Development of large numbers of mast cells at sites of idiopathic chronic dermatitis in genetically mast cell-deficient WBB6F1-W/Wv mice

The normal skin and other tissues of adult mast cell-deficient WBB6F1- W/Wv or WCB6F1-Sl/Sld mice contain less than 1.0% the number of mast cells present in the corresponding tissues of the congenic normal (+/+) mice. As a result, genetically mast cell-deficient WBB6F1-W/Wv or WCB6F1-Sl/Sld mice are widely used for studies of mast cell differentiation and function. We found that mast cells developed at sites of idiopathic chronic dermatitis in WBB6F1-W/Wv mice and that the number of mast cells present in the skin of WBB6F1-W/Wv mice was proportional to the severity of the dermatitis (in ear skin, there were 33 +/- 4 mast cells/mm2 of dermis at sites of severe dermatitis v 9 +/- 3 at sites of mild dermatitis, 0.8 +/- 0.3 in skin without dermatitis, and 100 +/- 7 in the normal skin of congenic WBB6F1-+/+ mice; in back skin, the corresponding values were 2.0 +/- 0.6, 1.1 +/- 0.9, 0.025 +/- 0.025, and 26.2 +/- 3.2). The development of mast cells was a local, not systemic, consequence of the dermatitis. Thus, WBB6F1-W/Wv mice with severe dermatitis lacked mast cells in skin not showing signs of dermatitis and also in the peritoneal cavity, stomach, cecum, and tongue. Idiopathic chronic dermatitis was not associated with the local development of mast cells in WCB6F1-Sl/Sld mice, a mutant whose mast cell deficiency is due to a mechanism distinct from that of WBB6F1-W/Wv mice. These findings may have implications for understanding the nature of the mast cell deficiency in WBB6F1-W/Wv and WCB6F1-Sl/Sld mice and for the use of these mutants to analyze mast cell differentiation and function.     

Hereditäre nichtsphärozytäre hämolytische Anämie mit hohem Erythrozyten-ATP

Zusammenfassung In den Erythrozyten der beschriebenen Patientin, die klinisch an einer schweren hereditären nichtsphärozytären hämolytischen Anämie leidet, findet sich ein stark erhöhter Gehalt an den Adeninnukleotiden ADP und ATP. Versuche an substratfrei inkubierten intakten Erythrozyten zeigen eine verminderte Rate der ATP-Spaltung. Veränderungen der Aktivitäten von ATPasen oder Enzymen des Diphosphoglyzeratzyklus in Hämolysaten wurden dabei nicht gefunden. Da ein verminderter ATP-Abbau allein die Befunde nicht zu erklären vermag, wird gleichzeitig eine Störung in der Regulation der Nukleotidsynthese in den betroffenen Erythrozyten diskutiert. Erythrokinetische Untersuchungen mit⁵¹Cr ebenso wie mit DF³²P ergaben einen Verlauf der Erythrozytenlebenszeitkurven, der auf eine zumindest quantitativ unterschiedliche Defektausprägung in zwei Erythrozytenpopulationen hinweist.Auch die Berechnung des absoluten ATP-Abfalles ergibt eine deutliche Verminderung in den pathologischen Zellen gegenüber der Norm. Er beträgt während der ersten 2 Stunden der Inkubation in den Patientenerythrozyten 0,83 nMol/ml Erythrozyten × min gegenüber 4,32 nMol in den Normalzellen. Berechnet man hieraus unter Berücksichtigung der jeweiligen Glykolyserate — näherungsweise — den absoluten ATP-Verbrauch der Zellen, so ergibt sich für die Patientenerythrozyten im Vergleich zu den Normalzellen eine Reduktion auf etwa 60%.Vortrag auf der 12. Tagung der Deutschen Gesellschaft für Hämatologie, Berlin, 17.–19. Oktober 1966.     

Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.