Concurrent systemic lupus erythematosus and common variable hypogammaglobulinemia.
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Adult↗
Biomedical subjects
A Winkelstein
Publications and source records attributed to A Winkelstein.
Defective in vitro T cell colony formation in the acquired immunodeficiency syndrome.
Depressed T cell immunity is a universal characteristic of the acquired immunodeficiency syndrome (AIDS). In the present study, 25 patients with AIDS and opportunistic infections, 22 individuals with AIDS-related complex (ARC, or chronic lymphadenopathy syndrome), and 20 healthy homosexuals were evaluated by means of the T cell colony assay. Forty-seven healthy heterosexual controls showed an average of 3964 +/- 319 colonies/7.5 X 10(5) cells, with a range of 880 to 9340. The mean in the 20 healthy homosexuals (3173 +/- 483) did not differ significantly from the controls; in this group, only three patients had values less than 1000 colonies/plate. By contrast, all AIDS patients and 14 ARC patients had colony counts less than 1000. The mean value for the AIDS patients was only 24 +/- 15 (p less than 0.0005 compared with either controls or healthy homosexuals); values in the ARC group were intermediate (1180 +/- 360). The addition of interleukin 2 to the plates promoted correction of the proliferative abnormality in ARC patients. This interleukin increased colony scores in the AIDS group, but the mean value was still significantly less than controls. Comparison indicated that the colony assay is a more sensitive indicator for detecting proliferative abnormalities than responses to PHA, Con A, or pokeweed mitogen in suspension cultures.
Acquired Immunodeficiency Syndrome↗
Thrombotic thrombocytopenic purpura: clinical course and response to therapy in eight patients.
The clinical manifestations, pathologic findings, and responses to therapy were reviewed in eight patients with thrombotic thrombocytopenia purpura (TTP). Only one exhibited all five cardinal manifestations; five showed a triad of anemia, thrombocytopenia, and neurologic abnormalities. Microangiopathic red cell changes on peripheral blood smear and severe thrombocytopenia were present in all. The serum LDH levels were initially elevated in all eight; this enzyme determination was extremely useful for following the course of the disease and its response to therapy. Pathologic evidence of TTP was most consistently found in lymph nodes, spleen, and bone marrow biopsies. All patients were treated with a combination of therapeutic modalities including plasma exchange with replacement by fresh frozen plasma. Using this approach, 7/8 entered a complete remission; however, disappearance of all clinical manifestations was not seen in two patients prior to splenectomy.
Adult↗
Antibody responses to meningococcal polysaccharide vaccine in adults without a spleen.
Asplenic persons are at risk for the development of overwhelming sepsis from certain encapsulated bacteria, including meningococci. Since it is not known if asplenic persons can have antibody responses, this study compared such responses following bivalent groups A and C meningococcal polysaccharide vaccine in 22 asplenic subjects and healthy control subjects. There were no adverse reactions to the vaccine. Antibody responses were measured using a solid-phase radioimmune assay; results were compiled for both seroconversions and changes in mean antibody titers of IgG, IgA, and IgM classes. Subjects who underwent splenectomy for trauma and control subjects with spleens showed a polyclonal antibody response to both vaccine antigens. Those persons who underwent splenectomy for nonlymphoid tumors had nearly as good a response as normal subjects. By contrast, asplenic subjects with lymphoid tumors who had received prior chemotherapy and radiotherapy had poor responses to both antigens. It is concluded that meningococcal vaccine is immunogenic in asplenic persons, with the aforementioned exceptions, and that this vaccine should be routinely administered to such persons.
Adolescent↗
The effects of cyclosporin and hydrocortisone on human T-lymphocyte colony formation.
The immunosuppressive activities of two compounds, cyclosporin A and hydrocortisone, were evaluated using a human T lymphocyte colony assay. Both compounds produced a dose-related reduction in colony formation. With cyclosporin, concentrations of 1.0-100 micrograms/ml virtually abolished PHA-induced lymphocyte growth; as little as 0.01 microgram/ml decreased clonal growth by 48%. Suppression was observed as late as 4 days after the addition of PHA. The addition of exogenous IL-2 did not completely restore clonal growth to normal. Similarly, hydrocortisone, in concentrations of 0.4 microgram/ml, produced a 96% inhibition in clonal growth. Partial suppression could also be obtained if the drug was added as late as 4 days after PHA. Exogenous IL-2 completely reversed the inhibitory effects of hydrocortisone. By contrast, IL-1 was able to only partially restore growth potential. Parallel studies using TPA indicated that both immunosuppressants inhibited responses to this mitogen. However, in plates containing both TPA and PHA, hydrocortisone failed to impair clonal growth.
