Bone marrow transplantation only partially restores purine metabolites to normal in adenosine deaminase-deficient patients.

Abstract

A B S T R A C T To delineate the extent to which bone marrow transplantation provides "enzyme replacement therapy", we have determined metabolite concentrations in two patients with adenosine deaminase (ADA) deficiency treated with bone marrow transplants and rendered immunologically normal. 10 yr after engraftment of lymphoid cells, erythrocyte deoxy ATP was markedly decreased compared to the marked elevations of deoxy ATP observed in untreated patients, but was still significantly elevated (62 and 90 vs. normal of6.0+6.0 nmol/ml packed erythrocytes). Similarly, deoxyadenosine and adenosine excretion were both markedly diminished compared to that of untreated patients but deoxyadenosine excretion was still clearly increased (20.1 and 38.6 vs. normal of <0.2 nmol/mg creatinine) while adenosine excretion was in the upper range of normal (7.0 and 8.1 vs. normal of 5.6+3.6 nmol/mg creatinine). Mononuclear cell deoxy ATP content was also elevated compared to normal (5.25 and 14.4 vs. 1.2+0.3). Separated mononuclear cells of bone marrow transplanted patients contain both donor lymphocytes and recipient monocytes. When mononuclear cells were depleted of the patients' own monocytes, the deoxy ATP content of the cells enriched for donor lymphocytes (i.e. monocyte depleted) was lower than that of the mixed mononuclear cells (2.2 vs. 5.26). Surprisingly, plasma adenosine was as high as in untreated ADA-deficient patients (3.2 and 1.5 vs. untreated of 0.3-3 ,uM). Consistent with the elevated plasma adenosine and Portions of this work were presented in part at the 92nd Annual Meeting ofthe Association ofAmerican Physicians and was published in abstract form in

Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency

“…For dAXP analysis, adequate systemic metabolic detoxification was classified as concentrations ,100 nmol/mL dAXP based on observations in patients receiving HLA-matched SCTs. [21][22][23][24][25] Immune reconstitution measures included lymphocyte subset counts, 26,27 T-cell receptor excision circle (TREC) analysis, and T cell proliferative capacity. 28 Physical growth was monitored.…”

Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors

“…Because adenosine receptors are typically tonically active in vitro [because of ambient adenosine in the serum of growth media and the efficient generation of adenosine from extracellular ATP by exonucleases (Hirschhorn et al, 1981;Dunwiddie et al, 1997)], we asked whether they were transactivating TrkB in our culture system and contributing to the TrkB-induced vulnerability of motor neurons to excitotoxic insult. One attraction of adenosine receptor antagonists is that they are small molecules in clinical use for human disease (Kase et al, 2003).…”

The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively.

“…These studies suggest that adenosine plays a unique role in modulation of inflammation. The concentration of adenosine present in blood (-0.3 ,M, Cronstein, B. N., and J. E. Slater, unpublished data, [54]) is sufficient to markedly inhibit generation of toxic oxygen compounds thereby protecting vascular endothelium from damage by activated neutrophils (1). At the low concentrations of adenosine that may be present in the relatively acellular extravascular tissues on the periphery of inflammatory sites adenosine occupies high affinity receptors on neutrophils to promote directed migration toward infected or inflammatory loci.…”