Depletion Of Lymphoid Tissue Research Articles

Distribution of viral antigen and development of lesions after experimental infection with highly virulent bovine viral diarrhea virus type 2 in calves.

To correlate tissue distribution with development of lesions after experimental infection with a virulent strain of noncytopathic bovine viral diarrhea virus (BVDV) type 2 in calves. Ten 14-day-old and two 2-month-old colostrum-deprived calves. Calves were intranasally inoculated with BVDV type-2 strain 1373 from an outbreak of clinically severe bovine viral diarrhea (BVD). Two 14-day-old calves served as noninfected controls. Two calves each were euthanatized on postinoculation days 3, 6, and 12, and 1 each on days 8, 9, 13, and 14. Tissues were collected for immunohistologic and histologic examination. Inoculated calves developed nonspecific clinical signs characterized by high fever and decreased numbers of leukocytes and thrombocytes. Viral antigen was detected focally in lymphoid tissues on day 3. On days 6, 8, 9, 12, and 14, viral antigen became increasingly widespread throughout organs and tissues. Viral antigen in lymphoid tissues was associated with severe depletion of all compartments. Lesions in other tissues were not well correlated with distribution of viral antigen. Depletion of lymphoid tissues was observed in a calf on day 13, but viral antigen had been cleared from most tissues and was detected in vascular walls only. Infection with a virulent BVDV strain resulted in wide dissemination of viral antigen in host tissues. Severe lymphoid depletion developed in lymphoid tissues, whereas viral antigen was generally not associated with lesions in other tissues. Findings suggest that development of lesions in acute BVD is not solely a function of viral replication and is also attributable to host reaction to infection.

Endotoxin Potentiation of Trichothecene-Induced Lymphocyte Apoptosis Is Mediated by Up-Regulation of Glucocorticoids

Exposure to bacterial endotoxin (lipopolysaccharide, LPS) is quite common and may increase human susceptibility to chemical-induced tissue injury. The purpose of this study was to identify mechanisms by which LPS potentiates lymphoid tissue depletion in B6C3F1 mice exposed to the common food-borne trichothecene mycotoxin, vomitoxin (VT). As demonstrated by DNA fragmentation and flow cytometric analysis, apoptosis in thymus, Peyer's patches, and bone marrow was marked in mice 12 h after administering Escherichia coli LPS (0.1 mg/kg body wt ip) concurrently with VT (12.5 mg/kg body wt po), whereas apoptosis in control mice or mice treated with either toxin alone was minimal. Based on observed increases in tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 serum concentrations following LPS and VT cotreatment, the roles of these cytokines in apoptosis potentiation were assessed. Injection with rolipram, an inhibitor of TNF-α expression, or use of IL-6 knockout mice was ineffective at impairing thymic apoptosis induction by the toxin cotreatment, suggesting that these cytokines did not mediate LPS potentiation. Toxin cotreatment increased splenic cyclooxygenase-2 mRNA expression, suggesting possible involvement of prostaglandins in apoptosis. However, indomethacin, a broad spectrum inhibitor of cyclooxygenases, failed to block thymus apoptosis. Toxin cotreatment increased serum corticosterone and, furthermore, RU 486, a glucocorticoid receptor antagonist, significantly abrogated apoptosis in thymus, Peyer's patches, and bone marrow following LPS + VT exposure. The results presented herein and the known capacity of glucocorticoids to cause apoptosis indicate that hypothalamic–pituitary–adrenal axis plays a key role in LPS potentiation of trichothecene-induced lymphocyte apoptosis.

Clinicomorphological studies in chicks fed ochratoxin A while simultaneously developing coccidiosis.

The progression of coccidiosis and the resultant mortality were followed in chicks fed a OTA-contaminated diet. More complex and rapid progress of coccidiosis occurred in OTA-treated chicks than in chicks fed a OTA-free diet. The concentration of total protein in the serum was significantly decreased in the chicks in the OTA-treated group, whereas this was significantly increased in chicks infected with Eimeria tenella, irrespective of additional treatment with OTA. The serum glucose concentration was significantly increased in all the chicks exposed to OTA and/or suffering from coccidiosis, as was serum retention of uric acid in all groups, most notably in those consuming OTA. OTA induced degenerative changes in, and an increase in the weight of the kidneys, liver, heart and ventriculum; there was depletion of lymphoid tissue and a decrease in the lymphoid organs' weight and body weight. Coccidiosis induced only a slight growth depression and a slight increase in the relative weight of the kidneys and liver. The intensity of the clinical signs, the impairment of kidney function, macroscopic and histopathological changes, deviations in the weight of some organs and general depression in growth were greater when chicks infected with E. tenella were also given OTA.

