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IL-2 infusion abrogates humoral immune responses in humans.

Although IL-2 infusion enhances cell-mediated cytotoxicity in patients with neoplastic disease, administration is paradoxically associated with a modest fall in total serum IgG and an increased risk of infection. We now show that the adverse effects of IL-2 infusion on the humoral immune system are substantial. Although IL-2 induces the B cell growth and differentiating factors IL-4 and IL-6, infusion abrogates primary antibody responses entirely and reduces secondary antibody responses 50-fold following antigen challenge. There is no evidence of the generation of cells with suppressive activity on B cells but IL-2 increases the ratio of circulating virgin:memory cells. These results may help to explain the increased rate of bacterial infection in patients receiving IL-2. As IL-2 plays a central role in the generation of an immune response, the finding that it is also sufficiently immunosuppressive to inhibit primary- and secondary-type antibody responses suggests that exploration of the underlying mechanisms may provide insights into immune system homeostasis and may offer new approaches to therapeutic immunosuppression.

Adolescent↗

Humoral immunity in Japanese quail following surgical bursectomy at various ages.

Four separate experiments were conducted to determine the effects of surgical bursectomy (BSX) at periodic intervals on subsequent antibody production in Japanese quail. At 0, 1, 3, 7, and 28 days of age, BSX resulted in graduated increments in humoral immune responsiveness. Quail BSX at 0 and 1 day of age exhibited significantly reduced primary hemagglutinin responses, as well as reduced mercaptoethanol resistant (IgG) antibody levels. The production of mercaptoethanol sensitive antibody (IgM) levels were affected to a lesser degree in BSX quail than in controls. At 7 and 28 days of age, BSX resulted in no significant effects. At 3 days of age, BSX resulted in an intermediate effect with minimal reduction in antibody levels. Secondary antibody responses were reduced to a lesser extent than the primary responses. At 0 day, BSX reduced hemagglutinin and mercaptoethanol sensitive antibody levels during the early stages of the secondary responses. At other times, however, BSX did not affect secondary antibody responses.

Age Factors↗

Analysis of recombinant dengue virus polypeptides for dengue diagnosis and evaluation of the humoral immune response.

Dengue is a serious cause of morbidity and mortality in tropical areas worldwide. We cloned and expressed recombinant polypeptides spanning the entire genome of a Brazilian dengue virus type 2 (DENV-2) strain in contiguous segments to generate antigens for dengue diagnosis and evaluation of the human humoral immune response. When analyzed by Western blot and an enzyme-linked immunosorbent assay (ELISA) using human sera, the most reactive polypeptide (pD2-3(E)) was located in the N-terminal portion of the envelope protein. The sensitivity of an IgG-ELISA using pD2-3(E) versus mouse brain antigen was 100% with convalescent sera and 79% with acute sera, with a specificity of 100%. Sera from patients infected with other DENV serotypes recognized pD2-3(E) equally well, whereas sera positive for yellow fever, rubella, and measles showed little or no reactivity. Using this novel approach, we identified a candidate antigen to facilitate diagnosis of DENV infections and observed a surprising variability in antibody patterns in the clinical response to DENV infections.

Antibodies, Viral↗

Humoral immune responses in L-selectin-deficient mice.

L-selectin regulates lymphocyte migration by mediating lymphocyte attachment to high endothelial venules of peripheral lymph nodes (PLN). L-selectin-deficient mice display a 70 to 90% reduction in the number of lymphocytes within PLNs and a 30 to 55% increase in spleen cellularity. The altered distribution of lymphocyte subpopulations in L-selectin-deficient mice resulted in significantly elevated serum IgM and IgG1 levels and augmented humoral immune responses to T cell-independent and T cell-dependent Ags following i.p. immunization. By contrast, s.c. immunization of L-selectin-deficient mice with a T cell-dependent Ag resulted in serum IgM responses that were 40% lower when compared with wild-type littermates on day 7, while primary IgG responses were essentially absent. Most serum Ig responses were normal by day 14 and secondary responses were higher in L-selectin-deficient mice. Although lymphocytes from L-selectin-deficient mice were unable to enter Ag-stimulated lymph nodes through high endothelial venules, the cellularity of draining lymph nodes increased significantly following immunization. Germinal centers developed rapidly following immunization, although PLNs of L-selectin-deficient mice contained few follicles. Germinal centers within PLNs and the spleen were also consistently much larger and more well defined in L-selectin-deficient mice when compared with wild-type littermates. These results confirm that lymphocyte migration plays an important role in the initiation of humoral responses and demonstrate complementary and overlapping roles for the spleen and other peripheral lymphoid tissues in the generation of immune responses.

