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Biomedical subjects

B Engelhardt

Publications and source records attributed to B Engelhardt.

11 recordsLinked to original sources
PubMed1992

Induction of persistently demyelinated lesions in the rat following the repeated adoptive transfer of encephalitogenic T cells and demyelinating antibody.

A chronic relapsing model of demyelinating experimental allergic encephalomyelitis (EAE) was induced in Lewis rats by the repeated co-transfer of encephalitogenic, myelin basic protein (MBP)-specific T cells in combination with a demyelinating monoclonal antibody (mAb) specific for the myelin oligodendrocyte glycoprotein (MOG). In controls, repeated injections of 5 x 10(5) MBP-specific T cells at intervals of 18-21 days resulted in an increasing resistance to the induction of further episodes of EAE. However, intravenous injection of the mAb 4 days after each T cell transfer overcame this 'vaccination' effect and induced severe clinical relapses associated with an increasing and persistent neurological deficit. Histological examination revealed that four cycles of treatment with T cells and mAb were sufficient to result in the formation of large plaques of demyelination in the spinal cord that failed to undergo significant remyelination within 60 days of the final injection of mAb. These lesions consisted of a matrix of astrocytic scar tissue traversed by numerous naked axons. These observations demonstrate that the formation of large, persistently, demyelinated lesions in a T cell-mediated model of EAE in the Lewis rat is dependent on the presence of an appropriate anti-myelin autoantibody response.

Animals↗
PubMed1991

Interaction of T lymphocytes with cerebral endothelial cells in vitro.

As a prerequisite of inflammatory lesion formation in (auto-)immune disease of the central nervous system, lymphocytes have to interact with brain endothelia. In recent years much progress has been made towards a better understanding of mechanisms and factors involved in organ specific homing of lymphocytes. Many lines of evidence indicate that T lymphocytes recognizing antigens which are exclusively beyond the blood-brain barrier cross this barrier only when they are in an activated state, irrespective of their antigen specificity. Antigen presentation by blood-brain barrier endothelia, however, may play a role in later stages of florid inflammation.

Animals↗
PubMed1990

Double-blind, placebo-controlled trial of alternate-day furosemide therapy in infants with chronic bronchopulmonary dysplasia.

To test the hypothesis that alternate-day administration of furosemide will result in a sustained improvement in pulmonary function without causing alterations in electrolyte or mineral homeostasis, we conducted a randomized, double-blind, placebo-controlled study of 11 hospitalized, oxygen-dependent, spontaneously breathing infants with chronic bronchopulmonary dysplasia. Infants were randomly selected to receive either furosemide, 4 mg/kg in two divided doses on alternate days orally, or placebo for 8 days, followed by crossover to the alternate-therapy for an additional 8-day period. The two study periods were separated by a 48-hour washout period. Dynamic compliance, total pulmonary resistance, the concentration of electrolytes in serum, and the concentrations of calcium and creatinine in urine were measured on nontreatment days. Alternate-day furosemide therapy increased dynamic lung compliance by 76 +/- 112% and decreased total pulmonary resistance by 20 +/- 39%, compared with placebo (both variables p = 0.032). Alternate-day furosemide therapy did not result in increased urine output, electrolyte abnormalities, or increased urinary calcium excretion. We conclude that this simplified treatment regimen may be useful in the management of infants with chronic bronchopulmonary dysplasia. The results support our previous speculation that furosemide improves pulmonary function by mechanisms unrelated to its diuretic properties.

Airway Resistance↗
PubMed1990

Immune function of the blood-brain barrier: incomplete presentation of protein (auto-)antigens by rat brain microvascular endothelium in vitro.

