In vivo Effectiveness of Lithium on Impaired Neutrophil Chemotaxis in Shwachman-Diamond Syndrome

Azzarà, Antonio; Carulli, Giovanni; Ceccarelli, M; Pucci, Catia; Raggio, Roberto; Ambrogi, F

doi:10.1159/000204865

Cited by 23 publications

(17 citation statements)

References 14 publications

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“…Other authors have proposed an intracellular cytoskeletal defect of microtubules or micro®laments to explain observations of impaired neutrophilic granulo-cyte random locomotion and chemotaxis [1,4,18]. The transmission electron microscopic studies of peripheral blood cells in our patient revealed dilated rough endoplasmic reticulum and Golgi apparatus in B-lymphocytes suggesting intracellular accumulation and poor secretion of proteins and signs of premature apoptosis.…”

Section: Discussionmentioning

confidence: 49%

“…It is characterised by exocrine pancreas insuciency, metaphyseal dysostosis and bone marrow dysfunction [1,8,21]. Neutropenia, either cyclic, intermittent, or constant, is the most common haematological manifestation [4,18] whereas pancytopenia is detected in only 10%±25% of patients [2,23]. Recurrent bacterial infections starting in the 1st year of life are the major clinical problem and contribute considerably to mortality in early childhood [1].…”

Section: Introductionmentioning

confidence: 99%

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Shwachman-Diamond syndrome: early bone marrow transplantation in a high risk patient and new clues to pathogenesis

Faber

Lauener

Wick

et al. 1999

European Journal of Pediatrics

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Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by exocrine pancreas insufficiency, metaphyseal dysostosis and bone marrow dysfunction. Recurrent severe bacterial infections and susceptibility to leukaemia are the major causes of morbidity and mortality occurring preferentially in patients with pancytopenia and features of myelodysplasia. Here we report a patient with SDS leading to recurrent bacterial infections and a deteriorating condition since early infancy. Extensive investigations disclosed severe pancytopenia, myelodysplasia and a clonal cytogenetic abnormality, inv(14)(q11q32), as risk factors of leukaemic transformation. He therefore underwent allogeneic geno-identical bone marrow transplantation which resulted in correction of all haematological and immunological abnormalities within an 18-month follow up period. Conclusion Bone marrow transplantation may be considered early as a valuable treatment option especially in high risk Schwachman-Diamond syndrome patients anticipating malignant transformation, life-threatening severe infections or further organ damage.

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Section: Discussionmentioning

confidence: 49%

Section: Introductionmentioning

confidence: 99%

Shwachman-Diamond syndrome: early bone marrow transplantation in a high risk patient and new clues to pathogenesis

Faber

Lauener

Wick

et al. 1999

European Journal of Pediatrics

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“…Our results, therefore, indicate that the functional defect of SDS PMNs resides in a pathway activated by the fMLP receptor(s) [Azzara et al, 1991] that transduces spatial gradient information. This information results in the orientation of a cell in the direction of increasing concentration in a spatial gradient of fMLP.…”

Section: The Molecular Nature Of the Sds Defectmentioning

confidence: 61%

“…Previous studies indicated that some aspect of the response of SDS PMNs to a spatial gradient of chemoattractant was defective [Aggett et al, 1979;Azzara et al, 1991;Ruuter et al, 1984;Theng, 1978;van Epps et al, 1983;Dror et al, 2001]. Since the two most recent of these studies utilized trans-membrane assays, a distinction could not be definitively made between a defect in chemokinesis and a defect in chemotaxis [Rhodes, 1982;Shutt et al, 1998;Wilkinson, 1988;Zigmond, 1978;Zigmond and Hirsch, 1973], and since none of the studies involved quantitative measurements of single cell behavior and pseudopod formation, the particular defect in chemotactic behavior was not identified.…”

