Showing papers in "Journal of Clinical Immunology in 1986"
TL;DR: The present studies define the cellular requirements for the release of soluble IL-2Rin vitro and demonstrate that such receptors are released by B cells, T cells, and both OKT4+ andOKT4− T-cell subsets.
Abstract: Following activationin vitro, peripheral blood mononuclear cells (PBMC) express cell-associated interleukin-2 receptors (IL-2R) and also release soluble IL-2R into culture supernatants. The present studies were undertaken to define which normal cells were responsible for the release of soluble IL-2Rin vitro. Both cell-associated and soluble IL-2R were quantitatively measured with a “sandwich” enzyme-linked immunoassay employing two monoclonal antibodies. PBMC were separated into populations of surface immunoglobulin-negative cells (T cells and monocytes) and surface immunoglobulin-positive cells (B cells and monocytes), and the T-cell population was further separated into OKT4-positive (OKT4+) cells and OKT4-negative (OKT4−) cells. Following activation with phytohemagglutinin, pokeweed mitogen, and the monoclonal antibody OKT3, large amounts of soluble IL-2R were released by PBMC, unseparated T cells, OKT4+ T cells, and OKT4− T cells. The population containing B cells and monocytes made small but readily detectable amounts of soluble IL-2R when stimulated with these T-cell mitogens; likely the result of contaminating T cells in the population. However, when highly purified B cells were stimulated withStaphylococcus aureus Cowan and recombinant IL-2, they also released small amounts of soluble IL-2R. The release of soluble IL-2R by T cells appeared monocyte dependent when OKT3, but not phytohemagglutinin, was employed for activation, and monocytes themselves released no detectable IL-2R under the conditions employed. These studies define the cellular requirements for the release of soluble IL-2Rin vitro and demonstrate that such receptors are released by B cells, T cells, and both OKT4+ and OKT4− T-cell subsets.
157 citations
TL;DR: Two groups of six adults with persistent asthma, who were identical clinically, received 0.1 or 4 g of purified eicosapentaenoic acid ethyl ester daily for 8 weeks, and both doses of EPA increased the responses of T lymphocytes to phytohemagglutinin by a mean of 73% or more without modifying the numbers of helper and suppressor T lymphocyte.
Abstract: Two groups of six adults with persistent asthma, who were identical clinically, received 0.1 or 4 g of purified eicosapentaenoic acid ethyl ester (EPA) daily for 8 weeks. Both doses increased significantly the generation of leukotriene B5 (LTB5) from EPA by polymorphonuclear (PMN) and mononuclear leukocytes, while only the high dose decreased leukocyte arachidonic acid (AA) and the generation of LTB4 and prostaglandin E2 from AA. Only the high dose led to inhibition of PMN leukocyte chemotaxis to multiple stimuli by a mean of 57–70% (P<0.01), without altering monocyte chemotaxis, the production of plateletactivating factor by mononuclear leukocytes, or the IgE-dependent release of histamine from basophils. Both doses of EPA increased the responses of T lymphocytes to phytohemagglutinin by a mean of 73% or more (P<0.01) without modifying the numbers of helper and suppressor T lymphocytes. EPA affects the functions of several types of leukocytes critical to inflammation and immunity.
153 citations
TL;DR: The idiopathic inflammatory bowel diseases comprise a spectrum of disorders that are marked by the presence of chronic inflammation of the gastrointestinal tract which cannot be ascribed to a specific pathogen.
Abstract: The idiopathic inflammatory bowel diseases (IBD) comprise a spectrum of disorders that are marked by the presence of chronic inflammation of the gastrointestinal tract which cannot be ascribed to a specific pathogen (1, 2). At one end of the spectrum is ulcerative colitis, a disease that affects the large bowel exclusively and which is characterized by mucosal ulceration, superficial inflammatory-cell infiltration of the bowel wall, and, in extensive long-standing cases, neoplastic transformation. Prominent symptoms in this form of IBD include severe bloody diarrhea, pain on defecation, weight loss, and, in children, growth failure. At the other end of the spectrum is Crohn's disease (regional enteritis or regional ileitis), a disease that in contrast to ulcerative colitis can affect any part of the alimentary canal, from the mouth to the rectum, but which most commonly involves the terminal ileum and the ascending colon. In this condition, the major pathology consists of a focal, transmural inflammatory,cell infiltration that is sometimes granulomatous in character and which may be complicated by intestinal strictures, fistula formation, and perforation, Symptoms that commonly occur in Crohn's disease include abdominal pain of a cramping nature and systemic complaints such as fever
135 citations
TL;DR: Levels of IgA1, IgA2, IgM, and IgG antibodies specific for 10 ubiquitous food and bacterial antigens were examined by radioimmunoassay in the sera of 29 patients with IgA-associated renal diseases and 22 normal individuals and there was no preponderance of one form in either patient or normal groups.
Abstract: Levels of IgA1, IgA2, IgM, and IgG antibodies specific for 10 ubiquitous food and bacterial antigens were examined by radioimmunoassay in the sera of 29 patients with IgA-associated renal diseases and 22 normal individuals. No significant differences were observed between patient and normal groups in the levels of IgA1 antibodies, and IgA2 antibodies were detected in only a few individuals in either group. Minor differences in IgM or IgG antibodies were seen against some antigens. Significant positive correlations between IgA1 and IgG and between IgA1 and IgM antibodies to casein were found in the patient group. Analysis of the molecular form of serum IgA1 antibodies revealed that although the pattern of polymeric and monomeric forms varied between individuals and between antibody specificities, there was no preponderance of one form in either patient or normal groups. Examination of kidney biopsies from 50 patients with IgA-associated renal diseases revealed that IgA1 represented the predominant subclass deposited in the glomerular mesangium; glomeruli from three patients contained both IgA1 and IgA2. Seventy-eight percent of the patients also had deposits of IgM, although IgA and IgM deposits did not always coincide. When IgG was present in glomeruli (45% of patients), the IgG1 subclass predominated. J chain was detectable in glomeruli of only four patients. C3 was detected in glomeruli of 95% of the patients, although the distribution of C3 did not always coincide with that of IgA. Indirect immunofluorescence staining with rabbit antisera to various environmental antigens showed that milk protein antigens could be deposited in association with IgA in the glomerular mesangium.