The endothelial blood-brain barrier (BBB) has a critical role in controlling lymphocyte traffic into the central nervous system (CNS), both in physiological immunosurveillance, and in its pathological aberrations. The intercellular signals that possibly could induce lymphocytes to cross the BBB include immunogenic presentation of protein (auto-)antigens by BBB endothelia to circulating T lymphocytes. This concept has raised much, though controversial, attention. We approached this problem by analyzing in vitro immunospecific interactions between clonal rat T lymphocyte lines with syngeneic, stringently purified endothelial monolayer cultures from adult brain micro-vessels. The rat brain endothelia (RBE) were established from rat brain capillaries using double collagenase digestion, density gradient fractionation and selective cytolysis of contaminating pericytes by anti-Thy 1.1 antibodies and complement. Incubation with interferon-gamma in most of the brain-derived endothelial cells induced Ia-antigens in the cytoplasm and on the cell surface in some of the cells. Before the treatment, the cells were completely Ia-negative. Pericytes were unresponsive to IFN-gamma treatment. When confronted with syngeneic T cell lines specific for protein (auto-)antigens (e.g., ovalbumin and myelin basic protein, MBP), RBE were completely unable to induce antigen-specific proliferation of syngeneic T lymphocytes irrespective of pretreatment with IFN-gamma and of cell density. RBE were inert towards the T cells, and did not suppress T cell activation induced by other "professional" antigen presenting cells (APC) such as thymus-derived dendritic cells or macrophages. IFN-gamma-treated RBE were, however, susceptible to immunospecific T cell killing. They were lysed by MBP-specific T cells in the presence of the specific antigen or Con A. Antigen dependent lysis was restricted by the appropriate (MHC) class II product. We conclude that the interaction of brain endothelial cells with encephalitogenic T lymphocytes may involve recognition of antigen in the molecular context of relevant MHC products, but that this interaction per se is insufficient to initiate the full T cell activation program.

Animals↗
PubMed1989

Immunotherapy of experimental autoimmune encephalomyelitis (EAE): differential effect of anti-IL-2 receptor antibody therapy on actively induced and T-line mediated EAE of the Lewis rat.

Treatment of Lewis rats with monoclonal anti-interleukin-2 receptor (IL-2 R) antibody ART-18 is highly efficient in protecting the recipients from T-line transferred experimental autoimmune encephalomyelitis (tEAE) in vivo. In contrast, ART-18 did not affect the development of EAE actively induced (aEAE) by immunization with myelin basic protein (MBP) in complete Freund's adjuvant (CFA). ART-18 caused a slight delay in the development of aEAE only in combination with a subtherapeutic dose of cyclosporine A (Cy-A), but failed to influence duration or severity of clinical signs. The discrepancy in therapeutic efficiency of ART-18 in tEAE and aEAE could be due to a different intensity of IL-2 R-expression on in vitro- and in vivo-activated MBP-specific T cells. Our results therefore caution against a general therapeutic application of anti IL-2 R-directed therapy in all manifestations of T-cell-mediated autoimmunity.

Animals↗
PubMed1989

Effect of spironolactone-hydrochlorothiazide on lung function in infants with chronic bronchopulmonary dysplasia.

To test the hypothesis that spironolactone-hydrochlorothiazide (Aldactazide) will improve urine output and lung function in infants with bronchopulmonary dysplasia, we studied 21 hospitalized, spontaneously breathing, oxygen-dependent infants with chronic bronchopulmonary dysplasia. Infants were randomly assigned to receive either a 1:1 mixture of spironolactone and hydrochlorothiazide orally (n = 12) (3 mg/kg/day of both compounds) or no treatment (n = 9) for 6 to 8 days each. Dynamic lung compliance, total pulmonary resistance, and hemoglobin oxygen saturation were measured on the first and last days of each study period. Fluid intake and urine output were measured each day. Although the treatment significantly increased urine output, neither lung mechanics nor oxygenation were improved by the drug. The magnitude of the diuresis achieved with spironolactone-hydrochlorothiazide treatment was comparable to the diuresis achieved in a previous study of furosemide treatment (J Pediatr 1986:109;1034-9). Statistical analysis indicated that a type II error was an unlikely explanation for our failure to detect a beneficial effect. In three patients, doubling the oral dose did not improve lung mechanics or oxygenation. We speculate that diuresis per se is not responsible for lung function improvement during treatment with other drugs with diuretic properties.

Bronchopulmonary Dysplasia↗
PubMed1988

Control of water balance in infants with bronchopulmonary dysplasia: role of endogenous vasopressin.

Babies with chronic bronchopulmonary dysplasia (BPD) can sometimes develop pallor, systemic and pulmonary edema, oliguria, and hyponatremia not attributable to cardiopulmonary or renal impairment. These signs and symptoms might, however, be explained by inappropriate control of vasopressin secretion. To test this hypothesis, we measured plasma vasopressin and osmolality, serum sodium and potassium concentrations, urine output and osmolality, and free water clearance in 26 normoxic infants with BPD aged 1-4 months. All of these infants required supplemental oxygen (FiO2 0.41 +/- 0.03, mean +/- 1 SE) to maintain O2 saturation of greater than 88%, and six infants also required mechanical ventilation. As controls, 10 infants of similar age but without BPD were also studied. None of the infants had been discharged from the nursery and was receiving any medications, and all were clinically stable when studied. Compared to control infants, infants with BPD had significantly elevated plasma vasopressin concentrations (control 5.2 +/- 0.9 pg/ml; BPD 42.4 +/- 5.1; mean +/- SE, p less than 0.05). Moreover, infants with BPD had hyponatremia and hypotonic plasma, and both urine output and free water clearance were significantly reduced. These data suggest that some infants with chronic BPD have elevated vasopressin levels that are functionally significant. We speculate that excessive stimulation of vasopressin secretion may explain some of the pulmonary and nonpulmonary signs and symptoms in infants with chronic BPD.

