Rebecca Buckley

Overview:

The overall emphasis of Dr. Buckley's research is in human T,B and NK cell development and in aberrations in their development and regulation. The work involves three particular areas of investigation: 1) the cellular and molecular bases of genetically-determined human immunodeficiency diseases, 2) the use of bone marrow stem cells to cure genetically-determined immunodeficiency diseases, and 3) the use of human SCID bone marrow stem cell chimeras to study human thymic education, T and B cell ontogeny, tolerance induction and MHC restriction mechanisms. Methodology includes monoclonal antibody (mAb) analyses of lymphocyte phenotypes, a variety of T cell and natural killer (NK) cell functional assays, studies of thymic output by T cell receptor recombination excision circle measurement, studies of T cell diversity by spectratyping, studies of T cell longevity by telomere analysis and assessment of B cell differentiation and function. A unique resource available for her studies is the largest populations of patients with genetically-determined immunodeficiency diseases in the U.S., which includes the largest population in the world of longterm SCID chimeras treated at a single center, some of whom have been studied and followed for more than 37 years. The administration of rigorously T cell depleted haploidentical bone marrow stem cells to SCID recipients without pre-transplant conditioning or post-transplant use of immunosuppressive drugs to prevent GVHD provides an unmanipulated system for studying human thymic education, T and B cell ontogeny, MHC restriction mechanisms and tolerance induction. Studies to identify mutations in patients with primary immunodeficiency are continuing, particularly in those with SCID.

Positions:

James Buren Sidbury Distinguished Professor of Pediatrics, in the School of Medicine

Pediatrics, Allergy and Immunology
School of Medicine

Professor of Pediatrics

Pediatrics, Allergy and Immunology
School of Medicine

Professor of Immunology in the Department of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1958

University of North Carolina - Chapel Hill

Grants:

Safety and Efficacy of Hizentra in Pediatric BMT

Administered By
Pediatrics, Allergy and Immunology
Awarded By
Carolinas HealthCare System
Role
Principal Investigator
Start Date
End Date

Identifying the Causes of Primary immunodeficiency through Next Generation Sequencing

Administered By
Pediatrics, Allergy and Immunology
Awarded By
Baxter Healthcare Corporation
Role
Principal Investigator
Start Date
End Date

Prospective Study of SCID Infants who receive Hematopoietic Cell Therapy

Administered By
Pediatrics, Allergy and Immunology
Awarded By
University of California - San Francisco
Role
Principal Investigator
Start Date
End Date

Identification of Disease-Causing Mutations in SCID Using Exome-Wide Sequencing

Administered By
Pediatrics, Allergy and Immunology
Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

Mechanisms of Allogeneic Stem Cell Education in SCID

Administered By
Pediatrics, Allergy and Immunology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.

BACKGROUND: Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. METHODS: We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. RESULTS: Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. CONCLUSIONS: Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).
Authors
Kohn, DB; Booth, C; Shaw, KL; Xu-Bayford, J; Garabedian, E; Trevisan, V; Carbonaro-Sarracino, DA; Soni, K; Terrazas, D; Snell, K; Ikeda, A; Leon-Rico, D; Moore, TB; Buckland, KF; Shah, AJ; Gilmour, KC; De Oliveira, S; Rivat, C; Crooks, GM; Izotova, N; Tse, J; Adams, S; Shupien, S; Ricketts, H; Davila, A; Uzowuru, C; Icreverzi, A; Barman, P; Campo Fernandez, B; Hollis, RP; Coronel, M; Yu, A; Chun, KM; Casas, CE; Zhang, R; Arduini, S; Lynn, F; Kudari, M; Spezzi, A; Zahn, M; Heimke, R; Labik, I; Parrott, R; Buckley, RH; Reeves, L; Cornetta, K; Sokolic, R; Hershfield, M; Schmidt, M; Candotti, F; Malech, HL; Thrasher, AJ; Gaspar, HB
MLA Citation
Kohn, Donald B., et al. “Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.N Engl J Med, vol. 384, no. 21, May 2021, pp. 2002–13. Pubmed, doi:10.1056/NEJMoa2027675.
URI
https://scholars.duke.edu/individual/pub1481715
PMID
33974366
Source
pubmed
Published In
The New England Journal of Medicine
Volume
384
Published Date
Start Page
2002
End Page
2013
DOI
10.1056/NEJMoa2027675

Correction to: Infections in Infants with SCID: Isolation, Infection Screening and Prophylaxis in PIDTC Centers.