Death of Bystander Cells by a Novel Pathway Involving Early Mitochondrial Damage in Human Immunodeficiency Virus–Related Lymphadenopathy

Destruction of immune cells in peripheral lymphoid tissues plays presumably a pivotal role in acquired immune deficiency syndrome pathogenesis. We found that cell suspensions obtained from lymph nodes of eight human immunodeficiency virus (HIV)-infected individuals contained variable proportions (2.1% to 18.3%, median 11.2%) of dead lymphocytes permeable to supravital dyes, represented by CD4+, CD8+, and B cells. The frequency of dead cells correlated directly (R = 0.847) with the amount of HIV provirus in the cell populations, and HIV provirus was enriched in the dead cell fractions. Similar proportions of dead cells were observed in cell suspensions from lymphadenopathic lymph nodes of HIV− donors, but not from small resting HIV− lymph nodes. Electron microscopic and flow cytometric analyses revealed that most dead cells from HIV+ lymph nodes lacked internucleosomal DNA fragmentation but displayed combined features of apoptosis and necrosis, eg, chromatin condensation and mitochondrial swelling. Cells with similar morphology were readily identified in lymph node tissue sections, and marked mitochondrial swelling could be occasionally observed in cells with otherwise normal morphology. Our findings have two major implications. One is that the in vivo cell death in HIV-infected lymph nodes occurs predominantly through a novel pathway, related to but distinct from classical apoptosis and characterised by early and severe mitochondrial damage. The second implication is that HIV-related lymphadenopathy is accompanied in vivo by massive destruction of uninfected lymph node cells. Comparable levels of cell death were observed in other inflammatory lymphadenopathies not related to HIV; however, the uniquely endless and generalized nature of HIV lymphadenopathy might render this “inflammatory” cell destruction a powerful pathogenetic mechanism, accounting for the progressive disruption and depletion of lymphoid tissues seen in HIV infection.

Death of Bystander Cells by a Novel Pathway Involving Early Mitochondrial Damage in Human Immunodeficiency Virus–Related Lymphadenopathy

AbstractDestruction of immune cells in peripheral lymphoid tissues plays presumably a pivotal role in acquired immune deficiency syndrome pathogenesis. We found that cell suspensions obtained from lymph nodes of eight human immunodeficiency virus (HIV)-infected individuals contained variable proportions (2.1% to 18.3%, median 11.2%) of dead lymphocytes permeable to supravital dyes, represented by CD4+, CD8+, and B cells. The frequency of dead cells correlated directly (R = 0.847) with the amount of HIV provirus in the cell populations, and HIV provirus was enriched in the dead cell fractions. Similar proportions of dead cells were observed in cell suspensions from lymphadenopathic lymph nodes of HIV− donors, but not from small resting HIV− lymph nodes. Electron microscopic and flow cytometric analyses revealed that most dead cells from HIV+ lymph nodes lacked internucleosomal DNA fragmentation but displayed combined features of apoptosis and necrosis, eg, chromatin condensation and mitochondrial swelling. Cells with similar morphology were readily identified in lymph node tissue sections, and marked mitochondrial swelling could be occasionally observed in cells with otherwise normal morphology. Our findings have two major implications. One is that the in vivo cell death in HIV-infected lymph nodes occurs predominantly through a novel pathway, related to but distinct from classical apoptosis and characterised by early and severe mitochondrial damage. The second implication is that HIV-related lymphadenopathy is accompanied in vivo by massive destruction of uninfected lymph node cells. Comparable levels of cell death were observed in other inflammatory lymphadenopathies not related to HIV; however, the uniquely endless and generalized nature of HIV lymphadenopathy might render this “inflammatory” cell destruction a powerful pathogenetic mechanism, accounting for the progressive disruption and depletion of lymphoid tissues seen in HIV infection.

