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Biomedical subjects

A M Dvorak

Publications and source records attributed to A M Dvorak.

At least 19 recordsLinked to original sources
PubMed1979

Rejection of first-set skin allografts in man. the microvasculature is the critical target of the immune response.

Recent reports of microvascular injury in delayed hypersensitivity skin reactions prompted us to reexamine the pathogenesis of first-set skin allograft rejection in man using morphologic techniques that allowed both extensive vessel sampling and unequivocal evaluation of microvascular endothelium. We here report that widespread microvascular damage is a characteristic, early consequence of the cellular immune response to first-set human skin allografts and is qualitatively similar to, but substantially more extensive than, that occurring in delayed hypersensitivity reactions. Microvascular damage in invariably preceded significant epithelial necrosis and affected initially and primarily those venules, arterioles, and small veins enveloped by lymphocytes. Vessels of both the allograft itself and the underlying graft bed (recipient tissue) were equally affected. These data suggest that endothelial cells of the microvasculature are the critical target of the immune response in first-set vascularized skin allograft rejection in man and that rejection can be attributed largely to ischemic infarction resulting from extensive microvascular damage. Other mechanisms, such as direct cellular contacts between infiltrating lymphocytes and epithelium, apparently played only a minor role. The findings presented here indicate that the rejection of first-set vascularized skin allografts, though induced by immunologically specific mechanisms, is primarily effected by final pathways that are relatively nonspecific and that may cause damage to both foreign and host vessels and cells. Rather than contradicting studies demonstrating the exquisite specificity of allograft rejection in other systems, these findings provide a further example of the heterogeneity of the cellular immune response. Recognition of the critical role of immunologically mediated microvascular injury may prove important both for an understanding of the biology of allograft rejection and for strategies aimed at prolonging allograft survival.

Antibody Formation↗
PubMed1979

Electron microscopy of Hodgkin's disease tissue cultures.

Cells from 9 monolayer tissue cultures prepared from Hodgkin's disease tumors in the spleen were examined in the electron microscope. Three established culture lines (carried in vitro for greater than 3 years and passaged greater than 200 times) that contained aneuploid karyotypes were composed of oval cells with numerous interdigitating surface microvilli. The nuclei were complex and convoluted with multiple large nucleoli and dispersed chromatin. The cytoplasm contained lysosomes, microfilaments, a complex Golgi apparatus, nondilated rough endoplasmic reticulum, polyribosomes, fat, and glycogen. One Hodgkin's disease monolayer with aneuploid chromosomes examined from the 4th to 48th passage in culture was composed of larger cells with fewer microvilli and numerous multinuclear giant cells. Two monolayers derived from transplanted tumors in nude mice inoculated with Hodgkin's disease cultured cells were similar to the original cell lines. The ultrastructural features of these 6 cultures with aneuploid karyotypes differed from those of 3 monolayers which, although prepared from Hodgkin's disease splenic tumors, were composed of fibroblastic cells with diploid chromosomes. The aneuploid Hodgkin's disease cultures did not resemble 6 normal spleen, thymus, or lung monolayers, Raji lymphoblastoid suspension cultures, or Hela cells. Our electron microscopic studies indicate that adherent cells which replicate in some monolayer tissue cultures derived from Hodgkin's disease tumors are related to and possibly derived from neoplastic macrophages.

Aneuploidy↗
PubMed1979

Crohn's disease: a scanning electron microscopic study.

A scanning electron microscopic study of Crohn's disease was done using surgically resected specimens. Grossly normal resection margins as well as nonulcerated portions from diseased areas were selected for study. Scanning electron microscopic findings in Crohn's disease included changes in villous size and shape, villous fusion and epithelial bridge formation, goblet cell hypertrophy and hyperplasia, and increased secretion of mucus. These changes were marked in involved areas, and many were also present in six of seven margins of resection available for study in the ileal group. The abnormalities found in grossly normal margins of resection suggest a more widespread involvement than can be appreciated by gross and light microscopic examination of the specimen. Formation of the increased coat of mucus observed may be stimulated by a number of agents and could contribute to an enhanced barrier function in areas of early involvement in Crohn's disease, thereby decreasing the uptake of toxic or antigenic macromolecules. A decrease in bacterial superinfections would also be facilitated. Later lesions, with severe villous changes and hypersecretion of mucus, may favor the uptake of toxic and antigenic macromolecules as well as aid in the establishment of bacterial superinfections.

Adolescent↗
PubMed1979

Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression.

