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Biomedical subjects

P R Caldwell

Publications and source records attributed to P R Caldwell.

At least 19 recordsLinked to original sources
PubMed1999

Membranous glomerulonephritis induced in the pig by antibody to angiotensin-converting enzyme: considerations on its relevance to the pathogenesis of human idiopathic membranous glomerulonephritis.

In the course of studies on the humoral consequences of swine to primate xenotransplantation, the investigators induced formation of glomerular subepithelial immune deposits and tubular lesions in pigs injected with heterologous antibody to angiotensin-converting enzyme. This study describes the morphology of the lesions, discusses their mechanism, explains their relevance for understanding the pathogenesis of human idiopathic membranous glomerulonephritis, and proposes future directions for investigations.

Animals↗
PubMed1996

Cellular mechanisms of adaptation of grafts to antibody.

New, more effective, strategies of immunosuppression, including those recently designed to induce durable T cell tolerance (by grafting allogeneic or xenogeneic haematopoietic cells into T lymphocyte-depleted recipients), leave humoral rejection as the main barrier to transplantation of vascularized organs between different species. Recent experimental work indicates that hyperacute rejection can be prevented by manipulations of antibodies and complement. In this paper, we review the mechanisms governing the interaction of antibodies with cell surface antigens in vitro and in vivo, and their cellular consequences. Evidence is presented that, in appropriate conditions, antibodies can protect by effecting modification of graft antigenicity (adaptation or accommodation).

Animals↗
PubMed1995

Interaction of antibody with Forssman antigen in guinea pigs. A mechanism of adaptation to antibody- and complement-mediated injury.

Forssman antigen is a glycosphingolipid with antigenic specificity determined by extra-membrane haptenic sugars similar to blood group antigens and antigens that are the main barrier to xenogeneic organ transplantation. Herein, we describe the localization of Forssman antigen in guinea pig lungs and kidneys and the consequences of its interaction with antibodies in vitro and in vivo (Forssman reaction). Exposure of cultured guinea pig aortic endothelial cells to Forssman antibodies induced rapid redistribution of antigen-antibody complexes at the cell surface, followed by shedding that occurred by blebbing of plasma membrane as vesicles or fragments, and was associated with disappearance of antigen from the cell surface (antigenic modulation). Guinea pigs surviving frequent intravenous infections of increasing amounts of antibodies, for a total of 20 to 40 lethal doses, developed a partial or complete adaptation to generalized Forssman reaction, and adaptation was associated with partial or complete modulation of Forssman antigen at the surface of the pulmonary and, in minor degree, renal endothelial and epithelial cells. These findings support the hypothesis that modulation of endothelial carbohydrate antigens contributes to adaptation of highly vascularized organs exposed to tolerable levels of allo- or xenoantibodies.

Animals↗
PubMed1993

Antibody-mediated redistribution and shedding of endothelial antigens in the rabbit.

We report the results of studies performed in vitro and in vivo that were designed to explore individual, sequential, and concurrent Ag-antibody interactions at the surface of rabbit endothelial cells. Divalent heterologous antibodies to rabbit lung angiotensin-converting enzyme and to rabbit lung thrombomodulin were employed. In cultured monolayers, both antibodies redistributed the specific Ag and co-redistributed the immunologically unrelated Ag inducing partial or complete disappearance of the Ag from the cell surface (antigenic modulation) in 15 to 60 min. When injected into living rabbits, each antibody induced a rapid (1 to 3 min) redistribution and subsequent modulation of the specific and of the unrelated Ag at the surface of alveolar endothelial cells. Immune complexes, and the unrelated Ag, were shed in the circulation, attaining peak levels 3 to 4 min after the injection; were rapidly bound by platelets, E, and polymorphonuclear leukocytes; and were subsequently found in phagocytic cells in the spleen and in the liver. Thrombomodulin co-shed by angiotensin-converting enzyme antibody and, to a lesser degree, angiotensin-converting enzyme co-shed by thrombomodulin antibody, crossed the glomerular capillary walls and were reabsorbed by the epithelial cells of the proximal tubules within 2 to 3 min. The results show that immunologically unrelated Ag can be passively entrapped during formation of immune complexes at the cell surface, and provide new information on the kinetics of clearance of immune complexes containing endogenous, structural Ag.