Encephalitis, lymphoid tissue depletion and secondary diseases associated with bovine immunodeficiency virus in a dairy herd

Encephalitis, lymphoid tissue depletion and secondary infections occurred over a 5-yr-period in Holstein cows infected with bovine immunodeficiency virus (BIV). There were 59 cattle studied, the majority during 1991, when a severe environmental stress occurred, each with one or more primary causes of death, natural or by euthanasia, and most with several secondary diseases. The encephalitis was characterized by meningeal, perivascular and parenchymal infiltration with lymphocytes, occasional plasma cells and macrophages with perivascular edema in some cows. Affected areas included the cerebrum, cerebellum, and spinal cord with no particular distribution pattern recognized. The lymphoid depletion was primarily an absence of follicular development in nodes draining regions with secondary infections such as chronic mastitis and chronic suppurative pododermatitis. Paucity of lymphocytes in thymic-dependent regions of lymph nodes and the spleen suggested a primary depletion of T cells. Secondary infections were often multiple with each cow having several minor conditions, usually considered short-term and treatable. These included mastitis and pododermatitis, with many cows having non-responding abscesses, cellulitis and myositis attributed to injection site infections. A large number of the cattle had parturition difficulties such as dystocia, obturator paralysis, and metritis. Pulmonary, cardiovascular, and intestinal disease were recognized as both primary and secondary disease conditions. There was a high level of infection with bovine leukemia virus with 4 of the 59 cattle having lymphosarcoma. Under practical conditions, the infection with BIV has a different effect on the host than has been observed under experimental conditions. The presence of BIV combined with the stresses associated with parturition and a modern dairy production system were considered causal for the development of untreatable secondary diseases in immunocompromised cattle. The peak incidence in 1991 was attributed to increased environmental stress during renovation of the barn facility. During this time the cattle were kept on open pasture, exposed to an extremely wet winter, and spring weather conditions. The effect of co-infection with bovine leukemia virus, the influence of immunocompromise on the chronicity of mastitis, the relationship with laminitis and pododermatitis, and several questions related to viral transmission, complementarism with bovine leukemia virus, viral reactivation and immunoprophylaxis all remain as viable avenues for future investigations.

Lesions and localization of viral antigen in tissues of cattle with experimentally induced or naturally acquired muscosal disease, or with naturally acquired chronic bovine viral diarrhea

SUMMARY Tissues from cattle that died of experimentally induced mucosal disease (n = 3), naturally acquired mucosal disease (n = 6), or naturally acquired chronic bovine viral diarrhea (n = 4) were examined. Consistent findings were lymphocytic depletion of lymphoid tissues, degeneration of myenteric ganglion cells, and mild adrenalitis. Intracytoplasmic viral antigen was detected in myenteric ganglia and in endocrine glandular cells. Noncytopathic virus was isolated from all cattle, and cytopathic virus was isolated from 12 of 13 cattle.

Immunotoxic effects of T-2 mycotoxin on cell-mediated resistance to [formula omitted] infection

The effect of T-2 toxin on cell-mediated resistance to bacterial infection was evaluated in mice exposed to Listeria monocytogenes . Mice were inoculated with 4.0 × 10 5 (LD 50) or 4.0 × 10 4 (nonlethal) L. monocytogenes on day 0 and treated orally on days 0, 1, 2, and 3 with 2.0, 1.0, or 0 mg/kg T-2 toxin. Toxin induced suppression of resistance was indicated by the rapid growth of Listeria in the spleen and by significant (P < 0.005) increases in mortality due to listeriosis. Necrosis and depletion of lymphoid tissue, lymphopenia, and a marked decrease in the influx of lymphocytes and macrophages into Listeria elicited peritoneal exudates and at sites of infection in the liver and spleen occured in the toxin treated mice. The immunotoxic effect of T-2 toxin on cell-mediated resistance to listeriosis was dosage dependent and attributed to toxin induced lymphoid depletion and the failure of surviving lymphocytes and mononuclear cells to clear the host of infection.

Lymphocytic depletion of bursa of Fabricius and thymus in chickens inoculated with Escherichia coli.

