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PubMed2004

Protective niche for Borrelia burgdorferi to evade humoral immunity.

The Lyme disease spirochete, Borrelia burgdorferi, is an extracellular microbe that causes persistent infection despite the development of strong immune responses against the bacterium. B. burgdorferi expresses several ligand-binding lipoproteins, including the decorin-binding proteins (Dbps) A and B, which may mediate attachment to decorin, a major component of the host extracellular matrix during murine infection. We show that B. burgdorferi was better protected in the joints and skin, two tissues with a higher decorin expression, than in the urinary bladder and heart, two tissues with a lower decorin expression, during chronic infection of wild-type mice. Targeted disruption of decorin alone completely abolished the protective niche in chronically infected decorin-deficient mice but did not affect the spirochete burden during early infection. The nature of protection appeared to be specific because the spirochetes with higher outer surface protein C expression were not protected while the protective niche seemed to favor the spirochetes with a higher dbpA expression during chronic infection. These data suggest that spirochetal DbpA may interact with host decorin during infection and such interactions could be a mechanism that B. burgdorferi uses to evade humoral immunity and establish chronic infection.

Adhesins, Bacterial↗

PubMed2006

The anti-nuclease humoral immune response of broiler chickens exposed to Staphylococcus aureus, infectious bursal disease virus and chicken anaemia virus in an experimental model for bacterial chondronecrosis and osteomyelitis.

This study aimed to develop an enzyme-linked immunosorbent assay to detect antibody associated with Staphylococcus aureus that is produced during the chicken immune response to this organism. The protein nuclease was tested for suitability as an antigen to detect antibody in sera from broiler chickens that had been exposed to aerosolized S. aureus on day 1 post hatch during experiments to reproduce bacterial chondronecrosis and osteomyelitis. An enzyme-linked immunosorbent assay was developed to measure the levels of nuclease antibody in 509 chicken sera from various experiments, which also enabled the examination of the influence of factors such as the S. aureus infection status and co-infection with chicken anaemia virus (CAV) and infectious bursal disease virus (IBDV) on nuclease antibody levels. Positive levels of nuclease antibody were detected in 71% of serum samples from chickens inoculated with S. aureus, CAV and IBDV, while positive levels were detected in 35% of chickens inoculated with S. aureus only. The influence of CAV and IBDV on the number of chickens with positive levels was most prominent in chickens aged up to 42 days. The study showed that nuclease-specific antibodies form part of the humoral immune response in broiler chickens that have been exposed to S. aureus. Co-infection with CAV and IBDV appeared to promote development of antibody in birds younger than 42 days; however, the presence of antibody did not necessarily prevent systemic infection.

Aging↗

PubMed2000

Airway inflammation in a murine model of chronic asthma: evidence for a local humoral immune response.

BACKGROUND: Asthma is an acute-on-chronic inflammatory disease of the airways characterized by recruitment of eosinophils into the epithelial layer, chronic inflammation in the lamina propria, as well as variable accumulation of mast cells in the airway wall. The role of local production of allergen-specific immunoglobulins in triggering mast cell-mediated asthmatic inflammation is unknown. METHODS: We used a chronic inhalational exposure model of asthma in ovalbumin-sensitized BALB/c mice to examine the phenotype of immunoglobulin-secreting cells and mast cells in the airway wall. In parallel, we assayed ovalbumin-specific IgG and total IgE in the plasma of these animals. RESULTS: In sensitized mice exposed to aerosolized ovalbumin for 6 weeks, aggregates of chronic inflammatory cells consisted of a majority of plasmacytoid cells, including numerous IgG-synthesizing cells, which were significantly increased in sensitized animals compared to controls. IgA-synthesizing cells were also present, but were not increased in the sensitized exposed mice. Immunoglobulins in the cytoplasm of the plasma cells were demonstrated to be antigen-specific. No IgM-or IgE-synthesizing cells were observed, although levels of total IgE in the plasma were significantly increased. There was no recruitment of mast cells of either the mucosal or the connective tissue phenotype into the lamina propria or the epithelium. CONCLUSION: In this experimental model of chronic asthma, the pattern of inflammation in the airway wall is consistent with development of a local IgG-mediated humoral immune response. However, there is no evidence of local production of IgE or recruitment of mast cells.

Animals↗

PubMed1995

Bacterial lipoproteins may substitute for cytokines in the humoral immune response to T cell-independent type II antigens.

Bacterial lipoproteins share a common structural motif that has been shown to stimulate proliferation and Ig secretion of murine B cells, in a manner distinct from that mediated by LPSs. Studies of lipoprotein-mediated B cell activation utilized heterogeneous populations of lymphoid cells, leaving unresolved their ability to directly activate resting B cells, as well as their ability to interact with other B cell stimuli. Using highly enriched and/or sort-purified resting murine B cells, we demonstrate that, in contrast to previous reports, lipoproteins (lipoprotein-D, lipoprotein-OspA, and/or the synthetic analogue Pam3Cys) stimulate little, if any, proliferation or Ig secretion in resting B cells. However, when combined with a multivalent membrane (m)Ig-mediated cross-linking signal, dextran-conjugated anti-IgD Abs (alpha delta-dex), lipoproteins mediate up to 10,000-fold inductions in IgM secretion and up to 25-fold enhancements in cellular proliferation relative to that observed with alpha delta-dex alone, in the absence of added cytokines. This mIg-mediated enhancement of Ig secretion was not observed when B cells were stimulated with bivalent, unconjugated anti-Ig. CD40 ligand (CD40L), shows a similar, although somewhat more moderate, synergy with lipoproteins for induction of proliferation and IgM secretion. By contrast, lipoproteins by themselves are relatively ineffective at costimulating Ig secretion in the presence of various combinations of cytokines. These data suggest that bacteria may induce Ag-specific humoral immunity through the action of bacterial polysaccharides that mediate an Ag-specific multivalent mIg signal, in concert with bacterial lipoproteins that deliver ancillary signals, without a requirement for recruitment of non-B cell types.

