Scholars@Duke
Michael Steven Hershfield

Michael Steven Hershfield

Professor of Medicine
Medicine, Rheumatology and Immunology
michael.hershfield@duke.edu
Duke Box 3049, Durham, NC 27710
230 Sands Building, Durham, NC 27710

Featured Works

Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients.

Journal article Arthritis Res Ther · March 7, 2014 Featured Publication INTRODUCTION: Pegloticase, a PEGylated recombinant porcine uricase, is approved for treating refractory gout at a dose of 8 mg intravenous (IV) every 2 weeks. However, during phase 1 testing, pharmacokinetics supported less frequent dosing. Also, single do ... Full text Link to item Cite

Early-onset stroke and vasculopathy associated with mutations in ADA2.

Journal article N Engl J Med · March 6, 2014 Featured Publication BACKGROUND: We observed a syndrome of intermittent fevers, early-onset lacunar strokes and other neurovascular manifestations, livedoid rash, hepatosplenomegaly, and systemic vasculopathy in three unrelated patients. We suspected a genetic cause because th ... Full text Link to item Cite

Tandem mass spectrometry, but not T-cell receptor excision circle analysis, identifies newborns with late-onset adenosine deaminase deficiency.

Journal article J Allergy Clin Immunol · June 2013 Featured Publication BACKGROUND: Adenosine deaminase (ADA)-severe combined immunodeficiency (SCID) is caused by genetic variants that disrupt the function of ADA. In its early-onset form, it is rapidly fatal to infants. Delayed or late-onset ADA-SCID is characterized by insidi ... Full text Link to item Cite

Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo.

Journal article Proc Natl Acad Sci U S A · August 10, 2010 Featured Publication A high plasma urate concentration (PUA), related to loss of urate oxidase in evolution, is postulated to protect humans from oxidative injury. This hypothesis has broad clinical relevance, but support rests largely on in vitro data and epidemiologic associ ... Full text Link to item Cite

How I treat ADA deficiency.

Journal article Blood · October 22, 2009 Featured Publication Adenosine deaminase deficiency is a disorder of purine metabolism leading to severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal and requires early intervention. Haematopoietic stem cell transplantation is the major treat ... Full text Link to item Cite

Reassessing serum urate targets in the management of refractory gout: can you go too low?

Journal article Curr Opin Rheumatol · March 2009 Featured Publication PURPOSE OF REVIEW: Growing awareness of patients with refractory gout is prompting a reassessment of treatment strategy. This article reviews the current practice of targeting serum urate concentrations (sUA) in the mid-normal range (roughly 4-6 mg/dl) and ... Full text Link to item Cite

Immunologic reconstitution during PEG-ADA therapy in an unusual mosaic ADA deficient patient.

Journal article Clin Immunol · February 2009 Featured Publication We report detailed genetic and immunologic studies in a patient diagnosed with adenosine deaminase (ADA) deficiency and combined immune deficiency at age 5 years. At the time of diagnosis, although all other lymphocyte subsets were depleted, circulating CD ... Full text Link to item Cite

Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout.

Journal article Arthritis Rheum · March 2007 Featured Publication OBJECTIVE: To evaluate the efficacy, immunogenicity, and tolerability of intravenous (IV) PEGylated recombinant mammalian urate oxidase (PEG-uricase) for the treatment of severe gout. METHODS: Single infusions of PEG-uricase (at doses ranging from 0.5 mg t ... Full text Link to item Cite

Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase.

Journal article Arthritis Res Ther · 2006 Featured Publication PEG-modified recombinant mammalian urate oxidase (PEG-uricase) is being developed as a treatment for patients with chronic gout who are intolerant of, or refractory to, available therapy for controlling hyperuricemia. In an open-label phase I trial, single ... Full text Link to item Cite

CD28 costimulatory signal induces protein arginine methylation in T cells.

Journal article J Exp Med · August 1, 2005 Featured Publication Protein phosphorylation initiates signal transduction that triggers lymphocyte activation. However, other posttranslational modifications may contribute to this process. Here, we show that CD28 engagement induced protein arginine methyltransferase activity ... Full text Link to item Cite

Genotype is an important determinant of phenotype in adenosine deaminase deficiency.

Journal article Curr Opin Immunol · October 2003 Featured Publication Adenosine deaminase (ADA) deficiency is associated with a broad clinical and mutational spectrum. Defining the relationship of genotype to phenotype among patients with different degrees of immunodeficiency has been complicated because the disease is rare, ... Full text Link to item Cite

Clustered charged amino acids of human adenosine deaminase comprise a functional epitope for binding the adenosine deaminase complexing protein CD26/dipeptidyl peptidase IV.