128 citations
TL;DR: NK-cell function was studied following the infusion of cortisol, epinephrine, and glucagon into volunteer subjects in amounts known to reproduce serum levels seen following injury of moderate severity, suggesting that the inhibition of NK- cell function seen in patients may be mediated by the stress response to injury.
Abstract: Depressed cell-mediated and humoral immune functions have been reported to occur following severe thermal and traumatic injury. In this study we have questioned whether another immune function, natural killing (NK), is also disturbed in these injured patients. Twenty-two thermally injured patients with burns ranging from 5 to 75% of the total body surface area and 15 traumatically injured patients with injury severity scores ranging from 9 to 56 were followed postinjury and compared to 29 age-matched controls. NK activity was measured as the percentage cytotoxicity in chromium-51 release assays with K562 target cells. The more severely burned patients had significantly depressed NK activity for the 40-day period following injury that remained reduced for the duration of the study. Patients with lesser burns had reduced NK-cell function for the initial 10-day period postburn that returned slowly to the normal range. Traumatically injured patients had depressed NK-cell function during the 3- to 6-day period postinjury. The percentage of cells bearing phenotypic markers for the groups in which NK cells are found was either normal or elevated in these patients. A correlation was found between NK activity and interleukin 2 generation by mononuclear cells from these patients. In order to investigate the mechanism of NK suppression in these patients, NK-cell function was studied following the infusion of cortisol, epinephrine, and glucagon into volunteer subjects in amounts known to reproduce serum levels seen following injury of moderate severity. NK-cell function was reduced an average of 66% following infusion, suggesting that the inhibition of NK-cell function seen in patients may be mediated by the stress response to injury.
86 citations
TL;DR: The sera of 265 patients with monoclonal gammopathies were examined for the presence of a dominant idiotype of the anti-DNA antibody [16/6 idiotype (Id) and for anti- DNA activity, and the specificity of the idiotype analysis was demonstrated with an unrelated dominant idiotypes of anti-HBsAg antibody.
Abstract: The sera of 265 patients with monoclonal gammopathies were examined for the presence of a dominant idiotype of the anti-DNA antibody [16/6 idiotype (Id)] and for anti-DNA activity An enzyme-linked immunosorbent assay (ELISA) with a rabbit anti-16/6 antibody revealed 23 (87%) sera that contained increased concentrations of the idiotype Seven of the patients had benign monoclonal gammopathy, three multiple myeloma, three Waldenstrom macroglobulinemia, five essential mixed cryoglobulinemia, and five monoclonal cryoglobulinema In 5 of the 23 sera, antinuclear activity was also noted In 11 of the 16/6 Id-positive sera the anti-nucleic acid antibody reactions were found to be polyspecific, reacting with polydeoxythymidilic acid and polyinosinic acid, in addition to single-stranded DNA and double-stranded DNA Similar results were achieved with the purified serum monoclonal components The specificity of the idiotype analysis was demonstrated with an unrelated dominant idiotype of anti-HBsAg antibody In none of the patients, except one (with essential mixed cryoglobulinemia), was lupus symptomatology noted
66 citations
TL;DR: Although some patients showed a moderate degree of lymphopenia, their OKT4/T8 lymphocyte ratios were mostly normal or close to normal, with the notable exception of one TB patient who has been diagnosed to have the acquired immune deficiency syndrome (AIDS).
Abstract: Production of interferon (IFN)-gamma by peripheral blood leukocytes (PBL) was examined in cultures of unseparated fresh whole blood exposed to phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM). The yield of IFN-gamma was measured by a newly developed immunoradiometric assay. Nine of 14 patients with acute pulmonary tuberculosis (TB) showed a depressed IFN-gamma response to Con A and/or PWM. Only four of these TB patients also showed a depressed IFN-gamma response to PHA. Stimulation of the patients' PBL cultures with PHA in the presence of exogenous interleukin 2 (IL 2) produced normal IFN-gamma yields in all but the most severely depressed patients. PBL cultures of TB patients with defective IFN-gamma production in response to mitogenic lectins also produced less IFN-gamma after stimulation with tuberculin PPD. Although some patients showed a moderate degree of lymphopenia, their OKT4/T8 lymphocyte ratios were mostly normal or close to normal, with the notable exception of one TB patient who has been diagnosed to have the acquired immune deficiency syndrome (AIDS).
62 citations
TL;DR: The lower IgM levels in saliva of IgA-deficient individuals with many infections was seen in spite of their frequent infections, suggesting a primary defect in an important compensatory defense mechanism.