Authors
Dorsey, M; Wright, NAM; Chaimowitz, NS; Dávila Saldaña, BJ; Miller, H; Keller, MD; Thakar, MS; Shah, AJ; Abu-Arja, R; Andolina, J; Aquino, V; Barnum, JL; Bednarski, JJ; Bhatia, M; Bonilla, FA; Butte, MJ; Bunin, NJ; Burroughs, LM; Chandra, S; Chaudhury, S; Chen, K; Chong, H; Cuvelier, G; Dalal, J; DeFelice, ML; DeSantes, KB; Forbes, LR; Gillio, A; Goldman, F; Joshi, AY; Kapoor, N; Knutsen, AP; Kobrynski, L; Lieberman, JA; Leiding, JW; Oshrine, B; Patel, KP; Prockop, S; Quigg, TC; Quinones, R; Schultz, KR; Seroogy, C; Shyr, D; Siegel, S; Smith, AR; Torgerson, TR; Vander Lugt, MT; Yu, LC; Cowan, MJ; Buckley, RH; Dvorak, CC; Griffith, LM; Haddad, E; Kohn, DB; Logan, B; Notarangelo, LD; Pai, S-Y; Puck, J; Pulsipher, MA; Heimall, J
MLA Citation
Dorsey, Morna, et al. “Correction to: Infections in Infants with SCID: Isolation, Infection Screening and Prophylaxis in PIDTC Centers.J Clin Immunol, vol. 41, no. 2, Feb. 2021, pp. 498–500. Pubmed, doi:10.1007/s10875-020-00917-0.
URI
https://scholars.duke.edu/individual/pub1466913
PMID
33274413
Source
pubmed
Published In
J Clin Immunol
Volume
41
Published Date
Start Page
498
End Page
500
DOI
10.1007/s10875-020-00917-0

Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers.

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study's objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913.
Authors
Dorsey, MJ; Wright, NAM; Chaimowitz, NS; Dávila Saldaña, BJ; Miller, H; Keller, MD; Thakar, MS; Shah, AJ; Abu-Arja, R; Andolina, J; Aquino, V; Barnum, JL; Bednarski, JJ; Bhatia, M; Bonilla, FA; Butte, MJ; Bunin, NJ; Chandra, S; Chaudhury, S; Chen, K; Chong, H; Cuvelier, GDE; Dalal, J; DeFelice, ML; DeSantes, KB; Forbes, LR; Gillio, A; Goldman, F; Joshi, AY; Kapoor, N; Knutsen, AP; Kobrynski, L; Lieberman, JA; Leiding, JW; Oshrine, B; Patel, KP; Prockop, S; Quigg, TC; Quinones, R; Schultz, KR; Seroogy, C; Shyr, D; Siegel, S; Smith, AR; Torgerson, TR; Vander Lugt, MT; Yu, LC; Cowan, MJ; Buckley, RH; Dvorak, CC; Griffith, LM; Haddad, E; Kohn, DB; Logan, B; Notarangelo, LD; Pai, S-Y; Puck, J; Pulsipher, MA; Heimall, J
MLA Citation
Dorsey, Morna J., et al. “Infections in Infants with SCID: Isolation, Infection Screening, and Prophylaxis in PIDTC Centers.J Clin Immunol, vol. 41, no. 1, Jan. 2021, pp. 38–50. Pubmed, doi:10.1007/s10875-020-00865-9.
URI
https://scholars.duke.edu/individual/pub1462174
PMID
33006109
Source
pubmed
Published In
J Clin Immunol
Volume
41
Published Date
Start Page
38
End Page
50
DOI
10.1007/s10875-020-00865-9

Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID) in the US Immunodeficiency Network (USIDNet) Registry.