Animals↗
PubMed1993

Role of the membrane attack complex of complement in lung injury mediated by antibodies to endothelium.

The potential pathogenic role of the membrane attack complex (MAC) of the complement system was investigated in two models of lung injury mediated by antibodies to angiotensin-converting enzyme (ACE), an endothelial cell enzyme. In the first model, acute and fatal lung edema was induced in rabbits by intravenous administration of divalent anti-ACE antibodies. These animals died acutely. C6-deficient rabbits tolerated anti-ACE antibodies without apparent ill effects. On the other hand, C6-deficient rabbits reconstituted with C6 and then receiving anti-ACE antibodies developed acute pulmonary edema and died. These results indicate that the MAC is required for the pathogenesis of this lung injury. In the second model, intravenous administration of monovalent anti-ACE Fab fragments over 4 consecutive days induced fatal interstitial pneumonitis in normal rabbits. For C6-deficient rabbits there was a reduced inflammatory response, and no animals died, implicating a mediator function for the MAC in this model as well. These results demonstrate that MAC is an important mediator of acute pulmonary edema induced by divalent antibodies to an endothelial antigen. Moreover, the complement system was also, to some extent, involved in the recruitment of inflammatory cells leading to the development of interstitial pneumonitis in the experimental lung injury induced by monovalent anti-ACE Fab fragments that 'per se' do not activate complement.

Acute Disease↗
PubMed1989

Lung injury in rabbits induced by intravenous administration of heterologous polyclonal antibodies to angiotensin converting enzyme (kininase II).

Antibody interactions with the endothelial cell membrane glycoprotein angiotensin converting enzyme (Kininase II) in vivo exhibit features of aggregation and capping with resultant shedding similar to those events described in several in vitro isolated cell systems. Requirements for divalent ligand binding, deposition of complement and participation of cytoskeletal elements are demonstrated in vivo. Persistence of antigen in immune complexes with complement interaction appear to be necessary to induce an inflammatory response. Abrogation of this response occurs when circumstances permit antigenic modulation with removal of the immune complex from the endothelial surface.

Animals↗
PubMed1988

Antibodies in the renin-angiotensin system.

Antibody interactions with the endothelial cell membrane glycoprotein angiotensin-converting enzyme (Kininase II) in vivo exhibit features of aggregation and capping with resultant shedding similar to those events described in several in vitro isolated cell systems. Requirements for divalent ligand binding and participation of cytoskeletal elements are demonstrated in vivo as well. Persistence of antigen in immune complexes with complement interaction appear to be necessary to induce an inflammatory response. Abrogation of this response occurs when circumstances permit antigenic modulation with disappearance of the immune complex.

Animals↗
PubMed1988

Local formation of immune deposits in rabbit renal proximal tubules.

Rabbits passively immunized with goat antibodies to rabbit angiotensin converting enzyme (ACE), an enzyme synthesized in the endoplasmic reticulum and mainly expressed on the apical membranes of the cells of proximal tubules, developed mild and transient immune deposits in this segment of the nephron. Granular deposits of goat IgG, rabbit ACE and C3 were found in the basolateral compartment and were maximal during the first week of immunization when the highest titers of anti-ACE antibodies were present. As the antibody titer fell to an undetectable level, the immune deposits were rapidly cleared and were virtually absent 21 days after the injections. Artificial increase of glomerular permeability allowed focal binding of ACE antibodies to the brush border of some tubules, but did not significantly alter the pattern of immune injury at the base of tubular cells. The data are consistent with the interpretation that the immune deposits result from in situ formation of immune complexes. This mechanism would involve passage of circulating antibodies across the tubular basement membrane and their combination with ACE associated with tubular cell surface membranes.