Section: Sds Pmn Orientation In a Spatial Gradient Of Fmlp Is Defectivementioning

confidence: 99%

The chemotaxis defect of Shwachman‐Diamond Syndrome leukocytes

Stepanovic

Wessels

Goldman

et al. 2004

Cell Motil. Cytoskeleton

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Shwachman-Diamond Syndrome (SDS) is a rare autosomal recessive, multisystem disorder presenting in childhood with intermittent neutropenia and pancreatic insufficiency. It is characterized by recurrent infections independent of neutropenia, suggesting a functional neutrophil defect. While mutations at a single gene locus (SBDS) appear to be responsible for SDS in a majority of patients, the function of that gene and a specific defect in SDS neutrophil behavior have not been elucidated. Therefore, employing 2D and 3D computer-assisted motion analysis systems, we have analyzed the basic motile behavior and chemotactic responsiveness of individual polymorphonuclear leukocytes (PMNs) of 14 clinically diagnosed SDS patients. It is demonstrated that the basic motile behavior of SDS PMNs is normal in the absence of chemoattractant, that SDS PMNs respond normally to increasing and decreasing temporal gradients of the chemoattractant fMLP, and that SDS PMNs exhibit a normal chemokinetic response to a spatial gradient of fMLP. fMLP receptors were also distributed uniformly through the plasma membrane of SDS PMNs as in control PMNs. SDS PMNs, however, were incapable of orienting in and chemotaxing up a spatial gradient of fMLP. This unique defect in orientation was manifested by the PMNs of every SDS patient tested. The PMNs of an SDS patient who had received an allogenic hematopoietic stem cell transplant, as well as PMNs from a cystic fibrosis patient, oriented normally. These results suggest that the defect in SDS PMNs is in a specific pathway emanating from the fMLP receptor that is involved exclusively in regulating orientation in response to a spatial gradient of fMLP. This pathway must function in parallel with additional pathways, intact in SDS patients, that emanate from the fMLP receptor and regulate responses to temporal rather than spatial changes in receptor occupancy.

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“…On this topic, we would like to refer to our several previous studies on functions of PMN induced by lithium carbonate (a drug widely used to correct myelosuppression until the onset of rhG-CSF). Although PMN phagocytosis was modulated in a positive way (Carulli et al, 1985), chemotaxis resulted in inhibition in normal donors (Azzarà et al, 1987), enhancement in chronic benign neutropenia (Carulli et al, 1984) and in Shwachman's syndrome (Azzarà et al, 1991), normal even under vinblastine chemotherapy (Azzarà et al, 1986). Indeed, we could clearly demonstrate that this ambiguous lithium interference with PMN motility was strictly dependent on the microtubules assembly, and its modulation was strictly dose-dependent.…”

Section: Discussionmentioning

confidence: 99%

Motility of rhG‐CSF‐induced neutrophils in patients undergoing chemotherapy: evidence for inhibition detected by image analysis

et al. 1996

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The motility of circulating neutrophils from seven patients affected by intermediate and high-grade non-Hodgkin's lymphoma was investigated before and after rhG-CSF administration (5 micrograms/kg/d for 5 d subcutaneously) in the course of chemotherapy. Random motility and bacterial lipopolysaccharide-induced chemotaxis were studied by the micropore filter technique in a Boyden chamber. These functions were evaluated by a very sensitive technique, based on a computer-assisted image processing system, capable of giving several parameters about the kinetics of cell migration. Along with a significant increase in neutrophil number, a significant decrease both in random and stimulated motility was found. The kinetics of cell migration showed that the cells maintained the typical gaussian pattern of random motility. On the contrary, neutrophils were found to have lost the typical stimulated migration peak. These findings are consistent with a rhG-CSF-induced impairment of the directional movement, rather than of the ability of moving at random. These effects were found in patients who, in the same experimental conditions, had displayed an enhanced phagocytosis and phagocytosis-associated chemiluminescence along with an enhanced CD32 expression, not due to an aspecific cell manipulation. Two hypotheses may be taken into account: (i) an increased adhesiveness due to a direct or an indirect activity of the cytokine; (ii) an abnormality in the cytoskeleton maturation and/or rearrangement during the accelerated bone marrow transit of myeloid cells. These findings emphasize that rh-GCSF administration can modulate several functions which play an important role in host defence, and suggest the utility of carrying out further studies to investigate the optimum dosage both to correct neutrophil number and preserve neutrophil functional activities.

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In vivo Effectiveness of Lithium on Impaired Neutrophil Chemotaxis in Shwachman-Diamond Syndrome

Cited by 23 publications

References 14 publications

Shwachman-Diamond syndrome: early bone marrow transplantation in a high risk patient and new clues to pathogenesis

Shwachman-Diamond syndrome: early bone marrow transplantation in a high risk patient and new clues to pathogenesis

The chemotaxis defect of Shwachman‐Diamond Syndrome leukocytes

Motility of rhG‐CSF‐induced neutrophils in patients undergoing chemotherapy: evidence for inhibition detected by image analysis

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