Cyclosporins↗
What are the immunological alterations induced by burn injury?
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Antibody Formation↗
Natural killer cells suppress human erythroid stem cell proliferation in vitro.
To determine the role of natural killer (NK) cells in the regulation of human erythropoiesis, we studied the effects of NK-enriched cell populations on the in vitro proliferation of erythroid stem cells at three different levels of maturation (day 14 blood BFU-E, day 5-6 marrow CFU-E, and day 10-12 marrow BFU-E). NK cells were enriched from blood by Percoll density gradient centrifugation and by fluorescence-activated cell sorting (FACS), using the human natural killer cell monoclonal antibody, HNK-1. The isolated enriched fractions were cocultured with autologous nonadherent marrow cells or blood null cells and erythropoietin in a methylcellulose erythroid culture system. Cells from low-density Percoll fractions (NK-enriched cells) were predominantly large granular lymphocytes with cytotoxic activity against K562 targets 6-10-fold greater than cells obtained from high-density Percoll fractions (NK-depleted cells). In coculture with marrow nonadherent cells (NA) at NK:NA ratios of 2:1, NK-enriched cells suppressed day 5-6 CFU-E to 62% (p less than 0.025) of controls, whereas NK-depleted cells slightly augmented CFU-E to 130% of controls (p greater than 0.05). In contrast, no suppression of day 10-12 marrow BFU-E was observed employing NK-enriched cells. The NK CFU-E suppressor effects were abolished by complement-mediated lysis of NK-enriched cells with the natural killer cell antibody, HNK-1. Highly purified HNK-1+ cells separated by FACS suppressed marrow CFU-E to 34% (p less than 0.025) and marrow BFU-E to 41% (p less than 0.025) of controls. HNK- cells had no significant effect on either BFU-E or CFU-E growth. NK-enriched cells were poor stimulators of day 14 blood BFU-E in comparison to equal numbers of NK-depleted cells or T cells isolated by E-rosetting (p less than 0.01). Interferon boosting of NK-enriched cells abolished their suboptimal burst-promoting effects and augmented their CFU-E suppressor effects. These studies provide evidence for a potential regulatory role of NK cells in erythropoiesis. The NK suppressor effect is maximal at the level of the mature erythroid stem cell CFU-E. These findings may explain some hypoproliferative anemias that develop in certain NK cell-activated states.
Adult↗
T lymphocyte colony assay in hemophiliacs.
Unexplained lymphadenopathy, with or without accompanying symptoms, known as the "lymphadenopathy syndrome," has been recognized in groups at risk for acquired immune deficiency syndrome (AIDS), namely, homosexuals and hemophiliacs. To date, however, no test has been defined that discriminates between asymptomatic individuals and those with adenopathy in these high-risk groups. The T colony assay, which measures T lymphocyte growth in soft agar and which allows selective T cell proliferation with minimal cell-cell contact, was evaluated in asymptomatic hemophiliacs. Significantly lower mean colony counts were found in eight hemophiliacs with adenopathy (HA), 763 +/- 348 (+/- SEM), than in 16 healthy hemophiliacs (HH) 3,044 +/- 661 (P less than .005), or than in 24 heterosexual control subjects, 3,964 +/- 395 (P less than .005). The in vitro addition of exogenous interleukin-2 (IL-2) restored normal colony growth in the HA population. These results indicate that the T colony assay can detect abnormal cell-mediated immunity among hemophiliacs and specifically discriminates between asymptomatic hemophiliacs (HH) and those with adenopathy (HA). In addition, IL-2 may be of potential benefit in improving T cell defects in AIDS or the "lymphadenopathy syndrome"; however, this remains to be proven.
Cell Division↗
Efficacy of combined therapy with plasmapheresis and immunosuppressants in rheumatoid vasculitis.