Animals↗
PubMed1987

Glomerulonephritis induced in the rabbit by antiendothelial antibodies.

The effects of interaction between endothelial angiotensin converting enzyme (ACE) and goat anti-rabbit ACE (GtARbACE) antibodies were studied in rabbit glomeruli. By immunofluorescence ACE was not detectable in normal glomeruli. However, when kidneys were perfused with GtARbACE antibodies glomerular bound IgG was seven times higher than that of non-immune IgG and granular deposits of goat IgG were found on the endothelium of glomeruli and arteries. Rabbits injected intravenous for 4 d with GtARbACE antibodies showed on day 1 granular deposits of goat IgG on the glomerular endothelium; from day 3 to 24 there was gradual development of subepithelial deposits of goat IgG, rabbit IgG and C3. When GtARbACE antibodies were similarly injected into proteinuric rabbits there was formation of subepithelial granular deposits of goat IgG and ACE. The results document that a glomerular endothelial antigen is redistributed in vivo by a specific ligand, an event associated with formation of immune deposits. Furthermore, if the glomerular permeability is artificially increased, immune complexes shed from nonglomerular endothelia into the circulation can contribute to form subepithelial immune deposits.

Animals↗
PubMed1987

Lung injury mediated by antibodies to endothelium. II. Study of the effect of repeated antigen-antibody interactions in rabbits tolerant to heterologous antibody.

The effect of repeated interactions of antibodies with cell surface antigens have been examined in in vitro, but not in in vivo systems. In this study are described the results of multiple antibody-cell surface antigen interactions in vivo. Rabbits were given repeated intravenous injections of goat antibodies to angiotensin converting enzyme (ACE), an antigen expressed on the surface of lung endothelial cells. For prevention of anaphylactic reactions, which would have been induced by multiple injections of heterologous immune or nonimmune IgG, the rabbits were made neonatally tolerant to goat IgG. Divalent immune IgG given daily for 21 days induced chronic antigenic modulation (antigen disappearance) with resistance to antibody-mediated inflammatory lesions. The rabbits, however, developed degenerative changes of alveolar endothelial and epithelial cells. Administration of immune IgG every other day for 43 days allowed partial reexpression of ACE and was associated with intravascular, but not interstitial, inflammatory changes. In contrast, repeated administration of monovalent immune Fab did not induce antigenic modulation but caused severe, lethal, interstitial pneumonitis. Thus, in this experimental model the development of acute interstitial inflammatory changes correlates with persistence of antigen and is abrogated by disappearance of antigen induced by divalent antibodies. Further, repeated endothelial antigen antibody interactions fail to induce chronic inflammatory or sclerosing lung lesions.

Animals↗
PubMed1986

Gametes contain angiotensin converting enzyme (kininase II).

The localization of angiotensin converting enzyme (ACE) in the gonads of the normal rabbit was studied by immunofluorescence and immunoelectron microscopy. The enzyme is present in the cytoplasm of testicular spermatids and of epididymal and ejaculated spermatozoa, and on the surface of follicular and tubal oocytes. These findings support the hypothesis that ACE has a role in gamete maturation and in fertilization.

Animals↗
PubMed1986

In vivo interaction of antibodies with cell surface proteins used as antigens.

Antibody interactions with cell membrane glycoproteins in vivo exhibit features of aggregation and capping with resultant shedding similar to those events described in several in vitro isolated cell systems. Requirements for divalent ligand binding and participation of cytoskeletal elements are demonstrated in vivo as well. Persistence of antigen in immune complexes with complement interaction in situ appear to be necessary to induce an inflammatory response in vivo. Abrogation of this response occurs when circumstances permit antigenic modulation with disappearance of the immune complex.

Animals↗
PubMed1985

In vivo interaction of antibodies with cell surface antigens. A mechanism responsible for in situ formation of immune deposits in the zona pellucida of rabbit oocytes.