Abstract: Total levels of IgM and secretory IgM as well as specific antibodies to poliovirus type I antigen,Escherichia coli O antigens, and β-lactoglobulin were measured in unstimulated and stimulated saliva as well as nasal secretion using an enzyme-linked immunosorbent assay (ELISA). The levels of these antibodies in IgA-deficient adults with and without frequent respiratory infections and children under immunosuppressive therapy for malignant disease were compared to those in normal adults and infants 1–7 months of age. The IgA-deficient adults had significantly higher IgM levels (P<0.002) than the normal adults as well as higher levels of IgM antibodies to poliovirus type I (P<0.05) andE. coli O antigen (P<0.002). There was a less pronounced IgM anti-β-lactoglobulin compensation. Secretory component (SC)-carrying antibodies against all three antigens were lower than in normal adults. The infants studied had levels of IgM in secretions close to those of the normal adults and significantly lower than those of the IgA-deficient adults (P<0.001) but with a higher proportion of SC-carrying IgM. The increase in total IgM and specific bacterial and viral IgM antibodies in saliva above that of the normal adults was significant(P<0.001–0.005) for those IgA-deficient individuals without, but not for those with, frequent infections. There was, however, no significant difference between the levels in the two groups of IgA-deficient adults. The total levels of SIgA and specific antibodies toE. coli O antigens and poliovirus type I antigen in saliva from children treated with multiple cytotoxic drugs for malignant disease did not differ from normal levels, irrespective of the duration of treatment. The lower IgM levels in saliva of IgA-deficient individuals with many infections was seen in spite of their frequent infections, suggesting a primary defect in an important compensatory defense mechanism.
62 citations
TL;DR: It seems clear that antibodies to the Ro/SSA and La/SSB antigens have a special place in the nosology of SLE and SS and that in certain instances the antibodies play a direct pathogenic role, while in other circumstances tissue damage might result from immune complex deposition on vascular structures.
Abstract: Knowledge about antibodies to the Ro/SSA and La/SSB antigens has expanded greatly. Recognition of these antibodies was probably achieved 25 years ago but their macromolecular structure, clinical associations, and genetic relationships have come to light only in the past 7 years. It seems clear that these antibodies have a special place in the nosology of SLE and SS and that in certain instances (e.g., neonatal LE) the antibodies play a direct pathogenic role, while in other circumstances (e.g., vasculitis, nephritis, SS) tissue damage might result from immune complex deposition on vascular structures. Certainly, the latter problems will be active areas of investigation in the coming years. If the pace of recent progress continues, many of the questions raised in this review should soon have clear answers.
62 citations
TL;DR: The reduced Th/Ts ratio and NK-cell function among these asbestos workers at high risk may be a direct consequence of asbestos exposure and might not be related to neoplastic processes.
Abstract: We have examined the primary immune responses, the numbers of total T (T11+) cells, T-helper (T4+) cells, T-suppressor (T8+) cells, and natural killer (NK) (Leu7+) cells, in 118 healthy control subjects and compared the data to those obtained from 20 patients with clinically diagnosed malignant mesothelioma and 375 long-term asbestos workers without neoplasia. The absolute numbers of total T (T11+) and T-helper (T4+) cells were normal in asbestos workers without neoplasia but were significantly reduced in patients with mesothelioma. T-suppressor (T8+) cells, on the other hand, remained unchanged in the patients but were significantly elevated among the asbestos workers. This resulted in a marked reduction in T-helper (Th) to T-suppressor (Ts) ratios in mesothelioma patients and in asbestos workers. Seventy percent of the mesothelioma patients (14 of 20) had significantly depressed NK-cell activity which could be augmented but not normalized by coincubation in patients' peripheral blood lymphocytes (PBL) with interferon (IFN). Among the asbestos workers three distinctive subgroups could be identified: heightened (H-NK), normal (N-NK), and low (L-NK) NK activity. The NK activity of the L-NK group could be stimulated but not normalized by coincubation with IFN, a finding closely resembling that in malignant mesothelioma patients. Phenotyping of the circulating NK cells revealed a unique Leu7+ subset in increased numbers with a brightly fluorescent property in stable mesothelioma patients with relatively stable or slowly progressive disease and in more than 30% of the asbestos workers. The reduced Th/Ts ratio and NK-cell function among these asbestos workers at high risk may be a direct consequence of asbestos exposure and might not be related to neoplastic processes.
55 citations
TL;DR: Twenty-five patients suffering from chronic granulomatous disease (CGD) and their families were investigated and it was confirmed that in most of the typical cases, the complete inability of superoxide generation was associated with the absence of detectable cytochrome b.
Abstract: Twenty-five patients suffering from chronic granulomatous disease (CGD) and their families were investigated. Defects in the superoxide generating system were characterized at the level of the heme-containing cytochrome b and of the FAD-containing flavoprotein, both localized in the plasma membrane of granulocytes. It was confirmed that in most of the typical cases (18 of 22), the complete inability of superoxide generation was associated with the absence of detectable cytochrome b. Mothers but not fathers of such male patients were characterized by a diminished content of cytochrome b, confirming that the affected gene is localized on the X chromosome. In contrast, the granulocytes of four other typical patients (two female and two male) contained normal amounts of cytochrome b, whereas oxidative activity was absent. Since no abnormality of oxidative activity as well as of cytochrome b was found in granulocytes of the mothers and fathers of these patients, an autosomal recessive mode of inheritance of the disease is probable. The flavoprotein deficiency found in the granulocytes of four male patients was always associated with an absence of detectable cytochrome b. This could indicate a structural relationship between flavoprotein and cytochrome b (e.g., a flavocytochrome). Three further patients with mild X-linked CGD contrasted with the patients with severe or classic X-linked disease; the oxidative activity of their phagocytes was diminished but not absent, and the cytochrome b present, albeit in small amounts.