Line 1 and line 10 tumors became invested in a fibrin-gel cocoon within hours after transplantation to the subcutaneous spaces of unsensitized syngeneic inbred Sewall Wright strain 2 guinea pigs. The fibrin gel comprised more than 80% of the line 1 tumor mass and, after day 3, became organized and was subsequently replaced by fibrous connective tissue, which gave the tumor the appearance of a scirrhous carcinoma. A cellular infiltrate of lymphocytes and basophils developed at the periphery of line 1 tumors after day 8, and tumors regressed by day 13. The fibrin gel investing the highly malignant line 10 tumors accounted for less than 10% of the tumor mass and persisted without fibrous organization as a tumor grew progressively and invaded adjacent tissues. These data provide new and potentially important insights into the biology of solid tumor growth and the mechanisms of immunologic tumor rejection. Envelopment of tumors in a fibrin gel created an anatomic barrier separating the tumors from the host. Neovascularization mimicking that about line 1 and line 10 tumors was induced by sc fibrin implants; these data suggest that activation of the clotting and/or fibrinolytic systems by tumor cells may itself provide sufficient stimulus for induction of tumor angiogenesis without requiring a separate tumor angiogenesis factor. The scirrhous pattern of growth characteristic of line 1 tumors apparently was achieved by organization of an abundant fibrin gel. Line 1 tumor regression did not for the most part involve direct contacts between tumor cells and any type of inflammatory cell, including macrophages; rather, tumor destruction was effected by ischemic necrosis secondary to widespread microvascular injury. The mechanisms of such injury are uncertain, but tumor rejection was correlated with evidence of developing cellular immunity and anatomic associations between lymphocytes and myofibroblasts. Further experiments will be necessary before these findings can be generalized to other tumor systems.

Animals↗
PubMed1979

Reaction of immune complexes with Hodgkin's disease tissue cultures: radioimmune assay and immunoferritin electron microscopy.

We examined the binding of soluble immune complexes in sera from patients with Hodgkin's disease to established tissue cultures derived from the tumor. Circulating immune complex levels were determined by the Raji cell assay, and the reaction of serum with cultured cells was examined with a radioimmune assay and by immunoferritin electron microscopy. Serum with elevated immune complexes was found to react with cells of Hodgkin's disease monolayers when tested with radioiodine-labeled antisera against human IgG heavy and light chains and the complement 3 (C3) component. When examined with the electron microscope, monolayers incubated with Hodgkin's disease serum containing immune complex and labeled with ferritin-conjugated antiserum to C3 contained surface-bound ferritin particles with a uniform but discontinuous pattern. Absorption of Hodgkin's disease serum with monolayer cells reduced immune complexes and decreased reactivity of the sample with cultured cells by radioimmune assay. Sera of patients with other disorders and aggregated gamma-globulin with complement, despite markedly elevated immune complex levels, did not react positively with monolayers derived from Hodgkin's disease tumors, and none of the sera reacted with normal cultured spleen. The approximate size of serum components reacting with Hodgkin's disease monolayers was estimated by sucrose density gradient centrifugation. Sedimentation fractions in the 19S region reacted with monolayer cells when tested with 125I-labeled antisera to both IgG and C3 and contained immunoglobulin-complement complexes by gel diffusion and immunoabsorption. A component sedimenting at 7-9S contained immunoglobulin not complexed with complement; this component reacted with monolayer cells when tested with anti-IgG antiserum but did not react when tested with antibody to C3. The reaction of Hodgkin's disease monolayers with serum containing immune complexes differed from that of two suspension culture lines composed of cells with surface complement and IgG Fc receptors. Inasmuch as cells of our long-term Hodgkin's disease monolayers do not contain these surface receptors, possibly the antibody component of the immune complex reacts with antigens on the surface of cultured cells.

Antigen-Antibody Complex↗
PubMed1979

Tumor-basophil interactions in vitro--a scanning and transmission electron microscopic study.

Purified guinea pig basophils, or basophils either specifically degranulated with antigen or nonspecifically degranulated with lectin, were cultured with guinea pig line 1 hepatoma cells for 1 to 24 hr and studied ultrastructurally. As early as 1 hr of culture, degranulated or nongranulated basophils and tumor cells formed close contacts by mutually intertwined elongated cell processes and also in cultures containing degranulated basophils, extruded membrane-free basophil cytoplasmic granules became firmly attached to tumor cells. At later intervals, some tumor cells cultured with basophils exhibited cytostatic and cytopathic changes, including dense mitochondria, centralization of organelles, dilated perinuclear and rough endoplasmic cisternae, cell swelling and cytoplasmic lucency, disrupted cytoplasmic organelle and plasma membranes, nuclear pyknosis and fragmentation. Some tumor cell specialized surface attachments were either disrupted or damaged at points of basophil or basophil granule adhesion. Tumor damage was most extensive in cultures containing degranulated basophils, although only a minority of tumor cells (less than 10%) was affected. Tumor injury was seen much less frequently in the presence of nondegranulated basophils, and was absent in control cultures of tumor alone. The occasional viable tumor cells that phagocytosed basophil granules were apparently unharmed, suggesting that internalization of basophil granules by tumor cells is not cytotoxic.