It was the aim of this study to test the hypothesis that the interaction of antibodies with antigens expressed on the plasma membrane of cells surrounded by a basement membrane or a basement membrane-like structure results in in situ formation of immune deposits. Ovary was chosen for the experiments because we found that a well-characterized protein, angiotensin-converting enzyme (ACE), is expressed in a diffuse pattern on the plasma membrane of mature oocytes. To investigate the events following the in vivo interaction of oolemma-ACE with its antibody, rabbits were injected with goat anti-rabbit ACE gamma-globulin or with Fab fragments of goat anti-rabbit ACE IgG in an ear vein for a maximum of 4 d; they were followed for up to 20 d thereafter. Ovary tissue was studied by immunofluorescence, and immunoelectron, light, and transmission electron microscopy. The results of this study document two new findings: First, that ACE is expressed on the oolemma of rabbit oocytes. Second, that the in vivo interaction of divalent antibodies to this cell surface antigen induces formation of granular immune deposits in the adjacent zona pellucida through a mechanism of "patching" and "shedding" of immune complexes, similar to that occurring in in vitro systems characterized by interaction of plasma membrane receptors with soluble ligands. This mechanism might have importance in the pathogenesis of Heymann glomerulonephritis and of other immunological diseases involving antigens expressed on the plasma membrane of cells.

Animals↗
PubMed1983

Lung injury mediated by antibodies to endothelium. I. In the rabbit a repeated interaction of heterologous anti-angiotensin-converting enzyme antibodies with alveolar endothelium results in resistance to immune injury through antigenic modulation.

To study the effects of relatively long-term interaction of antibodies with surface antigens of lung endothelium, rabbits were intravenously injected for a maximum of 4 d with goat anti-rabbit lung angiotensin-converting enzyme (Gt anti-RbACE) antibodies. On day 1 69%, on day 2 13%, and on days 3 and 4 of injection none of the rabbits developed lethal pulmonary edema. By immunofluorescence microscopy, deposits of GtIgG, frequently in association with RbC3, were found along the endothelium of alveolar capillary walls in all rabbits studied on day 1, in 57% on day 2, in 33% on day 3, and in none of them on day 4. While in vitro anti-ACE antibodies bound in a linear pattern to the lung endothelium, the binding pattern in vivo was distinctly granular. The in vivo interaction of antibodies with ACE also redistributed ACE in a granular pattern along capillary walls. In contrast to the granular deposition of injected anti-ACE IgG and F(ab')2 fragments of anti-ACE IgG, Fab fragments of anti-ACE IgG localized, without fixing C3, in a linear pattern along the endothelium of lung capillaries and did not modify the normal distribution of ACE. However, when the injection of Fab fragments of Gt anti-RbACE IgG was followed by an injection of Rb anti-GtIgG serum, granular deposits of Gt Fab fragments, RbIgG and RbC3 were seen along alveolar capillary walls. Biochemical measurement of ACE activity in lung homogenates provided data in agreement with those obtained by immunofluorescence microscopy, showing diminished activity to none on day 4, with some return of ACE activity on day 5, 24 h after the last injection of antibody, and normal values on day 21. The results obtained indicate that divalent antibodies to an antigen expressed on the plasma membrane of rabbit lung endothelial cells promotes a rapid redistribution of antigenic receptors, fixation of complement and, in surviving rabbits, disappearance of the antigen from the endothelial cells that are no longer susceptible to immune injury. In vivo "immunologic enzymectomy" induced by a ligand-surface antigen interaction is an example of antigenic modulation. These events may have an important role in the pathogenesis of inflammatory lesions induced by antibodies reacting with antigens expressed on the plasma membrane of cells in the lung and in other organs.

Animals↗
PubMed1983

Release of platelet activating factor in rabbits with antibody-mediated injury of the lung: the role of leukocytes and of pulmonary endothelial cells.