TL;DR: The data suggest that the quantitative abnormalities of Leu 2+7+ cells appear early during the evolution of immunologic changes in HTLV III/LAV infection.
Abstract: Peripheral blood mononuclear cells from patients with acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC), asymptomatic homosexuals, and healthy heterosexuals were analyzed for the proportions and numbers of Leu 7+ cells and double-labeled Leu 2+7+ cells and for the natural killer functions. A significant increase in the proportions and numbers of Leu 7+ cells was observed in patients with AIDS and ARC and in asymptomatic homosexuals compared to healthy heterosexual men. The proportions of Leu 2+7+ cells were significantly increased in AIDS, ARC, and asymptomatic homosexuals, whereas the numbers were increased in asymptomatic homosexuals and ARC but not in AIDS compared to heterosexual controls. A significant increase in the number of Leu 2+7+ cells was observed in AIDS with Kaposi's sarcoma but not in AIDS with opportunistic infections. The natural killer function was significantly depressed in patients with AIDS and ARC and in asymptomatic homosexuals. These data suggest that the quantitative abnormalities of Leu 2+7+ cells appear early during the evolution of immunologic changes in HTLV III/LAV infection.
TL;DR: The results suggest that the cause of the defect in IL 2 production in traumatic injury patients is not related to a lack of the IL 1 signal, producer T cells, or Ia+ monocytes or to increased suppressor T cells but to an active suppressor substance which has been identified in the serum of these patients.
Abstract: Depression of cell-mediated immunity in patients following severe traumatic injury has been well documentedin vitro andin vivo. However, the exact mechanism of this defect is still controversial. In this study, we have investigated the ability of injured patients' peripheral blood mononuclear cells (PBMC) to produce two important immunoregulatory molecules, interleukin 1 (IL 1) and interleukin 2 (IL 2). Eighteen traumatic injury patients were studied during the course of their hospital stay and their results compared with a group of 18 normal age- and sex-matched controls. The results showed the following. (1) Production of IL 2 by normal PBMC in response to optimal doses of mitogen may vary with sex as well as age. (2) Adherent mononuclear cells from trauma patients produced at least as much IL 1 as normals. (3) IL 2 production, however, was markedly suppressed (normals, 1.6 ± 0.2 U; traumatic injury, 0.6±0.1 U;P=0.001) and persisted for as long as 50 days postinjury. OKT4+ cells were not significantly decreased at any time, nor were OKT8+ suppressor/cytotoxic cells increased at any time. Decreased IL 2 production in patients treated with steroids or those who were septic was not different from that in those patients who were not treated with steroids or were not septic. These results suggest that the cause of the defect in IL 2 production in traumatic injury patients is not related to a lack of the IL 1 signal, producer T cells, or Ia+ monocytes or to increased suppressor T cells. However, it could be related to a lack of another macrophage signal to the T cell, another suppressor-cell population, or an active suppressor substance which has been identified in the serum of these patients.
TL;DR: The results indicate that the quantitative B-cell deficiency in patients was due to a nonrandom loss of selected sets of B cells, and the existence of an autoimmune inhibitory network mediating the arrest in B- cell differentiation and the humoral immune deficiency is postulated.
Abstract: Patients with multiple myeloma are generally immunodeficient, with pronounced depression in primary antibody responses. We have attempted to delineate the reasons for the humoral immunodeficiency by analyzing the specificity repertoire of the surface immunoglobulin (Ig)-positive B cells in patients with multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS), in comparison with normal donors. B lymphocytes from 26 patients with multiple myeloma, 12 patients with MGUS, and 8 normal donors were transformed with Epstein-Barr virus (EBV) and cultured at limiting dilution for clonal analysis. The Ig secreted by each clone was analyzed for class and anti-tetanus toxoid (TT) specificity to determine the frequencies of IgM, IgG, anti-TT IgM, and anti-TT IgG antibody-secreting clones. Our objective was to establish whether the inability to mount humoral responses to common environmental pathogens was due to a lack of specific B cells or to inhibition of B-cell function. Our results indicate that the quantitative B-cell deficiency in patients was due to a nonrandom loss of selected sets of B cells. Although most patients had a reduced aggregate number of B cells, the number of TT-specific B cells was normal. There was, on average, a threefold increase in the proportion of the B-cell specificity repertoire devoted to recognition of TT. Forty-four percent of the patients with MGUS were also affected. In addition, the TT-specific B cells in multiple myeloma patients were severely compromised in their ability to secrete antibody or to differentiate to antibody-secreting cellsin vivo. This arrest in differentiation appears to be extrinsic to the B cells, as they were fully able to secrete anti-TT antibody after transformation and culturein vitro. We postulate the existence of an autoimmune inhibitory network mediating the arrest in B-cell differentiation and the humoral immune deficiency.
TL;DR: The results suggest that the anti-interleukin-2 serum antibodies generated in the course of treatment do not react with the nonrecombinant lymphokine but recognize epitopes peculiar to recombinant forms which are not dependent on the amino acid substitution at position 125.