Animals↗
PubMed1979

The basophil. Its morphology, biochemistry, motility, release reactions, recovery, and role in the inflammatory responses of IgE-mediated and cell-mediated origin.

The current state of our knowledge of basophils is reviewed. Much has recently been learned about these cells-their morphology, biochemical contents, interactions with homocytotropic antibodies, release of mediators in anaphylaxis, capacity for ingesting and releasing exogenous tracers, motility, participation in and progressive degranulation in cell-mediated hypersensitivity reactions, and their recovery from degranulation. It seems unlikely that basophils exist to destroy the organism by anaphylactic shock. Nonetheless, basophil function is probably closely related to the potent chemicals stored in their cytoplasmic granules. Perhaps small amounts of these chemicals are required for homeostasis and these cells function by releasing such substances as they are needed. This hypothesis requires that basophils be capable of releasing their contents slowly and piecemeal, which apparently occurs. This hypothesis also requires that physiological, rather than pharmacological, roles be found for histamine.

Animals↗
PubMed1978

Development of a histiocytic medullary reticulosis-like syndrome during the course of acute lymphocytic leukemia.

A 54 year old woman presented with acute lymphocytic leukemia. Following an initial response to chemotherapy with vincristine and prednisone, progressive pancytopenia developed coincident with intense bone marrow infiltration by abnormal histiocytes. At autopsy two months later, no evidence of leukemia was found, but the bone marrow was replaced by abnormal histiocytes showing active erythrophagocytosis, consistent with histiocytic medullary reticulosis. Detailed morphologic, ultrastructural and histochemical studies performed throughout the course of the patient's illness served to confirm the transition from leukemia to histiocytosis. Four similar cases of acute lymphocytic leukemia terminating in histiocytic medullary reticulosis have been reported. This association may represent a distinct clinicopathologic syndrome.

Bone Marrow↗
PubMed1978

Urticaria associated with acute viral hepatitis type B: studies of pathogenesis.

To determine whether skin deposition of circulating immune complexes contributes to prodromal urticaria of acute hepatitis B, we studied two patients with hepatitis B who presented with urticaria and fever. During the urticarial prodrome but not thereafter, we found activation of both classic and alternative complement pathways. Hepatitis B surface antigen (HBsAg)-antibody complexes were identified (by electron microscopy) in cryoprecipitates from both patients and IgG (by immunodiffusion) in cryoprecipitates of one patient during urticaria. Light and electron microscopy of involved urticarial skin revealed necrotizing venulitis in both patients. Immunofluorescence microscopy showed fibrin within involved cutaneous vessel walls in one patient and C3, IgM, and HBsAg, which were not detected in simultaneously obtained uninvolved skin, in both patients. Our findings suggest that deposition of circulating immune complexes containing HBsAg is important in the pathogenesis of urticaria associated with acute hepatitis B virus infection.

Adult↗
PubMed1978

Plasminogen activator of guinea pig basophilic leukocytes: probable localization to the plasma membrane.

The plasminogen activator (PA) activity of guinea pig basophil-enriched leukocyte preparations was localized to basophils, and not to contaminating lymphocytes and eosinophils, by correlating PA activity with basophil frequency and, more directly, by means of an improved cytochemical method here described. PA activity was fully expressed in living cells in the absence of immunologic stimuli and was suppressed/lost to a variable extent by different techniques of cell disruption. Conversely, killed, but not living, basophils expressed significant plasminogen-independent fibrinolytic activity, presumably reflecting access of cytoplasmic proteases of broken basophils to fibrin substrate. The PA activity of intact cells was destroyed by gentle trypsinization under conditions that did not impair cell viability. When disrupted cells were ultracentrifuged on a sucrose density gradient, PA activity was absent from purified granules and was confined to fractions containing cell membranes. The simplest explanation of these data is that guinea pig basophils have PA activity associated with their plasma membranes. This conclusion has several important implications for basophil functions in cell-mediated and other immunologic reactions in vivo.

Animals↗