Specific-pathogen-free 10-week-old chickens were inoculated via the air sac with Escherichia coli and showed lymphocytic depletion of bursa of Fabricius and thymus. In experiment I, chickens were necropsied at 12 and 24 hours, 2, 3, and 5 days after inoculation. At 12 hours after inoculation there was lymphocytic depletion in the medulla of lymphoid follicles of the bursa. At 24 hours after inoculation there was lymphocytic depletion also in the cortex of follicles and edema in interfollicular interstitium and follicular medulla. At 2 and 3 days after inoculation there were more marked lymphocytic depletion in medulla and cortex, and fibrosis in interfollicular interstitium. Partial repopulation of follicles with lymphocytes was seen at 5 days after inoculation. In the thymus, lymphocytic depletion occurred in the cortex. At 12 hours after inoculation, lymphocytic necrosis increased in number more than that of control chickens. The width of the cortex and medulla decreased. At 24 hours after inoculation, lymphocytic necrosis increased further. At 2 to 5 days after inoculation, the boundary between the cortex and medulla of lobules was obscure and cellular elements of the cortex and medulla were mingled. In experiment II, chickens were necropsied as in experiment I and also at 8 and 14 days after inoculation. The relative weights of the bursa and thymus reduced rapidly to minimal relative weights at 8 days after inoculation. At 14 days after inoculation, both bursa and thymus had normal relative weights and histological structures. These findings indicate that E. coli infection may induce transient lymphocytic depletion of lymphoid tissues in the chicken.

Autopsy Findings in the Acquired Immune Deficiency Syndrome

The medical records, premortem biopsy specimens, and autopsy materials from 36 patients with acquired immune deficiency syndrome (AIDS) were reviewed. The majority of the patients were homosexual men. Widely metastatic Kaposi's sarcoma was seen in eight patients, while tumor was confined to the skin in an additional ten. Four patients had high-grade lymphomas. Thirty-five of the 36 patients had at least one opportunistic infection at some point in the course of their illness. Many patients had multiple infectious agents. The most consistent and striking autopsy finding was a severe depletion of lymphoid tissues. Death in the majority (83%) of the patients was attributable to opportunistic infections affecting most commonly the respiratory tract (64%) and meninges (11%). Three patients (9%) died with widely metastatic Kaposi's sarcoma and secondary hemorrhage.

Autopsy findings in the acquired immune deficiency syndrome

The medical records, premortem biopsy specimens, and autopsy materials from 36 patients with acquired immune deficiency syndrome (AIDS) were reviewed. The majority of the patients were homosexual men. Widely metastatic Kaposi's sarcoma was seen in eight patients, while tumor was confined to the skin in an additional ten. Four patients had high-grade lymphomas. Thirty-five of the 36 patients had at least one opportunistic infection at some point in the course of their illness. Many patients had multiple infectious agents. The most consistent and striking autopsy finding was a severe depletion of lymphoid tissues. Death in the majority (83%) of the patients was attributable to opportunistic infections affecting most commonly the respiratory tract (64%) and meninges (11%). Three patients (9%) died with widely metastatic Kaposi's sarcoma and secondary hemorrhage. (<i>JAMA</i>1984;252:1152-1159)

ANTILYMPHOCYTIC ANTIBODIES AND MARROW TRANSPLANTATION

The in vivo and in vitro effectiveness of several monoclonal antimouse T and B cell antibodies, of anti-Th-1 and of Iak serum, as well as of ATG were compared. The parameters were prolongation of skin graft survival, prevention of graft-versus-host disease (GVHD), antibody and primary and secondary plaque formation against sheep redblood cells (RBCs), and T cell depletion of lymphoid tissues. In general, in vitro effectiveness of the monoclonal antibodies exceeded their in vivo effectiveness. Skin graft survival was prolonged by ATG, but not by monoclonal anti-T, or anti-T plus anti-B antibody. GVHD was prevented by in vitro incubation of donor bone marrow with monoclonal anti-Th-1, but in vivo treatment of marrow donors was ineffective. Treatment with ATG was successful. Anti Iak antibody blocked plaque formation by spleen cells incubated with sheep RBCs, but had no effect on secondary plaque formation when given in vivo. Neither was there any in vivo effect of anti-Iak or anti-Th-1 on antisheep RBC agglutinin formation. ATG was effective in both of these assays, although its cytotoxic and complement-fixing titer did not exceed that of anti-Th-1 or anti-Iak. Although anti-Th-1 was cleared more rapidly from the serum of mice expressing the corresponding Th-1 alloantigen, than from mice with the noncorresponding alloantigen and although anti-Th-1 was shown to bind to the T cell areas of the lymphoid tissue, it did not--unlike ATG--deplete these areas of T cells. Possible reasons for the difference in effectiveness of in vitro and in vivo application of these monoclonal antibodies are discussed.

