Successful Fetal Liver Transplantation in a Child With Severe Combined Immunodeficiency

Keightley, RichardG.; Lawton, Alexander R.; Cooper, M. D.; Yunis, E. J.

doi:10.1016/s0140-6736(75)90238-x

Cited by 85 publications

(13 citation statements)

References 17 publications

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“…5,32,33 Hirschhorn et al postulated that these abnormalities may reflect interactions of high concentrations of adenosine with known adenosine A1 receptors in nervous tissue. 5 A metabolic basis of CNS manifestations was strongly supported by findings in 2 clinical studies, where improvements of neurologic symptoms were noticed during enzyme replacement therapy using multiple partial-exchange transfusions, which resulted in a rapid reduction in concentrations of accumulated metabolites.…”

Section: Discussionmentioning

confidence: 99%

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Hönig

Albert

Schulz

et al. 2006

Blood

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Adenosine deaminase (ADA) deficiency is a systemic metabolic disease that causes an autosomal recessive variant of severe combined immunodeficiency (SCID) and less consistently other complications including neurologic abnormalities. Hematopoietic stem cell transplantation (HSCT) is able to correct the immunodeficiency, whereas control of nonimmunologic complications has not been extensively explored. We applied HSCT in 15 ADA-deficient patients consecutively treated at our institutions since 1982 and analyzed long-term outcome.

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Section: Discussionmentioning

confidence: 99%

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Hönig

Albert

Schulz

et al. 2006

Blood

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“…Before enzyme replacement in the form of erthyrocyte transfusion was used, the immunodeficient state associated with deaminase deficiency had been successfully treated with bone marrow or fetal liver transplantation (4,33). When these preferential methods fail or are unavailable, an attempt might be made to modify the disease state at the molecular and cellular level.…”

Section: Discussionmentioning

confidence: 99%

Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: Possible role of nucleoside kinase(s)

Carson

Kaye

Seegmiller

1977

Proc. Natl. Acad. Sci. U.S.A.

335

140

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Inherited deficiencies of the enzymes adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) and purine nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase; EC 2.4.2.1) preferentially interfere with lymphocyte development while sparing most other organ systems. Previous experiments have shown that through the action of specific kinases, nucleosides can be "trapped" intracellularly in the form of 5'-phosphates. We therefore measured the ability of newborn human tissues to phosphorylate adenosine and deoxyadenosine, the substrate of adenosine deaminase, and also inosine, deoxyinosine, guanosine, and deoxyguanosine, the substrates of purine nucleoside phosphorylase. Substantial activities of adenosine kinase were found in all tissues studied, while guanosine and inosine kinases were detected in none. However, the ability to phosphorylate deoxyadenosine, deoxyinosine, and deoxyguanosine was largely confined to lymphocytes. Adenosine deaminase, but not purine nucleoside phosphorylase, showed a similar lymphoid predominance. Other experiments showed that deoxyadenosine, deoxyinosine, and deoxyguanosine were toxic to human lymphoid cells. The toxicity of deoxyadenosine was reversed by the addition of deoxycytidine, but not uridine, to the culture medium. Based upon these and other experiments, we propose that in adenosine deaminase and purine nucleoside phosphorylase deficiency, toxic deoxyribonucleosides produced by many tissues are selectively trapped in lymphocytes by phosphorylating enzyme(s).During the past 5 years, Giblett and her colleagues have demonstrated an association between severe deficiencies of either adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4), or purine nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase; EC 2.4.2.1) and inherited forms of human immunodeficiency disease (1, 2). Although the clinical pictures overlap, children with adenosine deaminase deficiency usually suffer from a combined immunodeficiency syndrome, with impairment of T cell development and in most cases of B cell function as well, while those with purine nucleoside phosphorylase deficiency have primarily a deficit in T cell development and the associated cellular immune functions.Both diseases are accompanied by severe lymphopenia. Although enzyme is virtually absent from all tissues examined, apparently only the growth and development of the lymphoid system is severely retarded (3). It is therefore likely that the immune defect in deaminase and phosphorylase deficiency is not due to a generalized disorder of growth, but rather to a primary lymphocyte abnormality and/or circulating toxins that are specifically lymphocytoxic. The latter concept is in accord with the reversal of the immunodeficient state accompanyingThe costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 5677 deaminase defici...

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“…Several authors have described biochemical abnormalities in materials obtained from immunodeficient, adenosine deaminase-deficient patients, including erythrocytes (5,6), lymphocytes (7,8), plasma (6,8), urine (6), and cultured fibroblasts (9), and others have described relevant observations in model systems, particularly cultured cells of another mammals (10)(11)(12)(13)(14). Several modes of therapeutic intervention have been tried in these patients, including transplantation of fetal liver (15,16), bone marrow (17), or thymic cells (18); interestingly, infusions of normal erythrocytes, containing adenosine deaminase, have demonstrable efficacy in some patients (8).…”

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confidence: 99%

Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency.

Cohen¹,

Hirschhorn²,

Horowitz³

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

340

144

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The inherited deficiency of adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in humans is associated with an immunodeficiency. Some of the immunodeficient and enzyme-deficient patients respond immunologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously reported that erythrocytes and lymphocytes from immunodeficient and enzyme-deficient children contained increased concentrations of ATP, and in the one child studied after erythrocyte infusion therapy, the intracellular level of ATP detoxifies adenosine by converting it to inosine (10). The hypotheses then differ in their proposed mechanisms by which adenosine exerts its cytotoxic effects in cells incapable of eliminating this purine nucleoside. It has been proposed that cyclic AMP mediates the cytotoxic effects of adenosine (11,19), that the accumulated nucleotides of adenosine induce a pyrimidine nucleotide starvation (10, 12) or inhibit glycolysis (5), and that adenosine combines intracellularly with homocysteine to form S-adenosylhomocysteine, which in turn acts as a potent inhibitor of methylation reactions, including the methylation of newly synthesized DNA (20).There are specific objections to most of these proposals. In a model system, Ullman et al. (12) We have observed very abnormal levels of 2'-deoxyadenosine triphosphate (dATP) in the erythrocytes of immunodeficient, adenosine deaminase-deficient patients but not in the erythrocytes of an immunocompetent, adenosine deaminase-deficient patient. Furthermore, we have followed the loss of erythrocyte dATP in two unrelated adenosine deaminasedeficient, immunodeficient patients after the infusion of erythrocytes containing the missing enzyme activity.f To whom reprint requests should be addressed

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Successful Fetal Liver Transplantation in a Child With Severe Combined Immunodeficiency

Cited by 85 publications

References 17 publications

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications

Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: Possible role of nucleoside kinase(s)

Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency.

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