This paper describes the release of platelet-activating factor (PAF) into the circulation of rabbits with acute pulmonary injury induced by antibody reacting with pulmonary endothelium. Eight rabbits were injected i.v. with 2 mg/kg of body weight of goat anti-rabbit lung angiotensin-converting enzyme gamma-globulin (GtARbACE). All animals developed acute pneumonitis, characterized by severe endothelial damage, accumulation of polymorphonuclear leukocytes (PMN) and platelets (Plt) in the lumina of alveolar capillaries, and deposits of goat IgG and rabbit C3 along alveolar capillary walls. Six of the rabbits died from acute pulmonary edema. PAF was detected in the plasma of all animals within 5 min after injection of GtARbACE. Five other rabbits were depleted of leukocytes by nitrogen mustard and then injected with 2 mg/kg of body weight of GtARbACE. In three of these rabbits release of PAF was demonstrated, though in amounts smaller than in non-leukocyte-depleted rabbits; all three animals died from pulmonary edema. After injection of 0.03 mg/kg of body weight of GtARbACE in six additional rabbits, three of them leukocyte-depleted, small amounts of PAF were detected in the circulation. None of these six rabbits died of pulmonary edema. PAF release was not observed in ten rabbits injected i.v. with 2 or 0.03 mg/kg of body weight of normal goat gamma-globulin. In separate experiments in vitro, incubation of isolated lung or thoracic aorta with GtARbACE resulted in deposits of goat IgG along endothelia and significant release of PAF. PAF was also released from endothelial cells removed from thoracic aorta by cellulose acetate paper and then incubated with GtARbACE. When segments of thoracic aorta were stripped of endothelium and then incubated with GtARbACE, PAF release could not be shown. The data obtained are consistent with the interpretation that PAF released into the circulation after binding of GtARbACE to the endothelia of lung and aorta originates from leukocytes and from lung and thoracic aorta endothelial cells.

Animals↗
PubMed1981

Lung injury induced by antibody fragments to angiotensin-converting enzyme.

Rabbits given goat anti-rabbit angiotensin-converting enzyme antibodies or derived antibody fragments develop rapidly fatal pulmonary edema. Endothelial cell injury is manifested by bleb formation and the disintegration of cell membranes. Platelets are found along the injured endothelium and leukocytes block capillary lumens. The pathologic features are similar when immune IgG, F(ab')2, or Fab are given. In vitro studies of complement activation show that solubilized, purified angiotensin-converting enzyme alone activates C1, with consumption of C4 and C3. Addition of immune IgG plus converting enzyme enhances this activation. F(ab')2 plus enzyme enhances only C3 consumption, while Fab with enzyme produces no additional complement utilization. Thus, while complement activation may be involved in the pathogenesis of injury induced by IgG or F(ab')2, the mechanism of Fab-induced endothelial injury remains unclear.

Animals↗
PubMed1980

Subcellular distribution of low- and high-molecular-weight renin and its relation to a renin inhibitor in pig renal cortex.

1. The subcellular distribution of low-molecular-weight and high-molecular weight forms of pig renin has been investigated. 2. Renin, in aqueous extracts of a 'renin granular fraction' prepared by differential centrifugation, after gel filtration on Sephadex G-100 displayed an apparent molecular weight of 40 000 and was not activated by acidification to pH 2.8. 3. Renin in the soluble fraction separated on Sephadex G-100 at neutral pH displayed a main peak of activity with an apparent molecular weight of 40 000. When eluates were acidified to pH 2.8 (2 degrees C, 60 min) a marked increase in renin activity was observed in the region corresponding to an apparent molecular weight of 50 000. 4. A renin inhibitory material was isolated from the soluble fraction by DEAE chromatography. This material displayed an apparent molecular weight of 50 000 and it was destroyed by acidification to pH 2.8. 5. The presence of the proteolytic inhibitor N-ethylmaleimide yielded an apparently high-molecular-weight form of renin (60 000--70 000) from the soluble fraction, but this was not found in the granular fraction. 6. We conclude that pig renal renin is stored within membrane-bounded subcellular organelles as the low-molecular-weight form. High-molecular-weight renin and renin inhibitory activity are localized to the cortical soluble fraction. In addition, the soluble fraction contains a material which in the presence of N-ethylmaleimide results in the formation of an apparently high-molecular-weight renin.

Animals↗