Journal article J Biol Chem · May 31, 2002 Featured Publication Human adenosine deaminase (ADA) occurs as a 41-kDa soluble monomer in all cells. On epithelia and lymphoid cells of humans, but not mice, ADA also occurs bound to the membrane glycoprotein CD26/dipeptidyl peptidase IV. This "ecto-ADA" has been postulated t ... Full text Link to item Cite

Adenosine deaminase deficiency with mosaicism for a "second-site suppressor" of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy.

Journal article Blood · February 1, 2002 Featured Publication Four patients from 3 Saudi Arabian families had delayed onset of immune deficiency due to homozygosity for a novel intronic mutation, g.31701T>A, in the last splice acceptor site of the adenosine deaminase (ADA) gene. Aberrant splicing mutated the last 4 A ... Full text Link to item Cite

Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase.

Journal article J Am Soc Nephrol · May 2001 Featured Publication Uricase-deficient mice develop uric acid nephropathy, with high mortality rates before weaning. Urate excretion was quantitated and renal function was better defined in this study, to facilitate the use of these mice as a model for evaluating poly(ethylene ... Full text Link to item Cite

The binding site of human adenosine deaminase for CD26/Dipeptidyl peptidase IV: the Arg142Gln mutation impairs binding to cd26 but does not cause immune deficiency.

Journal article J Exp Med · November 6, 2000 Featured Publication Human, but not murine, adenosine deaminase (ADA) forms a complex with the cell membrane protein CD26/dipeptidyl peptidase IV. CD26-bound ADA has been postulated to regulate extracellular adenosine levels and to modulate the costimulatory function of CD26 o ... Full text Link to item Cite

Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy.

Journal article Semin Hematol · October 1998 Featured Publication Adenosine deaminase (ADA) deficiency is the first known cause of severe combined immunodeficiency disease (SCID). Over the past 25 years, the metabolic basis for immune deficiency has largely been established. The clinical spectrum associated with ADA defi ... Link to item Cite

Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles.

Journal article Am J Hum Genet · October 1998 Featured Publication Adenosine deaminase (ADA) deficiency causes lymphopenia and immunodeficiency due to toxic effects of its substrates. Most patients are infants with severe combined immunodeficiency disease (SCID), but others are diagnosed later in childhood (delayed onset) ... Full text Link to item Cite

Adenosine-deaminase-deficient mice die perinatally and exhibit liver-cell degeneration, atelectasis and small intestinal cell death.

Journal article Nat Genet · July 1995 Featured Publication We report the generation and characterization of mice lacking adenosine deaminase (ADA). In humans, absence of ADA causes severe combined immunodeficiency. In contrast, ADA-deficient mice die perinatally with marked liver-cell degeneration, but lack abnorm ... Full text Link to item Cite

Correct splicing despite mutation of the invariant first nucleotide of a 5' splice site: a possible basis for disparate clinical phenotypes in siblings with adenosine deaminase deficiency.

Journal article Am J Hum Genet · May 1994 Featured Publication Adenosine deaminase (ADA) deficiency usually causes severe combined immune deficiency in infancy. Milder phenotypes, with delayed or late onset and gradual decline in immune function, also occur and are associated with less severely impaired deoxyadenosine ... Link to item Cite

Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype.

Journal article J Clin Invest · November 1993 Featured Publication We examined the genetic basis for adenosine deaminase (ADA) deficiency in seven patients with late/delayed onset of immunodeficiency, an underdiagnosed and relatively unstudied condition. Deoxyadenosine-mediated metabolic abnormalities were less severe tha ... Full text Link to item Cite

T lymphocyte ontogeny in adenosine deaminase-deficient severe combined immune deficiency after treatment with polyethylene glycol-modified adenosine deaminase.

Journal article J Clin Invest · August 1993 Featured Publication Adenosine deaminase (ADA) deficiency causes severe combined immune deficiency (SCID) by interfering with the metabolism of deoxyadenosine, which is toxic to T lymphocytes at all stages of differentiation. Enzyme replacement with polyethylene glycol-modifie ... Full text Link to item Cite

Enzyme replacement therapy with polyethylene glycol-adenosine deaminase in adenosine deaminase deficiency: overview and case reports of three patients, including two now receiving gene therapy.