The combined effects of plasmapheresis and immunosuppressive therapy in the treatment of rheumatoid vasculitis was evaluated in 8 patients. These modalities, in combination, proved to promote rapid healing of cutaneous ulcers. In addition, it appeared that this aggressive therapy can occasionally reverse early gangrenous lesions involving extremities. By contrast, little change occurred in longstanding neuropathic manifestations. Our preliminary results suggest that plasmapheresis, used as an acute treatment modality, and combined with prolonged therapy with immunosuppressive drugs, may reduce the morbidity associated with certain manifestations of rheumatoid vasculitis.
Aged↗
Fasting-enhanced immune effector mechanisms in obese subjects.
Acute nutritional deprivation occurs frequently in clinical practice, yet little data exist on its effect on immune host defenses. To investigate this question, various immune parameters were studied in 15 obese subjects before and after a 14-day fast. Blood monocyte bactericidal activity and natural killer cell cytolytic activity were enhanced by fasting: monocyte killing increased in 12 of 14 subjects (p less than 0.05) and natural killer cell activity increased an average of 24 percent in 13 subjects tested (p less than 0.02). Starvation also enhanced parameters of humoral immunity as evidenced by increases in serum concentrations of IgG, IgA, and IgM (p less than 0.01). By contrast, lymphocyte blastogenic responses to the mitogen phytohemagglutinin were modestly decreased. Peripheral blood leukocyte counts, including neutrophils, T cells, and B cells, did not decrease significantly. These results indicate that fasting has differential influences on immune function rather than a uniformly deleterious effect. Of potential import, this nutritional alteration appears to actually enhance certain effector functions of the host defense system.
Adult↗
Naturally occurring cell-mediated cytotoxicity against simian virus 40-transformed 3T3 murine tumor cells.
The tumorigenicity and host protective mechanisms induced by simian virus 40 (SV40)-transformed 3T3 cells (SV403T3) were evaluated in syngeneic BALB/c mice. Tumors were regularly produced by sc inoculation of SV403T3 cells; the incidence, latent period, and survival were proportional to the size of the initial inoculum. With the use of an in vitro 18-hour 51Cr cytotoxicity assay, spleen cells from normal mice showed a dose-related killing activity against the SV403T3 cells. At an effector cell-to-target cell ratio of 200:1, the average lysis was 56 +/- 6%. This reaction appeared specific for the virally transformed targets; the mean lysis of parent 3T3 cells was 23 +/- 5%. Effectors were resistant to anti-theta serum and not removed by adherence to plastic or nylon wool. Tissue distribution studies indicated that these effectors were present in high concentrations in spleen, bone marrow, lymph nodes, and peritoneal cavity. Low levels of activity were associated with cells from the thymus. In the present studies specific T-cell cytotoxicity against the SV403T3 cells could not be demonstrated. Animals challenged with nonviable SV403T3 cells prior to tumor cell inoculation did not show increased in vivo resistance. In parallel, the in vitro cytotoxicity of animals inoculated with SV403T3 tumor cells showed no heightened cell killing compared to the cytotoxicity of normal controls.
Animals↗
Dependency of human T lymphocyte colony formation on soluble factors produced by accessory or tumor cells.
When plated in agar, PHA-stimulated Ficoll-Hypaque separated human mononuclear cells readily form discrete T lymphocyte colonies. Separation of these mononuclear cells on Sephadex G-10 columns yields enriched populations of T lymphocytes (greater than 95% E rosette-positive); these purified cells do not respond to this nonspecific mitogen by undergoing clonal expansion. Colony growth, however, can be restored by the addition of irradiated adherent cells. T cell responses can also be reconstituted by incubating the Sephadex-nonadherent fraction with irradiated cultured human tumor cells of monocytic (U937 and HL60) and B lymphocytic (Raji and Daudi cells) lines, but not from a T cell clone (MOLT-4) or erythroleukemic (K562) cells. Growth can also be induced in cultures containing T cells by adding cells from patients with either acute myeloblastic or B cell chronic lymphocytic leukemia or by the addition of B cell-enriched, monocyte-depleted normal mononuclear cells. Soluble factors prepared from Sephadex-adherent cells or active tumor cell lines are effective in promoting T cell colony formation. These results indicate that accessory cells are required for PHA responses of cloned human T cells. This function can be supplied by both monocytic and B lymphocytic tumor cell lines and is due to the release of soluble factors that act, in conjunction with the mitogen, to activate responsive lymphocytes.