Abstract: Approximately 65% (11/17) of cancer patients participating in an ongoing Phase I clinical trial with recombinant interleukin-2 developed nonneutralizing serum IgG anti-interleukin-2 antibodies within 1 month of initiating therapy These antibodies could be detected using any of several standard techniques including immunoblots and enzyme-linked immunosorbent assays Western blot analysis and retention experiments with protein A-Sepharose indicate that the antibodies are specific for interleukin-2 The interleukin-2 mutein utilized in this clinical trial (des-ala-ser125 r-IL-2) differs from the major species of the human T cell-derived lymphokine in that it lacks the N-terminal alanine of the native molecule, is not glycosylated, and possesses a serine-cysteine substitution at position 125 Another recombinant interleukin-2, identical to the mutein except that it retains the cysteine at position 125 (des-ala-cys125 r-IL-2), strongly competes with the mutein in competitive enzyme-linked immunosorbent assays, suggesting that the amino acid substitution is not responsible for the recognition of the molecule by serum antibodies Conversely, nonrecombinant T cell-derived interleukin-2 fails to compete in these assays and is not retained by protein A-Sepharose columns when mixed with high-titer antiserum These results suggest that the anti-interleukin-2 serum antibodies generated in the course of treatment do not react with the nonrecombinant lymphokine but recognize epitopes peculiar to recombinant forms which are not dependent on the amino acid substitution at position 125 The failure of the antibodies to neutralize the biological activity of recombinant interleukin-2 (IL-2) in lymphocyte proliferation assays and to bind to the native lymphokine suggests that they may not affect IL-2-dependent cellular immune functionsin vivo
TL;DR: The abnormal serological responses to EBV in CHS are considered manifestations of a chronic active EBV infection which may result in lethal lymphoproliferation.
Abstract: The results of clinical and Epstein-Barr virus (EBV) serological studies on nine Chediak-Higashi syndrome (CHS) patients are reported. Persistently elevated antibodies to the viral capsid antigen (VCA) and the restricted component of the early antigen complex (EA-R) developed in six patients who experienced primary EBV infection which either remained silent or were accompanied by clinical signs of infectious mononucleosis (IM). Hepatosplenomegaly and moderate lymphadenopathy, both clinical signs of the accelerated phase, remained detectable in the six patients for a long period of time after seroconversion. The clinical, serological, and histopathological observations are suggestive of a nonmalignant lymphoproliferative disease and consistent with an immunodeficiency to EBV. The abnormal serological responses to EBV in CHS are therefore considered manifestations of a chronic active EBV infection which may result in lethal lymphoproliferation. The three as yet seronegative CHS patients revealed no signs of the accelerated lymphoproliferative phase of the syndrome.
TL;DR: A possible streptococcal strain specificity in ARF is suggested and persistent sensitization is demonstrated, which explains the increased susceptibility to recurrences in the 2 years following the acute episode.
Abstract: Acute rheumatic fever (ARF) has the characteristics of an autoimmune disease, triggered by cross-reactive antigens shared by the group A streptococcus and a variety of tissues including the heart, endothelium, and basal ganglia. Using two parameters of cellular reactivity, migration inhibition and blastogenic transformation, ARF patients from Trinidad show significant lymphocyte reactivity to streptococcal antigens, particularly those from an ARF associated streptococcal strain. This reactivity, studied over a 2-year period, peaked at 1 to 6 months after the acute onset and remained significantly elevated for at least 2 years. The reactivity is directed mainly toward a nonionic detergent extractable material in the cell membrane. These studies suggest a possible streptococcal strain specificity in ARF and demonstrate persistent sensitization, which explains the increased susceptibility to recurrences in the 2 years following the acute episode.
TL;DR: Biochemical analysis and comparative studies suggest that NKCF is a distinct molecule from other cytotoxins studied to date, and the selective susceptibility to lysis of tumor or infected cells by NKCF suggests a possible role of their effectiveness inin vivo therapy.
Abstract: Studies on the mechanism of cell-mediated cytotoxicity (CMC) have suggested a stimulus-secretion model and implicated a role of soluble cytotoxic mediators. Our studies in the natural killer (NK) system provide several lines of evidence for the involvement of natural killer cytotoxic factors (NKCF) in NK CMC and led to the development of a model for the NK lytic mechanism. This model delineates several interactions between NK cells and targets that are deemed necessary to achieve target-cell lysis. The first stage is the interaction of the effector with the target cell, resulting in contact and adhesion. This is presumably mediated by NK recognition structures and target-cell structures. Following binding, the target cell stimulates the NK cell to release NKCF. This step is functionally distinct from the initial effector-target binding. The trigger mechanism for release of NKCF appears to be dependent on protein kinase C. The released NKCF binds to NKCF binding sites on the target cell followed by "processing" or "internalization" and, ultimately, resulting in cell death. This model has been shown to be useful in investigating the mechanism of defective NK activity in certain disease states. Biochemical analysis and comparative studies suggest that NKCF is a distinct molecule from other cytotoxins studied to date. The studies in the NK CMC system supporting a role of cytotoxic mediators also suggest a possible role for cytotoxic factors in other cytotoxic systems. Furthermore, the selective susceptibility to lysis of tumor or infected cells by NKCF suggests a possible role of their effectiveness in in vivo therapy.
TL;DR: Evidence suggests that good responders to IVGG may have inhibition of antiplatelet antibody production, as well as normalizein vitro immunoglobulin secretion and its suppression in those ITP patients with good clinical responses in conjunction with decreased levels of autoantibody.
Abstract: Intravenous γ-globulin (IVGG) effectively elevates the platelet count of most patients with chronic idiopathic thrombocytopenic purpura (ITP). This study examined whether this effect was related to changes inin vitro immunoglobulin secretion and suppression in coculture. Before treatment, patientin vitro immunoglobulin secretion was less than 50% of the concurrent control in all eight cases and the patients suppressed antibody synthesis in coculture an average of 39%. After treatment, increases inin vitro immunoglobulin secretion and decreases in suppression were closely related to a good response to IVGG therapy as measured both by acute increases in the platelet count (P<0.05) and by the long-term outcome from therapy (P<0.05). Decreases in platelet-associated IgG correlated with increases inin vitro immunoglobulin secretion (P<0.05). Data consistent with the lack of inhibition ofin vitro immunoglobulin secretion following IVGG included long-term increases in both serum IgM and IgG (independent of transfused IgG) and maintenance of the percentage of total IgG that was IgG3. T-cell numbers and subsets and lymphocyte proliferation were unaffected by IVGG. IVGG tends to normalizein vitro immunoglobulin secretion and its suppression in those ITP patients with good clinical responses in conjunction with decreased levels of autoantibody. This evidence suggests that good responders to IVGG may have inhibition of antiplatelet antibody production. IVGG does not appear to interfere with normal antibody production.