Animals↗

Humoral immune response in disease-free advanced melanoma patients after vaccination with melanoma-associated gangliosides. EORTC Cooperative Melanoma Group.

Several studies have shown that melanoma-associated gangliosides are immunogenic in melanoma patients and that antibodies against them have a favorable prognostic effect. Our study aims at characterizing the humoral immune response in disease-free, advanced melanoma patients vaccinated with a total ganglioside fraction extracted from pooled metastases of human melanoma, containing as major gangliosides GM3 and GD3, and as minor ones GM2 and GD2. Prior to vaccination, all patients were made disease-free by surgical removal of skin, lymph-node or other distant metastases. Repeated vaccinations were carried out intradermally with gangliosides either in the native form in buffered solution, or in the form of liposomes. Serum samples were collected at regular intervals and assayed by ELISA for the presence of specific IgG and IgM antiganglioside antibodies. Selected samples were tested by immunostaining on thin-layer plates to specify the ganglioside species involved in the reactivity. Out of 32 evaluable patients, 17 presented a significant increase in antibody titer, mostly of the IgG isotype, which was maximal between 2 and 4 months after starting injections of gangliosides, and gradually disappeared within 1 year. No significant difference could be seen between the group of 20 patients treated with native gangliosides and the group of 12 vaccinated with the gangliosides in liposomes. All gangliosides seemed to be immunogenic, but GM2 and GD2 were somewhat more reactive. The disease-free intervals for the patients who showed an antibody response to the treatment were significantly higher (p less than 0001) than those of the non-responding group, as compared by the Kaplan-Meier method.

Antibody Formation↗

Effect of chronic irradiation on the humoral immune response of a marine fish, the eelpout (Zoarces viviparus L.).

Eelpout (Zoarces viviparus), a marine fish, were exposed to gamma-radiation at a dose-rate of 2.0 mGy h-1. They were injected with the antigen trinitrophenyl-keyhole limpet haemocyanin (TNP-KLH) and their specific humoral immune response to the TNP hapten measured. There were no differences in the primary antibody response between unirradiated controls and treated fish. However, the response to a second injection of antigen was significantly increased in irradiated fish. There were no significant radiation effects on total serum protein or serum lysozyme. Radiation effects on testis were also examined and there was a significant radiation-induced reduction in relative weight (gonadosomatic index). These results are discussed with reference to environmental radiation levels in areas of authorized radioactive waste disposal.

Animals↗

Dietary beta-carotene stimulates cell-mediated and humoral immune response in dogs.

The role of beta-carotene on immune response in domestic dogs is not known. Female Beagle dogs were fed 0, 2, 20 or 50 mg beta-carotene/d; blood was sampled at wk 0, 1, 2, 4 and 8 for analysis of the following: lymphoproliferation, leukocyte subpopulations and concentrations of interleukin-2 (IL-2), immunoglobulin (Ig)G and IgM. Delayed-type hypersensitivity (DTH) response was assessed at wk 0, 3 and 7. beta-Carotene supplementation increased plasma beta-carotene concentrations in a dose-dependent manner. Compared with unsupplemented dogs, those fed 20 or 50 mg of beta-carotene had higher CD4+ cell numbers and CD4:CD8 ratio. However, there was no treatment difference in CD8+, CD21+ and major histocompatability complex (MHC) class II+ cells. Plasma IgG, but not IgM concentration was higher in dogs fed beta-carotene throughout the study period. The DTH response to phytohemagglutinin (PHA) and vaccine was heightened in beta-carotene-supplemented dogs. beta-Carotene feeding did not influence mitogen-induced lymphocyte proliferation or IL-2 production. Immune response was impaired in dogs classified as low beta-carotene absorbers compared with similar dogs fed the same amount of beta-carotene. Therefore, dietary beta-carotene heightened cell-mediated and humoral immune responses in dogs.

Animals↗

[Effects of complexes of alpha-fetoprotein and amphiphilic docosaenoic acid derivatives on the humoral immune response in C57BL/6 mice].