Journal article Pediatr Res · January 1993 Featured Publication During the past 6 y, 29 adenosine deaminase (ADA)-deficient patients with combined immunodeficiency have been treated with polyethylene glycol (PEG)-modified bovine ADA (PEG-ADA). We have monitored plasma ADA activity, metabolic effects of treatment, and t ... Full text Link to item Cite

Use of site-directed mutagenesis to enhance the epitope-shielding effect of covalent modification of proteins with polyethylene glycol.

Journal article Proc Natl Acad Sci U S A · August 15, 1991 Featured Publication Modification by covalent attachment of polyethylene glycol (PEG) can reduce the immunogenicity and prolong the circulating life of proteins, but the utility of this approach for any protein is restricted by the number and distribution of PEG attachment sit ... Full text Link to item Cite

Involvement of the TCL5 gene on human chromosome 1 in T-cell leukemia and melanoma.

Journal article Proc Natl Acad Sci U S A · July 1989 Featured Publication We analyzed a t(1;14)(p32;q11) chromosomal translocation in a human lymphohemopoietic stem cell line derived from a patient with acute T-lymphoblastic leukemia. The chromosomal joining on the 1p+ chromosome occurred at the T-cell receptor delta diversity ( ... Full text Link to item Cite

Sequence of full length cDNA for human S-adenosylhomocysteine hydrolase.

Journal article Ann Hum Genet · May 1989 Featured Publication Two cDNA clones for human S-adenosylhomocysteine hydrolase isolated from a placental cDNA library were sequenced. Each contained a sequence of 1299 nucleotides encoding a 432 amino-acid protein of MW 47,660. Clone 16-1 contained 47 nucleotides 5' of the co ... Full text Link to item Cite

A radiochemical-high-performance liquid chromatographic assay for urate oxidase in human plasma.

Journal article Anal Biochem · February 1, 1989 Featured Publication Polyethylene glycol-modified urate oxidase (PEG-uricase) holds promise as a hypouricemic agent for treating gout and as an adjunct to cytolytic therapy of hematologic malignancies. Spectrophotometric assays of urate oxidase are not sensitive enough for pha ... Full text Link to item Cite

CD7+, CD4-, CD8- acute leukemia: a syndrome of malignant pluripotent lymphohematopoietic cells.

Journal article Blood · February 1989 Featured Publication Following our initial observation of in vivo conversion of CD7+, CD4-, CD8- acute lymphoblastic leukemia (ALL) cells from lymphoid to myeloid lineages (Proc Natl Acad Sci (USA) 81:253, 1984) we have studied eight additional cases of ALL with this leukemic ... Link to item Cite

Basis for resistance to 3-deazaaristeromycin, an inhibitor of S-adenosylhomocysteine hydrolase, in human B-lymphoblasts.

Journal article J Biol Chem · January 15, 1989 Featured Publication Clones resistant to 3-deazaaristeromycin, a potent inhibitor of S-adenosylhomocysteine hydrolase, were selected from a nucleoside kinase-deficient derivative of the WIL-2 human B-lymphoblastoid cell line. The resistant clones took up 3-deazaaristeromycin a ... Link to item Cite

Use of polyethylene glycol-modified uricase (PEG-uricase) to treat hyperuricemia in a patient with non-Hodgkin lymphoma.

Journal article Ann Intern Med · July 15, 1988 Featured Publication Modification by covalent attachment of monomethoxypolyethylene glycol (PEG) can reduce the immunogenicity and prolong the circulating life of injected enzymes, making their use as therapeutic agents feasible. We report the first clinical use of PEG-modifie ... Full text Link to item Cite

Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase.

Journal article N Engl J Med · March 5, 1987 Featured Publication We treated two children who had adenosine deaminase deficiency and severe combined immunodeficiency disease by injecting bovine adenosine deaminase modified by conjugation with polyethylene glycol. The modified enzyme was rapidly absorbed after intramuscul ... Full text Link to item Cite

Establishment of the DU.528 human lymphohemopoietic stem cell line.

Journal article J Exp Med · November 1, 1985 Featured Publication We have established the DU.528 cell line from the pretreatment leukemia cells of a patient who underwent a T lymphoblastic-to-promyelocytic phenotype conversion during treatment with the adenosine deaminase inhibitor, deoxycoformycin. The cell line and clo ... Full text Link to item Cite

Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2'-deoxycoformycin.

Journal article Proc Natl Acad Sci U S A · January 1984 Featured Publication Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpec ... Full text Link to item Cite

S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine.