TL;DR: The presence of circulating serum antibodies to tetanus toxoids and the production of specific anti-tetanus toxoid antibody by peripheral blood lymphocytes from marrow recipients show that engrafted donor lymphocytes can produce in vitro specific antibodies to recall antigens without postgrafting reimmunization.
Abstract: This study shows that specific humoral immunity could be transferred from marrow donors to marrow recipients. Peripheral blood lymphocytes from long-term human marrow recipients produced IgG anti-tetanus toxoid antibody afterin vitro tetanus toxoid stimulation. Antitetanus toxoid antibody biosynthesis was induced using a new tetanus toxoid-specific system employing high lymphocyte numbers, many replicate microcultures, and antigen washout. Anti-tetanus toxoid antibody in 12-day culture supernatants was detected using an enzyme-linked immunosorbent assay. Of 14 marrow recipients, 6 (5 with and 1 without chronic graft-vs-host disease) had lymphocytes that produced anti-tetanus toxoid antibody. Culturing additional numbers of marrow recipient lymphocytes increasedin vitro biosynthesis of anti-tetanus toxoid antibody. The presence of circulating serum antibodies to tetanus toxoid and the production of specific anti-tetanus toxoid antibody by peripheral blood lymphocytes from marrow recipients show that engrafted donor lymphocytes can producein vitro specific antibodies to recall antigens without postgrafting reimmunization.
TL;DR: This study suggests that human T-lymphotropic virus Type I or a related virus may be involved in the pathogenesis of some cases of systemic lupus erythematosus.
Abstract: Twenty-six percent of 53 systemic lupus erythematosus sera had high levels of IgM antibody to human T-lymphotropic virus Type I, significantly more than the 5% of normal controls. Neither IgG antibodies to Type I virus nor IgM or IgG antibodies to Type II virus were increased in lupus. Further analysis using competition immunoassay and Western blot techniques also suggested that the IgM Type I antibodies in lupus sera were directed against viral antigens but did not completely exclude a nonviral reaction. Other studies also have not found IgG antibodies to the Type I virus but have not tested for IgM antibodies. Our study suggests that human T-lymphotropic virus Type I or a related virus may be involved in the pathogenesis of some cases of systemic lupus erythematosus.
TL;DR: The long-term home administration of intravenous γ-globulin by seven patients themselves using a portable infusion pump over a period of as long as 2 years has proven to be effective, safe, and cost efficient and a good alternative to hospital or physicians' office-based infusions.
Abstract: Immunoglobulin replacement therapy is required by patients with certain antibody deficiency syndromes and is finding increasing application in other immune disorders such as immune thrombocytopenia. We describe the long-term home administration of intravenous gamma-globulin by seven patients themselves using a portable infusion pump. Over a period of as long as 2 years, this has proven to be effective, safe, and cost efficient and a good alternative to hospital or physicians' office-based infusions.
TL;DR: Analysis of lymphocyte function for Ig synthesisin vitro, using a coculture of counterpart T and B cells from healthy individuals and patients with SIgMD, revealed that the increased function of IgM isospecific suppressor T cells (Ts) was responsible for the IgM deficiency in all seven patients.
Abstract: Seven patients with selective IgM deficiency (SIgMD) were studied for cell surface immunoglobulin (SmIg), T-cell subpopulations, and immunoglobulin (Ig) synthesisin vitro by peripheral blood lymphocytes (PBL). Serum IgM levels were less than 25 mg/dl, while IgA, IgG, and IgD were within normal levels. The patients had respiratory or urinary tract infections and two were diagnosed as having systemic lupus erythematosus (SLE). T/B-cell ratios in PBL were within normal ranges. Percentage ratios of B cells bearing SmIg were normal in five patients and decreased in two; however, normal values were seen after 7 days of culture in the presence of PWM. OKT4/OKT8 ratios decreased in five of seven patients, in whom two were due to a decrease in OKT4 and two to an increase in OKT8 cells. One showed a decrease in OKT4 and an increase in OKT8. Analysis of lymphocyte function for Ig synthesisin vitro, using a coculture of counterpart T and B cells from healthy individuals and patients with SIgMD, revealed that the increased function of IgM isospecific suppressor T cells (Ts) was responsible for the IgM deficiency in all seven patients.
TL;DR: In the context of a clinical phase I/II therapy study with recombinant interleukin-2 (rIL-2), the authors monitored immunological alterations in four patients with acquired immune deficiency syndrome (AIDS) and three patients with AIDS-related complex (ARC).