The immunotropic activity of three derivatives of docosahexaenic acid (N-docosahexaenoyl-L-serine phosphate, N-docosahexaenoyl-L-threonine phosphate, and N-docosahexaenoyl-L-tyrosine phosphate) in complexes with high-purity human alpha-fetoprotein was evaluated. The polyene compounds stimulate the humoral immunity in mice immunized with T-dependent antigen (ram red blood cells). The immunotropic activity of the alpha-fetoprotein-ligand complexes studied depends on the structure and the content of polyene ligands.

Animals↗

[Mechanisms of chorionic gonadotropin action on splenocytes, suppressed in their humoral immune response].

Chorionic gonadotropin (CG) used at 10 and 50 IU/ml concentrations was introduced into a short-term macroculture of splenocytes of CBA mice suppressors fractionated on a nylon wool column. Regulatory effects of CG were evaluated in a syngeneic transfer system by the degree of inhibition of a humoral immune response in recipients. It was found that CG (50 IU/ml) inhibits the functional activity of splenocyte suppressors. The observed effect of the hormone was blocked by introduction into the incubation medium of the inhibitor, inositol-1-monophosphatase (lithium), and did not depend on cyclooxygenase (voltaren) or potential-independent Ca(2+)-channel (verapamil) inhibitors. Determination of the intracellular cAMP level by radioimmunoassay revealed a reliable increase of this secondary messenger in splenocyte suppressors during their incubation with CG. The ability of CG (50 IU/ml) to inhibit the functional activity of intact T-lymphocytes (but not B-cells) was established. The suppressive hormone activity was also followed by cAMP level increase in target cells. These findings suggest that the mechanism of a transmembrane transfer of the CG signal in splenocyte suppressors is related to the adenylate cyclase system and, probably, to phosphoinositide metabolism products.

Animals↗

The effect of chronic emotional stress on the humoral immune response to Porphyromonas gingivalis in mice.

Previous studies have shown that psychological stress plays a significant role in the outcome of infectious diseases, but data related to the effect of stress on periodontal infection is limited. The present study was designed to test the impact of emotional stress on the humoral immune response to the periodontal pathogen Porphyromonas gingivalis in a mouse model of local inflammation. Chambers constructed from titanium wire were implanted in the subcutaneous dorsolumbar region of mice. All mice were immunized with P. gingivalis followed by an intrachamber challenge with the bacteria. One group of mice was used as control, while the other two experienced experimental stress conditions (isolation/restraint stress). Stress-1 group was stressed during the immunization period, while Stress-2 group was stressed during the local challenge period. Chamber exudates and serum were collected and analyzed for levels of anti-P. gingivalis antibodies (IgG, IgG1 and IgG2a). The levels of serum antibodies to P. gingivalis were not different between the three tested groups, excluding increased levels of IgG2a in Stress-1 group at baseline. The levels of antibodies in the chamber exudates were significantly lower in the stressed groups at baseline, but higher at d 7. The IgG1 to IgG2a ratio was significantly higher in the control group compared with the two stressed groups. The findings of the present study suggest that chronic psychological stress had a marked impact on the localized response to P. gingivalis challenge. The lower IgG1/IgG2a ratio observed in the stress groups suggests elevated Th1 response during stress.

Analysis of Variance↗

Suppression of the humoral immune response by particulate material extracted from spleen cell subpoulations of MOPC-315 tumor-bearing mice.

Particulate extracts were prepared from MOPC-315 plasmacytoma cells, from whole spleen cells or from splenic macrophages of MOPC-315 tumor-bearing mice. These preparations, when injected into normal mice, inhibited their primary humoral immune response to sheep red blood cells (SRBC). At the same time, particulate extracts from whole spleens or splenic macrophages of normal mice and T cell extracts from spleens of MOPC-315 tumor-bearing mice had no effect on the primary immune response to SRBC. The results suggest that phagocytic spleen cells of tumor-bearing mice contain immunosuppressive particles which originate from the tumor cells.

Animals↗

Restraint stress differentially affects anti-viral cellular and humoral immune responses in mice.

Physical restraint administered to C57BL/6 mice significantly altered the inflammatory response to influenza virus infection and depressed anti-viral cellular immunity. Restraint-stressed animals showed a pattern of reduced mononuclear cell infiltration and lung consolidation which coincided with elevated plasma corticosterone levels. Furthermore, cellular immunity to virus was significantly depressed; interleukin-2 secretion was reduced by 96% and 59% in the mediastinal lymph nodes and spleens, respectively, as compared to a non-restrained group. However, the magnitude of the humoral immune response to influenza virus was unaffected by restraint stress. Anti-viral IgG antibody levels in restrained/infected mice did not differ when compared to a non-restrained/infected control group 14 days post-infection.

