By using karyotypic analysis of female mice treated with busulphan or isopropyl methane sulphonate (IMS), and injected with male bone marrow the donor contribution to both total marrow cellularity and spleen colony forming cells (CFU-S) was assessed for up to 6 months after transplant. In the mice treated with busulphan the marrow cells yielded metaphases of which between 40% and 83% were of donor type. Between 60% and 97% of metaphases in spleen colonies formed in irradiated mice were of donor type during the 24-week study period. In contrast, mice prepared for the transplant with IMS showed no cells of donor type at any time after transplant, neither did they possess CFU-S of donor type. We were therefore led to conclude that the donor cells made no contribution to longterm engraftment in mice prepared with IMS, whilst in those prepared with busulphan they were the predominantly active haemopoietic cells. These results are consistent with a model of haemopoiesis in which the most primitive cells reside in a 'niche' where they are resistant to the effects of IMS but susceptible to the action of busulphan. Busulphan may vacate some niches to allow engraftment by transplanted marrow, whilst IMS yields no unoccupied niches for grafted cells to occupy, and cannot therefore lead to a stable chimaerism.
BACKGROUND
CD40 ligand (CD40L) is a mediator of inflammation and platelet aggregation. High levels are associated with increased risk in individuals with cardiovascular disease (CVD). Statin effects on CD40L in normocholesterolemic people are unknown. We investigated whether atorvastatin decreases serum or leukocyte‐produced CD40L levels.
METHODS
Twenty‐five normocholesterolemic subjects without CVD were studied. After a drug‐free run‐in, subjects took atorvastatin 80 mg once daily for 16 weeks. CD40L was measured in serum and leukocyte culture supernates after 24‐hr incubation. Immunofluorescence detection (R&D Systems, MN; Luminex 100IS, TX) was used at baseline and end of study. Non‐parametric statistical tests were performed (significant P<0.05).
RESULTS
Baseline age, total cholesterol, LDL, HDL, and triglycerides were: 32±11 yrs, 179±33 mg/dl, 97±29 mg/dl, 62±20 mg/dl, and 102±69 mg/dl. Serum CD40L was non‐significantly lower at 16‐weeks (2.3 ng/ml, IQR: 3.3 ng/ml) than at baseline (3.0 ng/ml, IQR: 1.6 ng/ml; P=0.4). However, atorvastatin significantly lowered CD40L from leukocytes by 57% (P=0.02[21 pg/mg protein, IQR: 28 pg/mg protein vs. 49 pg/mg protein, IQR: 128 pg/mg protein]).
CONCLUSIONS
While atorvastatin did not lower serum CD40L, significant reduction in leukocyte production was seen. These data suggest a potential benefit in normocholesterolemic individuals that should be further investigated. However, clinical response phenotype should be carefully chosen.
Clinical Pharmacology & Therapeutics (2005) 79, P37–P37; doi:
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