B-Lymphocytes↗
Immune complexes in progressive systemic sclerosis (scleroderma).
Serum immune complexes were measured in 92 patients with progressive systemic sclerosis, and elevated levels were found as follows: Raji cell assay 72% (59% after pronase treatment of Raji cell), agarose gel electrophoresis 52%, and C1q binding 24%. Forty-three (47%) had abnormal results on two or more of these tests, but only 17 (18%) had normal results by all three assays. Computer-assisted analysis of immune complex results and extensive clinical and laboratory data compiled on these patients revealed that the patients with abnormal Raji cell assays more often had diffuse scleroderma, tendon friction rubs, and positive serum antinuclear antibody tests than did patients with negative results on Raji cell assays. Individuals with immune complexes detected by C1q binding had evidence of pulmonary involvement and positive serum rheumatoid factor more frequently than did patients whose C1q tests were negative.
Adolescent↗
Circulating immune complexes in eosinophilic fasciitis.
Serum immune complexes were measured in 22 patients with eosinophilic fasciitis, 8 of whom had serial determinations. Elevated levels were found by Raji cell radioimmunoassay in 14 (64%) patients, by agarose gel electrophoresis in 13 (59%), and by C1q agglutination-inhibition in 9 (41%). Elevated levels by Raji cell assay were present more frequently at times of active disease [17 of 22 sera (77%)] than at times of inactive disease [2 of 24 (8%) (P less than 0.0005)] and were more closely correlated with disease activity than were eosinophilia, hypergammaglobulinemia, or increased erythrocyte sedimentation rate.
Adult↗
Reduced T lymphoid colony growth in patients with progressive systemic sclerosis and rheumatoid arthritis.
T cell colony growth in semisolid medium, a sensitive indicator of disease-associated lymphoycte defects, was found to be depressed in patients with PSS and RA. In both disorders, more pronounced abnormalities were observed after incubation with suboptimal concentrations of the polyclonal mitogen PHA. Depletion of monocytes by adherence to plastic surfaces of addition of the prostaglandin synthetase inhibitor indomethacin did not correct the growth abnormality observed in PSS. Reduced colony-forming activity could not be attributed to serum inhibitory factors. The cellular abnormalities detected in patients with these connective tissue diseases were less pronounced than those found in SLE patients.
Adult↗
Murine B-lymphocyte colony formation: the effects of cyclophosphamide and azathioprine.
The present studies assessed the relationship between murine splenic B-lymphocyte colony-forming cells and the number of mature B lymphocytes in the spleen following administration of either cyclophosphamide or azathioprine. Cyclophosphamide (200 mg/kg) reduced the number of splenic B lymphocytes by a mean of 77%. However, a greater reduction in colony-forming cells was noted. Five days after cyclophosphamide administration, the number of colonies per spleen was reduced by more than 90%. Furthermore, the recovery of colony-forming activity was delayed in comparison with restoration of the B-cell system. The number of B lymphocytes returned to normal by day 10; colony formation was still reduced on day 28. Azathioprine, administered for 5 consecutive days, caused only a minimal reduction in B-cell clonal growth. These findings suggest that colony-forming cells may not be progenitor cells which are required for recovery from drug-induced lymphocyte destruction. Rather, this activity may be a property of mature B cells. The majority of potential colony-forming cells appear to be non-proliferating, as the phase-specific drug azathioprine caused only minimal reduction in colony-forming activity.
Animals↗
Potentiation of carmustine-cranial irradiation-induced myelosuppression by cimetidine.
In nine patients with glioblastomas, the histamine H2-receptor antagonist cimetidine was found to augment the myelosuppressive activities of carmustine and cranial irradiation. The nadir in neutrophil cell counts in this group averaged 650 +/- 220/microL. In a comparable series of 31 patients who did not receive cimetidine, the lowest neutrophil cell count averaged 2,160 +/0 240/microL. Further, marked suppression of these cells in the patients receiving cimetidine extended through day 42 of the treatment cycle. By contrast, the patients treated with carmustine and cranial irradiation alone did not experience significant neutropenia. This suggests that cimetidine may enhance the myelosuppressive effects of cytotoxic therapy.
Adult↗
Mechanisms in the in vivo release of lymphokines. V. Responses in alloxan-treated and genetically diabetic mice.
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Alloxan↗