Turkey
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14
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Shah NN, Freeman AF, Su H, Cole K, Parta M, Moutsopoulos NM, Baris S, Karakoc-Aydiner E, Hughes TE, Kong HH, Holland SM, Hickstein DD. Haploidentical Related Donor Hematopoietic Stem Cell Transplantation for Dedicator-of-Cytokinesis 8 Deficiency Using Post-Transplantation Cyclophosphamide. Biol Blood Marrow Transplant 2017; 23:980-990. [PMID: 28288951 PMCID: PMC5757872 DOI: 10.1016/j.bbmt.2017.03.016] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 03/09/2017] [Indexed: 01/02/2023]
Abstract
Dedicator-of-cytokinesis 8 (DOCK8) deficiency, a primary immunodeficiency disease, can be reversed by allogeneic hematopoietic stem cell transplantation (HSCT); however, there are few reports describing the use of alternative donor sources for HSCT in DOCK8 deficiency. We describe HSCT for patients with DOCK8 deficiency who lack a matched related or unrelated donor using bone marrow from haploidentical related donors and post-transplantation cyclophosphamide (PT/Cy) for graft-versus-host disease (GVHD) prophylaxis. Seven patients with DOCK8 deficiency (median age, 20 years; range, 7 to 25 years) received a haploidentical related donor HSCT. The conditioning regimen included 2 days of low-dose cyclophosphamide, 5 days of fludarabine, 3 days of busulfan, and 200 cGy total body irradiation. GVHD prophylaxis consisted of PT/Cy 50 mg/kg/day on days +3 and +4 and tacrolimus and mycophenolate mofetil starting at day +5. The median times to neutrophil and platelet engraftment were 15 and 19 days, respectively. All patients attained >90% donor engraftment by day +30. Four subjects developed acute GVHD (1 with maximum grade 3). No patient developed chronic GVHD. With a median follow-up time of 20.6 months (range, 9.5 to 31.7 months), 6 of 7 patients are alive and disease free. Haploidentical related donor HSCT with PT/Cy represents an effective therapeutic approach for patients with DOCK8 deficiency who lack a matched related or unrelated donor.
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Affiliation(s)
- Nirali N Shah
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
| | - Alexandra F Freeman
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Helen Su
- Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Kristen Cole
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Mark Parta
- Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Niki M Moutsopoulos
- Oral Immunity and Inflammation Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Safa Baris
- Division of Pediatric Allergy and Immunology, Ministry of Health, Marmara University, Training and Research Hospital, Istanbul, Turkey
| | - Elif Karakoc-Aydiner
- Division of Pediatric Allergy and Immunology, Ministry of Health, Marmara University, Training and Research Hospital, Istanbul, Turkey
| | - Thomas E Hughes
- Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, Maryland
| | - Heidi H Kong
- Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Steve M Holland
- Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Dennis D Hickstein
- Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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15
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Schatz M, Sicherer SH, Zeiger RS. The Journal of Allergy and Clinical Immunology: In Practice - 2016 Year in Review. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2017; 5:218-236. [PMID: 28143692 DOI: 10.1016/j.jaip.2016.12.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 12/14/2016] [Indexed: 01/19/2023]
Abstract
As editors, we concluded that it would be helpful to our readers to write a Year in Review article that highlights the Review, Original, and Clinical Communication articles published in 2016 in The Journal of Allergy and Clinical Immunology: In Practice. We summarized articles on the topics of asthma, rhinitis/rhinosinusitis, food allergy, anaphylaxis, drug allergy, urticarial/angioedema, eosinophilic disorders, and immunodeficiency. Within each topic, epidemiologic findings are presented, relevant aspects of prevention are described, and diagnostic and therapeutic advances are enumerated. Diagnostic tools described include history, skin tests, and in vitro tests. Treatments discussed include behavioral therapy, allergen avoidance therapy, positive and negative effects of pharmacologic therapy, and various forms of immunologic and desensitization management. We hope this review will help you, our readers, consolidate and use this extensive and practical knowledge for the benefit of your patients.
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Affiliation(s)
- Michael Schatz
- Department of Allergy, Kaiser Permanente Southern California, San Diego, Calif.
| | - Scott H Sicherer
- Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Robert S Zeiger
- Department of Allergy, Kaiser Permanente Southern California, San Diego, Calif
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16
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Cunningham-Rundles C. Primary Immunodeficiency: New Insights and Practical Clinical Approaches. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2016; 4:1109-1110. [PMID: 27836060 DOI: 10.1016/j.jaip.2016.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 10/01/2016] [Indexed: 11/28/2022]
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