Clinical data from ADA-SCID patients registered in the U.S. Immunodeficiency Network (USIDNet) Repository were analyzed. Sixty-four ADA-SCID patients born between 1981 and 2017 had clinical data entered by their local (or home) enrolling institution. Median age at diagnosis was 1 month for those with a positive family history and 3 months for those without a prior family history, with some diagnosed at birth and one as late as 9 years of age. Overall survival was 79.7%, which increased to 94.1% since 2010. These patients had multiple infections and pulmonary, gastrointestinal, and neurological complications. The majority received enzyme replacement therapy (ERT) at some time, including 88% of those born since 2010. Twenty-six patients underwent allogeneic hematopoietic stem cell transplant (HSCT). HSCT successfully supported survival (17/26, 65%) using a variety of cell sources (bone marrow, mobilized peripheral blood, and cord blood) from sibling, family and unrelated donors. Nineteen patients underwent autologous HSCT with gene therapy (GT) using retroviral and lentiviral vectors and all are surviving. The prognosis for patients with ADA-SCID has continued to improve but these patients do have multiple early and potentially long-term conditions that require medical monitoring and management.
Authors
Kuo, CY; Garabedian, E; Puck, J; Cowan, MJ; Sullivan, KE; Buckley, RH; Cunningham-Rundles, C; Marsh, R; Candotti, F; Kohn, DB
MLA Citation
Kuo, Caroline Y., et al. “Adenosine Deaminase (ADA)-Deficient Severe Combined Immune Deficiency (SCID) in the US Immunodeficiency Network (USIDNet) Registry.J Clin Immunol, vol. 40, no. 8, Nov. 2020, pp. 1124–31. Pubmed, doi:10.1007/s10875-020-00857-9.
URI
https://scholars.duke.edu/individual/pub1459543
PMID
32880085
Source
pubmed
Published In
J Clin Immunol
Volume
40
Published Date
Start Page
1124
End Page
1131
DOI
10.1007/s10875-020-00857-9

Genotype, Phenotype and T Cell Counts at One Year Predict Survival and Long Term Immune Reconstitution after Transplantation in Severe Combined Immune Deficiency (SCID)-The Primary Immune Deficiency Treatment Consortium (PIDTC)

Authors
Haddad, E; Logan, BR; Griffith, LM; Buckley, RH; Parrott, RE; Dvorak, CC; Puck, J; Prockop, SE; Kapoor, N; Abdel-Azim, H; Hanson, IC; Martinez, C; Bleesing, J; Chandra, S; Smith, AR; Pai, S-Y; Jyonouchi, S; Sullivan, K; Haight, AE; Tumlin, AG; Burroughs, L; Saldana, BJD; Seroogy, C; Petrovic, A; Shyr, DC; Quigg, TC; Gillio, AP; Decaluwe, H; Kletzel, M; Knutsen, A; Moore, TB; Aquino, V; Davis, JH; Yu, LC; Kang, EM; Schroeder, ML; Shereck, E; Craddock, JA; Connelly, JA; Bednarski, JJ; Goldman, F; Porteus, MH; Fleisher, T; Kohn, DB; Malech, HL; Pulsipher, MA; Shearer, W; Szabolcs, P; Thakar, M; Lugt, MV; Yin, Z; Notarangelo, LD; Cowan, MJ; O'Reilly, RJ
URI
https://scholars.duke.edu/individual/pub1452137
Source
wos-lite
Published In
Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation
Volume
23
Published Date
Start Page
S101
End Page
S102

Research Areas:

Acute Disease
Adenosine Deaminase
Agammaglobulinemia
Age Factors
Aged
Allergens
Allergy and Immunology
Amino Acid Sequence
Antibodies
Antibodies, Anti-Idiotypic
Antibodies, Viral
Antibody Formation
Antibody Specificity
Antibody-Producing Cells
Antigen-Antibody Reactions
Antigen-Presenting Cells
Antigens, CD34
Antigens, CD40
Antigens, CD45
Antigens, Surface
Apoptosis
Asthma
Ataxia Telangiectasia
Australia
B-Lymphocytes
Blood
Blood Protein Disorders
Bone Marrow Cells
Bone Marrow Transplantation
Brain
CD40 Antigens
CD40 Ligand
CD8-Positive T-Lymphocytes
Candida albicans
Candidiasis
Cause of Death
Cell Division
Cell Line
Cell Line, Transformed
Cell Membrane
Cerebrospinal Fluid
Child, Preschool
Chimera
Chimerism
Chromatography, Ion Exchange
Chromosome Deletion
Chromosomes, Human, Pair 14
Chromosomes, Human, Pair 4
Chronic Disease
Clinical Trial
Cohort Studies
Colon
Common Variable Immunodeficiency
Consanguinity
Cytokines
DNA
DNA Mutational Analysis
DNA Primers
DNA Transposable Elements
Databases, Factual
Dendritic Cells
Deoxyadenosines
DiGeorge Syndrome
Disease Susceptibility
Double-Blind Method
Duodenum
Echovirus 9
Echovirus Infections
Enterovirus B, Human
Esophagitis
Exons
Fatal Outcome
Female
Flow Cytometry
Follow-Up Studies
Frameshift Mutation
Gastroesophageal Reflux
Gene Deletion
Gene Frequency
Gene therapy
Genes, Dominant
Genes, Recessive
Genetic Carrier Screening
Genetic Diseases, X-Linked
Genetic Markers
Genetic Predisposition to Disease
Genetic Therapy
Genotype
Giardiasis
Goats
Graft Survival
Graft vs Host Disease
Granulocytes
Granulomatous Disease, Chronic
Growth
HLA Antigens
Haplotypes
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
Herpesvirus 4, Human
Heterozygote Detection
Homozygote
Humans
Hypersensitivity
Hypersensitivity, Immediate
IgA Deficiency
Immune Adherence Reaction
Immune Sera
Immune System
Immune System Diseases
Immunity, Maternally-Acquired
Immunization, Passive
Immunocompromised Host
Immunodiffusion
Immunoenzyme Techniques
Immunoglobulin A
Immunoglobulin Class Switching
Immunoglobulin D
Immunoglobulin E
Immunoglobulin G
Immunoglobulin Isotypes
Immunoglobulin M
Immunoglobulin mu-Chains
Immunoglobulins
Immunoglobulins, Intravenous
Immunologic Deficiency Syndromes
Immunologic Memory
Immunologic Techniques
Immunophenotyping
Immunotherapy
Incidence
Infant
Infant, Newborn
Infection
Infection Control
Injections, Intravenous
Interleukin-13
Interleukin-2
Interleukin-4
Intestine, Small
Janus Kinase 3
Kidney Neoplasms
Killer Cells, Natural
Lectins
Leiomyomatosis
Leukocyte Common Antigens
Leukocytes
Leukocytes, Mononuclear
Liver Function Tests
Loss of Heterozygosity
Lymph Nodes
Lymphangiectasis, Intestinal
Lymphatic Diseases
Lymphocyte Activation
Lymphocyte Count
Lymphocytes
Lymphopenia
Lymphoproliferative Disorders
Major Histocompatibility Complex
Male
Maltose
Medical Records
Membrane Glycoproteins
Mice
Microfluidic Analytical Techniques
Middle Aged
Mitogens
Molecular Sequence Data
Monocytes
Multicenter Studies as Topic
Mutagenesis, Site-Directed
Mutation
Myelodysplastic Syndromes
Neonatal Screening
Neutrophils
Nucleoside Deaminases
Pediatrics
Pedigree
Phagocytes
Phenotype
Phytohemagglutinins
Pneumonia, Aspiration
Point Mutation
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Polymorphism, Single-Stranded Conformational
Practice Guidelines as Topic
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Prevalence
Prospective Studies
Protein-Tyrosine Kinases
RNA
RNA Splicing
RNA, Messenger
Rabbits
Radioimmunoassay
Receptors, Antigen, B-Cell
Receptors, Antigen, T-Cell
Receptors, Cytokine
Receptors, Interleukin
Receptors, Interleukin-2
Receptors, Interleukin-7
Registries
Retreatment
Retrospective Studies
Rhinitis, Allergic, Seasonal
Rosette Formation
S-Adenosylhomocysteine
STAT6 Transcription Factor
Sequence Analysis, DNA
Serotherapy
Severe Combined Immunodeficiency
Sheep
Siblings
Signal Transduction
Skin Tests
Survival Analysis
Survival Rate
T-Lymphocytes
Thymus Gland
Tomography, X-Ray Computed
Trans-Activators
Transduction, Genetic
Transplantation Chimera
Transplantation Conditioning
Transplantation Immunology
Uniparental Disomy
United States
Unrelated Donors
Up-Regulation
Virus Diseases
Volunteers
Vomiting
Wiskott-Aldrich Syndrome
X Chromosome
Young Adult