IMMUNE RESPONSES TO ORGAN ALLOGRAFTS

Untreated LEW rats reject primarily vascularized Ag-B-incompatible LBNF1, BN, and WF cardiac allografts in 6 to 8 days. Cyclosporin A (CyA) administered 15 mg/kg/day i.m. for 7 days after grafting extends graft function greater than 100 days. Histological studies demonstrated that CyA treatment strikingly reduces the size and cellularity of the thymic medulla, splenic marginal zone, and splenic periarterial sheath by 97, 67 and 50%, respectively. These compartments are thought to contain cells of a single T lymphocyte lineage with helper and cytotoxic functions. CyA was less effective against cells in the thymic cortex and splenic red pulp, compartments thought to contain suppressor cells. CyA-induced depletion of lymphoid tissues was maximal 7 to 14 days after completion of treatment. All compartments recovered nearly normal morphology by 50 to 100 days, although hyperplastic nodules were found in spleens of three WF heart graft recipients during the recovery phase. CyA was more effective, histologically, in inhibiting the immune response to heart grafts from WF than from LBNF1 or BN donors. Within 3 days after LBNF1 or BN heart grafting, moderate antibody production occurred in the spleen (as noted by increase in Ig-positive immunoblasts) and vascular damage occurred in the grafts. These signs of rejection were delayed until 14 days in WF heart grafted rats. In none of the strain combinations were these early reactions followed by a vigorous cellular infiltrate. Thus, CyA seems to decrease preferentially cytotoxic and helper T lymphocyte responses to cardiac allografts.

Toxicity of Penicillium citrinum AUA-532 Contaminated Corn and Citrinin in Broiler Chicks

The toxicity and histopathological changes in broiler chicks fed 0, 33, 65, 130, and 260 ppm citrinin were investigated. Dietary citrinin caused subacute toxicity with increased water consumption and diarrhea at the 130 and 260 ppm levels, but no mortality was observed during the 6-week period. At necropsy, chicks fed 130 and 260 ppm citrinin had hemorrhagic jejunums, mottled livers, and enlarged kidneys. Chicks fed lower levels of citrinin appeared normal macroscopically; however, all levels of dietary citrinin caused cellular infiltrations in the liver, kidney, and pancreas suggestive of an allergen. Anaplastic areas in the kidney and pancreas and increased mitosis of tubular epithelial cells in the kidney of chicks fed 260 ppm citrinin indicated citrinin could be a carcinogen in the chick. Feeding a 62% level of Pencillium citrinum-contaminated corn caused markedly different symptoms from those of the citrinin toxicosis. Acute toxicity was observed with 58% chick mortality in 2 weeks. Severe growth depression, organ atrophy, and enlarged gallbladders were observed macroscopically. Depletion of lymphoid tissue, cardiac and skeletal myopathy, necrosis of centrilobular hepatocytes and glomerular atrophy and hyperplasia were observed microscopically. The toxic factors in the P. citrinum-contaminated ration are unidentified.

Immunological reconstitution of neonatally thymectomized rats following implantation of thymic epithelial cells.

Experimental neonatal thymectomy in rodents has profoundly deleterious effects on the immune system. These include histological depletion of lymphoid tissues, decrease in circulating lymphocyte numbers, and defective immune functions (16). Of the immunological defects appearing after thymectomy, cell-mediated immune responses including transplantation immunity and delayed hypersensitivity reactions are affected to the greatest degree, although some humoral immune responses (i.e. sheep red blood cells) are also impaired. These effects are attributed to a depletion of thymus-derived (T) lymphocytes. The thymus has thus been shown to play an essential role in the development and maintenance of an intact immune system.

