Synergistic actions of the vitamin D analogue MC 1288 and 15-deoxyspergualin in xenotransplantation

Abstract: The vitamin D analogue MC 1288 (20-epi-1α,25-dihydroxycholecalciferol) effectively postpones rejection of cardiac, intestinal, skin, and aortic allografts. MC 1288 binds to the vitamin D receptor and is thus assumed to exert its immunosuppressive effects via the same mechanisms as 1α,25-dihydroxycholecalciferol, the active form of vitamin D. 1α,25-Dihydroxycholecalciferol has been demonstrated to inhibit the production of various cytokines (interleukin-2, interferon-γ, granulocyte macrophage colony-stimulating factor, and interleukin-12) and to prevent B lymphocyte secretion of immunoglobulins. In the present study MC 1288 was evaluated for its ability to prevent rejection of mouse-to-rat cardiac xenografts, alone and in combination with 15-deoxyspergualin (DSG). Combined treatment with MC 1288 (given days -1 to 9) and DSG (given day -1 and onward) postponed rejection from day 3.0 (untreated recipients) until day 19.5. In rats treated with MC 1288 or DSG as monotherapy, rejection occurred after 3.0 and 7.5 days, respectively. Functioning grafts, obtained on day 9 from recipients treated with MC 1288 and DSG in combination, displayed an almost normal morphology without any obvious deposition of immunoglobulins in the vessels of the grafts and with just a few infiltrating cells. Thus, we have demonstrated synergistic actions of MC 1288 and DSG in delaying rejection of xenografts. Analysis of cellular infiltration, immunoglobulin deposition and graft survival times in the various treatment groups indicate a combined inhibitory effect of these two drugs on the level of macrophage effector function, direct or indirect via T lymphocytes, as well as on antibody production.     

Engulfment of mast cell secretory granules on skin inflammation boosts dendritic cell migration and priming efficiency

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Generation of the eosinophil chemotactic factor (ECF) from various cell types by melittin

The peptide melittin, the main constituent of bee venom is a potent stimulus for the generation of an eosinophil chemotactic factor (ECF) from human polymorphonuclear neutrophils, rat mast cells and rat peritoneal cells depleted in mast cells. Optimal EFC induction required a sublytic activation of the cells. With each cell type the kinetics of ECF generation were similar in that after an early rise in activity a steep fall off occurred at later times of incubation suggesting a mechanism of inactivation. The induction of ECF by melittin is increased in the presence of calcium. The polar portion of the melittin molecule (aminoacids 20–26) is responsible for the generation of the chemotactic activity. Other peptides of honey bee venom such as the mast cell degranulating peptide (MCD) or apamine do not initiate ECF release. It appears that melittin leads to ECF induction via the phospholipase A₂-arachidonic acid dependent pathway of cell activation. Our data suggests that the lipid mediator ECF can be obtained from phagocytes and mast cells thus indicating the interdependence of inflammatory reactions.     

Dual function of Langerhans cells in skin TSLP-promoted TFH differentiation in mouse atopic dermatitis

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Immunofluorescent detection of anti-cytoskeleton antibodies using vinblastine-treated mononuclear cells

A reliable and reproducible immunofluorescence method is described for the detection of anti-cytoskeleton antibodies in human sera, based on the use of vinblastine-treated peripheral blood mononuclear cells as substrate. Three immunofluorescence patterns associated with antibodies to microfilaments, intermediate filaments and microtubules are readily identified.     

Clinical implications of continuous measurement of energy expenditure in mechanically ventilated patients

Energy expenditure was monitored in 20 critically-ill mechanically ventilated patients using the Siemens-Elema Oxygen Consumption Calculator (OCC 980). Energy expenditure was measured continuously over the 24-h period in all patients (altogether, over 2500 patient hours; range 48-288 h). A predicted energy expenditure was calculated for each patient from standard tables for basal metabolic rates modified according to previously published reports on the influence of trauma, infection and elevated body temperature. For all patients combined, the agreement between the predicted and the measured energy expenditure was good. However, in individual patients the measured energy expenditure varied between 48 and 148% of the predicted value. The measured energy expenditure in surviving traumatized and/or septic patients correlated well (95-100%) with the predicted value at the time when weaning off the ventilator could be initiated. On the first day of measurements, the energy expenditure (in % of the predicted value) in the six patients who later died was significantly lower than in surviving patients (84 +/- 6 vs 107 +/- 2%; p < 0.01). Over a 24-h period, energy expenditure, defined as the value noted during a stable 30-40-min period of measurement, varied between 12 and 50% in the individual patients. This study shows that energy expenditure cannot be accurately predicted in the individual patient, that an energy expenditure below predicted values appears to be indicative of a poor prognosis and that short periods of energy expenditure monitoring may fail to reflect 24-h conditions.     

Subtotal colectomy for obstructing carcinoma of the left colon

This retrospective review of seven patients with completely obstructing cancers of the left half of the colon, in addition to other reports in the literature, suggests that subtotal colectomy with primary ileal

1 Clinical data on seven patients who underwent subtotal colectomy for obstructing carcinoma of the left colon: 1975–1982.

Patient	Age (yr) and Sex	Tumor Location	Hospital Stay	Comments
1	68, F	Decending	10 days	A and W 40 mo postop1
2	71, F	Sigmoid	22 days	A and W 18 mo postop
3	73, F	Sigmoid	…	A and W 5 yr postop
4	66, F	Decending	8 mo	Dead from complications
5	72, M	Sigmoid	11 days	Incidental cecal cancer; A and W 3 mo postop
6	66, M	Sigmoid	28 days	Alive with metastasis 16 mo postop
7	78, M	Left transvers	34 days	Many other polyps; A and W 9 mo postop

1

A and W = alive and well.

proctostomy may be the treatment of choice for those lesions that are technically resectable and located high enough to permit an intraperitoneal ileal proctostomy. The morbidity and mortality is less than that seen with the staged approach and the length of hospitalization is shorter. By eliminating a second or third hospitalization and a temporary colostomy, palliation is better in those patients who ultimately die from recurrent cancer. Furthermore, those patients resected for cure may have increased rates of long-term survival.     

The relative ethylumbelliferone dealkylase activity characterizing the effect of different inducers on the hydroxylase system in the liver musomes of female mice

d,l-Camphor was detected as a new inducer of hydroxylase in the liver musomes of female mice. After a 2-day inhalation of d,l-camphor, cyt. P-450 and the ethylumbelliferone dealkylase were increased by 250 per cent and the NADPH-cyt. P-450 reductase by 350 per cent. The product [NADPH-cyt. P-450 reductase activity × cyt. P450 concentration] was shown to be a suitable reference parameter for the ethylumbelliferone dealkylase activity in the liver musomes during the treatment with four different inducers. The relative dealkylase activity Q was much decreased during inhalation of cyclohexane or d,l-camphor.

$\text{Q =}\text{mU ethylumbelliferone dealkylase}\text{mU NADPH-cty. P-450 reductase × nmoles cty. P-450/mg protein}$

Obviously these two inducers preferably enhanced cyt. P-450 species with a low dealkylase activity. The Q-values were reproducible. Q was increased by 100 per cent during induction of a MC-sensitive mouse strain with 3-methylcholanthrene, but it was only moderately decreased by induction with phenobarbital. Corresponding to this, methylcholanthrene is known to selectively induce a cyt. P-448 with high dealkylase activity whereas phenobarbital is known to change the hydroxylase specificity in the liver musomes not very much.