Journal article Cancer Res · July 1983 Featured Publication A patient with refractory T-cell acute lymphoblastic leukemia was treated with eight courses of the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), over a 5-month period. After developing resistance to dCF, he responded to treatment with the combi ... Link to item Cite

The human genes for S-adenosylhomocysteine hydrolase and adenosine deaminase are syntenic on chromosome 20.

Journal article Science · May 14, 1982 Featured Publication Human-Chinese hamster cell hybrids and a monoclonal antibody to human S-adenosylhomocysteine hydrolase were used to identify chromosome 20 as the location of the human gene for this enzyme. The gene for adenosine deaminase had previously been mapped to thi ... Full text Link to item Cite

Mechanism of deoxyadenosine-induced catabolism of adenine ribonucleotides in adenosine deaminase-inhibited human T lymphoblastoid cells.

Journal article Proc Natl Acad Sci U S A · April 1982 Featured Publication Loss of ATP accompanying accumulation of dATP has recently been reported to occur in the erythrocytes and lymphoblasts of patients with T lymphocytic leukemia during treatment with deoxycoformycin, an inhibitor of adenosine deaminase (adenosine aminohydrol ... Full text Link to item Cite

Resistance of an adenosine kinase-deficient human lymphoblastoid cell line to effects of deoxyadenosine on growth, S-adenosylhomocysteine hydrolase inactivation, and dATP accumulation.

Journal article Proc Natl Acad Sci U S A · July 1980 Featured Publication Accumulation of dATP derived from 2'-deoxyadenosine (dAdo), causing inhibition of ribonucleotide reductase and depletion of the other deoxynucleotide substrates required for DNA synthesis, has been suggested as the cause of the lymphopenia and immune defec ... Full text Link to item Cite

S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin.

Journal article Proc Natl Acad Sci U S A · May 1979 Featured Publication The human lymphoblast line WI-L2 is subject to growth inhibition by a combination of the adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4.) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and adenosine. Although adenosine-induced pyrimi ... Full text Link to item Cite

In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients.

Journal article J Clin Invest · April 1979 Featured Publication The cytotoxic nucleoside 2'-deoxyadenosine is excreted in excessive amounts by individuals with genetic deficiency of adenosine deaminase, and may be in part responsible for the severe combined immune dysfunction from which they suffer. Earlier studies fro ... Full text Link to item Cite

Apparent suicide inactivation of human lymphoblast S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine and adenine arabinoside. A basis for direct toxic effects of analogs of adenosine.

Journal article J Biol Chem · January 10, 1979 Featured Publication Adenosylhomocysteine hydrolase from human lymphoblasts binds 2'-deoxy[3H]adenosine tightly. Binding is associated with time-dependent, saturable, irreversible inactivation of catalytic activity which occurs with first order kinetics, suggesting "suicide" i ... Link to item Cite

S-adenosylhomocysteine hydrolase is an adenosine-binding protein: a target for adenosine toxicity.

Journal article Science · November 17, 1978 Featured Publication When adenosine deaminase activity is inhibited, low concentrations of adenosine are toxic to human lymphoblast mutants that are unable to convert adenosine to intracellular nucleotides. In order to identify the mediator of this cytotoxicity, we searched fo ... Full text Link to item Cite

Adenine and adenosine are toxic to human lymphoblast mutants defective in purine salvage enzymes.

Journal article Science · September 23, 1977 Featured Publication Mutants deficient in adenosine kinase or adenine phosphoribosyltransferase activities were selected from the WI-L2 line of human lymphoblasts. The adenosine kinase-deficient mutant was still as sensitive as its parent to growth inhibition caused by adenosi ... Full text Link to item Cite

Regulation of de novo purine biosynthesis in human lymphoblasts. Coordinate control of proximal (rate-determining) steps and the inosinic acid branch point.

Journal article J Biol Chem · December 10, 1976 Featured Publication Purine nucleotide synthesis de novo has been studied in a permanent tissue culture line of human splenic lymphoblasts with particular attention to coordination of control of the proximal (rate-determining) steps with the distal branch point of the pathway. ... Link to item Cite

In vitro characterization of a mutator T4 DNA polymerase.

Journal article Genetics · April 1973 Featured Publication Link to item Cite

Placental transport of free palmitic and linoleic acids in the guinea pig.

Journal article J Lipid Res · July 1968 Featured Publication Radioisotopic tracers were used to measure the unidirectional transfer rates of free fatty acids across the placenta of fed and fasted pregnant guinea pigs. Free (14)C-labeled palmitic and linoleic acids (in serum) were injected simultaneously into a jugul ... Link to item Cite