Abstract: In the context of a clinical phase I/II therapy study with recombinant interleukin-2 (rIL-2), we monitored immunological alterations in four patients with acquired immune deficiency syndrome (AIDS) and three patients with AIDS-related complex (ARC). By determining the surface phenotypes andin vitro functions of peripheral blood mononuclear cells (PBMC) before, during, and after treatment with rIL-2, we observed transient changes in all important leukocyte subpopulations, a minor restoration of immune reactivityin vitro, and an improvement in skin reactivityin vivo. In particular, we found (i) a transient increase in C3b receptor-mediated monocyte activation in ARC patients; (ii) no influence of therapy on the otherwise intact LPS-induced interleukin-1 productionin vitro; (iii) in some patients a transient corrective influence on the high pretherapeutic immunoglobulin secretion of B cells and their nonresponsiveness to pokeweed mitogen; (iv) low T-cell responses to soluble antigens and alloantigens, which were partially restored during rIL-2 treatment in ARC patients and in one AIDS patient; (v) defective NK activity in PBMC of two AIDS patients, which was found to be restored when measured at the end of rIL-2 therapy; and (vi) a rather constant phenotypic pattern of PBMC in each patient during therapy except for the decreasing proportion of OKT9-positive lymphocytes in AIDS patients, the increasing proportion of Leu8−Leu3a+ lymphocytes in all patients, and in particular, the transient significant decrease in the Leu7+/OKT3+ ratio, which pretherapeutically was very high in AIDS patients (0.78±0.21) and high in ARC patients (0.48±0.06) as compared to healthy controls (0.18±0.08).
TL;DR: The half-life and clearance of IgG and tetanus antibody in 16 patients with severe primary humoral immunodeficiency diseases while they received several doses of intravenous γ-globulin (IVIG) were determined by following the decline in the serum IgG concentration.
Abstract: Published studies of the metabolism of human IgG using trace amounts of radiolabeled IgG demonstrated that the elimination of native IgG followed first-order kinetics but that the half-life of IgG was shortest in patients with the highest serum concentrations of IgG. To evaluate the effect of increasing the serum concentration of IgG on the metabolism of IgG, we determined the half-life and clearance of IgG and tetanus antibody in 16 patients with severe primary humoral immunodeficiency diseases while they received several doses of intravenous gamma-globulin (IVIG). Each patient received 100 mg/kg of IVIG each month and the half-life and clearance of IVIG were determined by following the decline in the serum IgG concentration. The dose of IVIG was adjusted to give a minimum IgG level of 200 mg/dl and the half-life was reevaluated. The dose was again adjusted to give minimum concentrations of 450 mg/dl and two additional studies were performed. Mean doses of IVIG infused increased from 100 to 346 mg/kg. The mean trough serum IgG concentration was 191 mg/dl on the standard dose and increased to 427 mg/dl at the highest dose. The serum half-lives of IgG were highly variable, ranging from 22 to 96 days. The mean decreased from 43 days in the first to 33 days in the third and fourth studies, and the clearances of IgG increased from 1.8339 to 2.4302 mg/kg/day, but the differences were not statistically significant. Patients with the highest serum IgG concentrations tended to have the longest half-lives, suggesting that intrinsic IgG production might falsely prolong the calculated half-life of IgG.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Alveolar macrophages lavaged from the lungs of patients with inflammatory lung disease have an increased capacity to secrete interleukin 1 after stimulation with lipopolysaccharide, and possible mechanisms for this increase are discussed.
Abstract: Interleukin 1 secretion from human alveolar macrophages was studied in patients with interstitial pulmonary fibrosis, sarcoidosis, and the acquired immunodeficiency syndrome with pneumonitis and compared to secretion from alveolar macrophages of normal volunteers. Macrophages lavaged from the lungs were stimulated with 10 micrograms/ml of lipopolysaccharide and cultured for 24 hr. In some cases macrophages were also stimulated with 1 microgram/ml lipopolysaccharide. After dialysis of the culture supernatants, interleukin 1 secretion was quantified by the thymocyte proliferation assay and probit analysis and expressed in terms of secretion from 1 million macrophages. Results showed that, on average, macrophages derived from patients secreted more interleukin 1 after stimulation with lipopolysaccharide compared to normal subjects. Mean secretion was significantly greater from macrophages of patients with acquired immunodeficiency syndrome and interstitial pulmonary fibrosis when stimulated with 10 micrograms/ml lipopolysaccharide. Of the 24 individuals studied, spontaneous interleukin 1 secretion was detected from unstimulated macrophages in only 1 patient and 1 normal volunteer. We conclude that alveolar macrophages lavaged from the lungs of patients with inflammatory lung disease have an increased capacity to secrete interleukin 1 on in vitro stimulation with lipopolysaccharide. Possible mechanisms for this increase are discussed.
TL;DR: Although newborns have phenotypically identifiable NK cells and the capacity for IFN production, the ability of the NK cells to inhibit HSV replication is impaired, and their level of response and augmentation by specific lymphokines is target specific.
Abstract: Human adult natural killer (NK) cells were recently demonstrated to inhibit herpes simplex virus (HSV) replicationin vitro. In this study we compared the ability of newborn and adult NK cells to inhibit HSV replication. Cord blood mononuclear cells (MNCs) from healthy, term newborns and MNCs from adults were analyzed for their percentage of Leu-11+ cells and comparedin vitro for their NK-cell activity against HSV-infected fibroblasts and the tumor cell line K562. Cord blood MNCs, compared with adult MNCs, had significantly lower percentages of Leu-11+ cells (5 vs 11%;P<0.01), less anti-K562 NK activity (6 vs 54 lytic units/107 cells;P<0.001), and less anti-HSV NK activity (5 vs 52% HSV plaque inhibition;P<0.02). Comparing individual neonates and adults with equal percentages of Leu-11+ cells, neonatal MNCs still had less NK activity against either target. When Leu-11+ MNCs were isolated using the fluorescence-activated cell sorter, neonatal Leu-11+ MNCs still inhibited HSV replication less than adult Leu-11+ MNCs (P<0.01). MNCs from some neonates had significant anti-K562 NK activity but poor anti-HSV NK activity, suggesting either nonidentical NK-cell subpopulations or specific suppression. Whereas neonatal NK activity against K562 was always augmented by prior exposure to either interferon (IFN) or interleukin-2 (IL-2), the neonatal NK activity against HSV-infected cells was only augmented for half of the neonates tested. Endogenous production of alpha-IFN and gamma-IFN by MNCs exposed to HSV-infected fibroblasts was the same for cells from neonates or from HSV-seronegative adults. More gamma-IFN was produced by MNCs from HSV-seropositive adults than from neonates or HSV-seronegative adults. These results suggest that although newborns have phenotypically identifiable NK cells and the capacity for IFN production, the ability of the NK cells to inhibit HSV replication is impaired, and their level of response and augmentation by specific lymphokines is target specific.