Bronchopulmonary Dysplasia↗
PubMed1987

Pulmonary response to group B streptococcal toxin in young lambs.

Marked respiratory distress is seen in severe early onset group B beta-hemolytic streptococcal (GBS) disease in newborn infants. To investigate the pathophysiological effects of a polysaccharide toxin from GBS type III cultures, obtained from an infant who died from this disease, young chronically instrumented, unanesthetized lambs were studied with measurements of lung mechanics, lung volumes, ventilation, hemodynamics, and lung vascular permeability. Intravenously administered GBS toxin resulted in a biphasic response with an early threefold increase in total lung resistance, 40% decrease in dynamic lung compliance, and 30% increase in minute ventilation coinciding with hypoxemia, pulmonary hypertension, and fever. A second phase of the response followed consisting of less prominent changes in these variables as well as increased lung lymph protein clearance compatible with increased vascular permeability. The temporal close relationship between marked leukopenia and increased lung lymph thromboxane B2 concentrations to the simultaneously occurring pulmonary hypertension and changes in lung mechanics suggests that leukocytes and thromboxane A2 may be mediators of these GBS toxin-induced effects.

Airway Resistance↗
PubMed1987

The role of granulocytes in the pulmonary response to group B streptococcal toxin in young lambs.

Marked leukopenia and sequestration of granulocytes in the lung are consistently seen in severe early onset group B streptococcal (GBS) disease in human infants. To investigate the role of granulocytes as potential mediators in the pulmonary pathophysiology of this disease, the effects of intravenously administered GBS type III toxin were studied in young lambs before and after granulocyte depletion with hydroxyurea. Granulocyte depletion markedly reduced the 4-fold increase in total lung resistance and the decrease in dynamic compliance observed after GBS toxin. Granulocyte depletion significantly attenuated the pulmonary hypertension, hypoxemia and increased minute ventilation present during the first phase of the response (0.5-1 h after GBS toxin). It did not significantly alter the increase in body temperature, the marked increase in lung lymph thromboxane B2 concentrations during the first phase or the increase in lung lymph flow and protein clearance during the second phase of the response (3.5-5 h after GBS toxin). The results indicate that granulocytes are involved as mediators of the changes in lung mechanics seen after GBS toxin infusion in young lambs. Granulocytes contribute to the pulmonary hypertension and decrease in arterial oxygenation, but other mediators appear to be responsible for the injury of the vascular endothelium.

Animals↗
PubMed1986

Short- and long-term effects of furosemide on lung function in infants with bronchopulmonary dysplasia.

Although furosemide improves lung mechanics in some infants with broncho-pulmonary dysplasia (BPD), this may not be important unless gas exchange also improves. To determine the relationship between improvement in mechanics and improvement in gas exchange, the short- and long-term effects of furosemide therapy were studied in 16 spontaneously breathing infants with severe BPD who were both oxygen dependent and hypercarbic (mean PCO2 54 +/- 11 torr). Each infant was examined at least three times: before furosemide therapy, 1 hour after the first dose of furosemide, and after a 6- to 10-day course. Ten of the 16 infants were also examined three times during a 7-day control period. Transcutaneous PO2 and PCO2, esophageal pressure, air flow, and tidal volume were measured. Pulmonary resistance, lung compliance, and the alveolar to skin PO2 difference were calculated. After a single dose of furosemide, only compliance significantly improved. After prolonged therapy, compliance, resistance, and oxygenation significantly improved in the group as a whole, but better oxygenation was achieved in only six of 16 infants. tcPCO2 was unaffected by long-term furosemide therapy, but in all infants with decreased tcPCO2 1 hour after a single dose, there was sustained decrease in PCO2 after prolonged therapy. Changes in gas exchange were not explained by changes in lung mechanics. These data indicate that long-term diuretic therapy can improve the mechanical properties of the lungs of spontaneously breathing infants with BPD, but that gas exchange is usually unaffected.

Airway Resistance↗