Induction of tolerance to skin homografts with a methylhydrazine derivative. Synergism with antilymphocytic serum and morphologic responses of the lymphoid system.

CBA mice were treated before skin grafting with a course of either the methylhydrazine derivative Ro 4-6824 or cyclophosphamide, combined with donor type lymphoid cells. No further immunosuppressive treatment was applied after the grafting. Marked prolongation of graft survival and specific tolerance to (CBAxA)F1 and A skin homografts could be induced with Ro 4-6824, but not with cyclophosphamide. Tumors occurred in two tolerant mice after 10 months. Besides by administration of donor lymphoid cells, the effect of Ro 4-6824 pretreatment is also potentiated by heterologous antilymphocytic serum (ALS) and by thymectomy. The mice treated with Ro 4-6824 showed more profoud depletion of lymphoid tissue in the lymph nodes than after ALS. In addition, marked atrophy of the thymus occurred. In the spleen, Ro 4-6824 prevented the plasma cell response to ALS.

Pathological aspects of a case of cardiac allograft transplantation and a discussion of cardiac rejection

A cardiac transplant was carried out on a patient suffering from intractable heart failure due to extensive old antero-septal infarction, the result of severe atherosclerotic coronary artery disease. Death occurred 45 days later following haemorrhage from a perforation in the recipient aorta above the line of anastomosis. To the naked eye the anastomosis appeared healthy but microscopically each aorta was necrotic and contained colonies of cocco-bacilli. These organisms were present in the pericardial cavity and cultures yielded <i>Serratia marcescens</i>. Macroscopic appearances of rejection were not present in the transplanted heart. Microscopically, the myocardium contained foci of myocytolysis and collapse fibrosis; thrombi were present in small blood vessels. Areas of infarction were present in the atria. The left lung contained an abscess from which <i>Pseudomonas pyocyanea and Aspergillus flavus</i> were cultured. There was severe ulceration of the tongue and, to a lesser degree, of the oesophagus around which squamous epithelial cells contained large intranuclear inclusions characteristic of herpes. Spleen and lymph nodes showed striking depletion of lymphoid tissue. It was concluded that there was evidence of minor cardiac rejection in this patient. Evidence of immune suppression was striking and this was accompanied by proliferation of various opportunistic microorganisms which was largely responsible for death.

The canine lymphoid system: a study of the effect of surgical excision.

AbstractA detailed study of the lymph node anatomy of the dog is presented, and a technique for surgical excision of the thymus, spleen, and all gross lymph nodes is described. The dissections were performed after intravenous administration of pontamine blue to living animals.Major excision of the lymphoid tissue of the dog led to a modest prolongation of skin allograft survival, but it did not lead to a further increase in the allograft prolongation achieved with 6‐mercaptopurine immunosuppression when these two measures were used simultaneously. Neither did lymphadenectomy alter the leucopenia or toxicity of 6‐mercaptopurine when node excision was performed immediately prior to initiation of drug therapy. The transient nature of both the lymphopenia produced and the alteration of allograft response after lymphadenectomy suggest that there is another major contributor to the circulating lymphocyte pool. It is suggested that this may well be the lymphoid tissue in the intestinal wall.The surgical preparation described is proposed as a model for the study of lymphoid tissue depletion and regeneration in the dog.

DISSOCIATION OF DELAYED-HYPERSENSITIVITY AND ANTIBODY-SYNTHESISING CAPACITIES IN MAN: Report of Two Sibships with Thymic Dysplasia, Lymphoid Tissue Depletion, and Normal Immunoglobulins

DISSOCIATION OF DELAYED-HYPERSENSITIVITY AND ANTIBODY-SYNTHESISING CAPACITIES IN MAN: Report of Two Sibships with Thymic Dysplasia, Lymphoid Tissue Depletion, and Normal Immunoglobulins

Aplastic anemia and alymphocytosis in an infant with hypogammaglobulinemia: Graft-versus-host reaction?

The case of an infant with a defect in production of immune globulin, lymphopenia, and pancytopenia, with pathologic changes including severe bone marrow aplasia, lymphoid tissue depletion, and generalized histiocytosis is described. The similarity between these manifestations and the clinical and pathologic findings in animals with graft-versus-host reaction or runting syndrome is striking.