TL;DR: Whereas CR2 appears to be the functionally relevant receptor for Epstein-Barr virus on B cells, the effects of ligand interactions with CR1 and CR2 on normal B-cell proliferation or differentiation remain unidentified.
Abstract: A panel of monoclonal antibodies and ligands that bind to the CR1 or CR2 complement receptors of B cells has been used to investigate the role of these membrane molecules in regulating B-cell proliferation and differentiation. When CR2 was modulated from the surface of B cells by treatment with the HB-5 antibody and a secondary goat anti-mouse immunoglobulin antibody, Epstein-Barr virus-induced polyclonal B-cell proliferation and immunoglobulin production were inhibited by 83 and 90%, respectively. In contrast, modulation of other cell surface molecules, HB-2, B1, and the C3b receptor (CR1), or pretreatment of B cells with C3d,g (a CR2 ligand) or HB-5 antibody, alone minimally inhibited these responses. Neither the HB-5 antibody C3d,g, nor a monoclonal antibody (YZ-1) reactive with CR1 induced resting B cells to proliferate, nor did they alter anti-μ antibody-induced proliferation. Similarly, treatment with C3d,g or with the HB-5 or YZ-1 antibodies did not induce B cells to secrete immunoglobulin or affect pokeweed mitogen-induced plasma-cell formation. Whereas CR2 appears to be the functionally relevant receptor for Epstein-Barr virus on B cells, the effects of ligand interactions with CR1 and CR2 on normal B-cell proliferation or differentiation remain unidentified.
TL;DR: The increased interferon- and interleukin-2-induced enhancement of NK activity and reduced suppressor activity of lymphocytes from IDDM patients may be involved in the pathogenesis of the disease.
Abstract: Peripheral blood lymphocytes from 13 patients with established insulin-dependent diabetes mellitus (IDDM) and 2 prediabetic patients were examined for natural killer (NK) and antibody-dependent cellular cytotoxic activities (ADCC), lectin-dependent cellular cytotoxicity (LDCC), interferon- and interleukin-2-induced cytotoxicity, and concanavalin A-induced suppressor-cell activities in comparison with age-matched normal controls. IDDM patients demonstrated normal levels of NK and ADCC activities against K562 and antibody-coated SB target cells, respectively, compared to controls. IDDM patients showed normal levels of LDCC activity. Notable deviations from control values were, however, observed with diabetic lymphocytes in the following systems. Interferon-and interleukin-2-induced NK activities were significantly higher with IDDM lymphocytes than with control cells. IDDM lymphocytes precultured with concanavalin A demonstrated lower NK and ADCC activities than control cells and manifested decreased suppressor effects on the NK activity of normal allogeneic lymphocytes. Lymphocytes from one of two prediabetic patients showed increased NK, ADCC, and LDCC activities in comparison to controls. The increased interferon- and interleukin-2-induced enhancement of NK activity and reduced suppressor activity of lymphocytes from IDDM patients may be involved in the pathogenesis of the disease.
TL;DR: The ratio of enzyme-linked immunosorbent assay (ELISA) activity using rabbit anti-human secretory component versus rabbitAnti-human alpha chain was significantly higher in subjects less than 12 months of age compared with older groups, suggesting either that free secretory components was binding to tetanus toxoid or that secretory antibody of isotypes other than IgA was present in these youngest subjects.
Abstract: Salivary IgA antibody to poliovirus and tetanus toxoid was measured in whole salivas of 151 children between 2 and 48 months of age from North America and from Scandinavia. Children from urban and suburban populations in the greater Boston, MA, area receive both oral poliovaccine and a parenteral injection with tetanus toxoid (TT), initially at approximately 2 months of age. Children from Goteborg, Sweden, initially receive parenteral injections of TT at 2 months of age and parenteral injections of killed polio vaccine initially at 9 to 10 months of age. Twenty-six percent of the Boston subjects who were less than 12 months old had detectable salivary IgA antibody to poliovirus after oral immunization. In contrast, within the first year after parenteral immunization with killed poliovirus, the Swedish group had detectable salivary antibody in 9% (1 of 13) of the subjects. Forty to 65% of the children in the older Boston-area age groups had positive salivary IgA antibody levels to this antigen. No differences were seen in salivary IgA antibody to TT among the three populations. By 36 months of age at least 50% of all populations had detectable salivary antibody to TT. The ratio of enzyme-linked immunosorbent assay (ELISA) activity using rabbit anti-human secretory component versus rabbit anti-human alpha chain was significantly higher in subjects less than 12 months of age compared with older groups. This suggested either that free secretory component was binding to tetanus toxoid or that secretory antibody of isotypes other than IgA was present in these youngest subjects.