Animals↗

Vaccination with gp120-depleted HIV-1 plus immunostimulatory CpG oligodeoxynucleotides in incomplete Freund's adjuvant stimulates cellular and humoral immunity in rhesus macaques.

Whole killed human immunodeficiency virus type 1 (HIV-1) immunogens contain the more conserved epitopes of HIV-1 and therefore may provide some utility as potential HIV-1 vaccine candidates. Previous studies have shown that synthetic oligodeoxynucleotides (ODN) containing unmethylated cytosine-guanine (CpG) dinucleotides trigger rapid stimulation of both CD4+ and CD8+ T cells. Here, we investigated whether immunization of rhesus macaques with an inactivated gp120-depleted HIV-1 immunogen, emulsified in incomplete Freund's adjuvant (IFA) together with immunostimulatory CpG-containing ODN (ODN 2006), would elicit HIV-specific cellular and humoral immune responses. High titer anti-p24 antibody levels were induced in all four immunized animals that were sustained 6 weeks after the fifth and final boost at 23 months. These anti-gag antibodies mapped to linear B-cell epitopes within the matrix (MA), capsid (CA), p2, nucleocapsid (NC) and p6 proteins of HIV-1 gag. HIV-specific interferon-gamma-producing CD4+ and CD8+ T-cell responses were measured before and after the fourth and fifth immunizations by both intracellular cytokine (ICC) and ELISPOT techniques; responses were detected in three of the four immunized animals. CD4+ T-cell epitopes appear to map within amino acids 261-290 and 291-320 of p24 CA protein. Immunizations were well tolerated both locally and systemically. Based on these results, further studies of this approach are warranted.

AIDS Vaccines↗

Corticosterone selectively decreases humoral immunity in female eiders during incubation.

Immunity is hypothesized to share limited resources with other physiological functions and this may partly account for the fitness costs of reproduction. Previous studies have shown that the acquired immunity of female common eider ducks (Somateria mollissima) is suppressed during their incubation, during which they entirely fast. Corticosterone was proposed to be an underlying physiological mechanism for such immunosuppression. Therefore, the current study aimed to assess the effects of exogenous corticosterone on acquired immunity in captive eiders. To this end, females were implanted with corticosterone pellets at different stages of their incubation fast. We measured total immunoglobulin levels, T-cell-mediated immune response, body mass and corticosterone levels in these females and compared them with those of control females prior to and after manipulation (i.e. corticosterone pellet implantation). To mimic corticosterone effects on body mass, we experimentally extended fasting duration in a group of females termed ;late fasters'. Implanted females had corticosterone levels 6 times higher and lost 35% more mass than control females. Corticosterone levels in ;late fasters' were similar to those in control females but body mass was 8% lower in the former. The decrease in the immunoglobulin levels of corticosterone implanted females was twice as high as in control females, while the T-cell-mediated immune response was not significantly affected by the treatment. We found a decrease in the T-cell-mediated immune response only in ;late fasters' (by 60%), while the immunoglobulin level was not lower in this group than in corticosterone implanted or control females. Our study shows that in incubating eiders, exogenous corticosterone only decreased humoral immunity. We suggest that the immunosuppressive effect of corticosterone could be mediated through its effects on body reserves. Further experiments are required to determine the relationship between body condition and immune system in fasting birds.

Animals↗

A histological and immunohistochemical study of the humoral immune system of the lungs in young Thoroughbred horses.

Lungs were obtained from 16 Thoroughbred horses, aged 1 day to 2 years, which had died or been humanely killed for reasons unrelated to disease of the lower respiratory tract. The lungs were then subjected to a histological and immunohistochemical examination of the humoral immune system. At birth there was no evidence of organized lymphoid tissue, and lymphocytes and plasma cells were virtually absent in all tissue compartments in the first week of life. However, by 12 weeks, foals exhibited well developed bronchus- and bronchiole-associated lymphoid tissue, but this had regressed progressively at 1 and 2 years of age. Plasma cells were present in large numbers in the walls of bronchi and bronchioles in foals aged 8 to 12 weeks. IgA-producing plasma cells were common in the lower respiratory tract of these young horses, in addition to IgG- and IgM-producing plasma cells.

Aging↗