During chemotherapy for acute leukemia, severe neutropenia allows acquisition of life-threatening infections which are difficult to clear with antibiotics alone. With return of myelopoiesis, even severe infections often improve dramatically. Polymorphonuclear leukocytes (PMNL) obtained from most leukemic patients at the time of recovery from chemotherapy have markedly increased (""""""""activated"""""""") oxidative metabolic responses when stimulated in vitro. In contrast, a subset (about 12%) of patients have defective (""""""""deactivated"""""""") metabolic PMNL responses. PMNL from 30% of patients have decreased total myeloperoxidase (MPO) content and degranulation. The patients with defective metabolic and/or degranulation responses may have a much higher risk of dying during that hospitalization. The data prompt the following hypothesis: That the leukemic patients most susceptible to infections are those where quantitative (neutropenia) and qualitative (degranulation, oxidative metabolism) abnormalities summate to cause maximal compromise in host defense. We therefore propose to do the following: 1. Correlate increased susceptibility to bacterial infection with altered granulocyte function in patients with ANLL, ALL and myelodysplastic syndromes. a) Determine rate of bacterial infections induced by the disease and the increased risk following chemotherapy, in particular after circulating PMNL have returned to """"""""adequate"""""""" numbers, in this patient population. b) Correlate infection risk with sequential studies of alterations in degranulation, oxidative metabolism and microbicidal ability. Since defects have been shown to occur in subpopulations of PMNL, single cell (flow cytometric) analytic techniques will be employed. These will be closely corroborated by standard biochemical assays. 2. At selected time points, determine the mechanism(s) of altered (activated or deactivated) functions: a) due to the leukemic process itself (PMNL obtained pre-chemotherapy), b) induced by chemotherapy (PMNL obtained after 3 days of chemotherapy), c) occuring after recovery from chemotherapy-induced neutropenia (PMNL obtained when circulating PMNL rise above 500/mm3), by a systematic study of stimulus-response coupling mechanisms of PMNL.
| Bass, D A; McPhail, L C; Schmitt, J D et al. (1988) Selective priming of rate and duration of the respiratory burst of neutrophils by 1,2-diacyl and 1-O-alkyl-2-acyl diglycerides. Possible relation to effects on protein kinase C. J Biol Chem 263:19610-7 |
| Bauldry, S A; Wykle, R L; Bass, D A (1988) Phospholipase A2 activation in human neutrophils. Differential actions of diacylglycerols and alkylacylglycerols in priming cells for stimulation by N-formyl-Met-Leu-Phe. J Biol Chem 263:16787-95 |
| Bass, D A; Gerard, C; Olbrantz, P et al. (1987) Priming of the respiratory burst of neutrophils by diacylglycerol. Independence from activation or translocation of protein kinase C. J Biol Chem 262:6643-9 |