Animals↗

PubMed2003

Effect of humoral immune responses on controlling viremia during primary infection of rhesus monkeys with simian immunodeficiency virus.

Cellular immune responses mediated by CD8+ lymphocytes exert efficient control of virus replication during primary simian immunodeficiency virus (SIV) infection. However, the role that antibodies may play in the early control of virus replication remains unclear. To evaluate how antibody responses may affect virus replication during primary SIVmac infection, we depleted rhesus monkeys of B cells with anti-CD20 antibody. In normal rhesus monkeys immunized with tetanus toxoid, anti-CD20 treatment and resulting depletion of B cells inhibited the generation of antitetanus antibodies, while tetanus-specific T-cell responses were preserved. During the first 4 weeks after inoculation with SIVmac251, development of SIV-specific neutralizing antibody was delayed, and titers were significantly lower in B-cell-depleted monkeys than control-antibody-treated monkeys. Despite the lower neutralizing antibody titers, the levels of plasma SIV RNA and the linear slope of the decline seen in B-cell-depleted monkeys did not differ from that observed in monkeys treated with control antibody. However, beginning at day 28 after SIV infection, the B-cell-depleted monkeys showed a significant inverse correlation between neutralizing antibody titers and plasma virus level. These results suggest that the rapid decline of peak viremia that typically occurs during the first 3 weeks of infection was not significantly affected by SIV-specific antibodies. However, the inverse correlation between neutralizing antibodies and plasma virus level during the postacute phases of infection suggests that humoral immune responses may contribute to the control of SIV replication.

Animals↗

PubMed2004

Maternally derived humoral immunity to bovine viral diarrhea virus (BVDV) 1a, BVDV1b, BVDV2, bovine herpesvirus-1, parainfluenza-3 virus bovine respiratory syncytial virus, Mannheimia haemolytica and Pasteurella multocida in beef calves, antibody decline by half-life studies and effect on response to vaccination.

The passive immunity transferred to calves from their dams was investigated in a beef herd to determine half-life of antibody, estimated time to seronegative status and effect on immunization. One hundred two beef calves in a commercial ranch under standard management conditions were utilized. Samples were collected at branding (day 0). This was the first possible date to collect samples postcalving. This was approximately 2 months postcalving, and days 95 and 116. The calves were divided into two groups: vaccinates (51) and nonvaccinates (51). The calves were vaccinated with a commercial inactivated viral vaccine containing bovine viral diarrhea virus (BVDV)1a, BVDV2, bovine herpesvirus-1 (BHV-1), parainfluenza-3 virus (PI-3V), and bovine respiratory syncytial virus (BRSV) on days 0 and 95. Half of the vaccinated and unvaccinated calves also received one dose of an experimental Mannheimia haemolytica and Pasteurella multocida vaccine at day 95. Serums were tested for neutralizing antibody titers to BVDV1a, BVDV1b, BVDV2, BHV-1, PI-3V, and BRSV. Antibodies were detected by ELISA to M. haemolytica whole cell, M. haemolytica leukotoxin, and P. multocida outer membrane protein (OMP). The mean half-life of viral antibodies in nonvaccinated calves to each virus was: BVDV1a, 23.1 days (d); BVDV1b, 22.8 d; BVDV2, 22.9 d; BHV-1, 21.2 d; PI-3V, 30.3 d; and BRSV, 35.9 d. The mean half-life of viral antibodies was greater for vaccinates than for nonvaccinates for all viruses except BRSV. The calculated mean time to seronegative status for nonvaccinates based on titers at day 0 was: BVDV1a, 192.2 d; BVDV1b, 179.1 d; BVDV2, 157.8 d; BHV-1, 122.9 d; PI-3V, 190.6 d; and BRSV, 186.7 d. There was an active immune response after vaccination with two doses to all the viruses, except BRSV. Mean antibody titers of vaccinates at day 116 were statistically higher than nonvaccinates for all viruses except BRSV. However on an individual calf basis there were few seroconversions (four-fold rise or greater to BVDV1a, BVDV1b, BVDV2, PI-3V, or BRSV; or two-fold rise for BHV-1) in the presence of viral antibodies. The predicted time of seronegative status for a group of calves for vaccination programs may not be appropriate as there may be a range of titers for all calves at day 0. In this study the range for BVDV1a was 16-16,384; BVDV1b, 8-8192; BVDV2, 0-8192; BHV-1, 0-935; PI-3V, 8-2048; and BRSV, 8-4096. Using the half-life of 23 d for BVDV1a, the time thereafter for seronegative status would be 46 and 299 d compared to the calculated date of 192.2 d using the mean of estimated time to seronegative status for all the calves. There was an active humoral response in the vaccinated calves to M. haemolytica and P. multocida. Cowherd humoral immunity based on serum antibodies should be monitored as it may relate to transfer of maternal antibodies to calves. Exceptionally high levels of viral antibodies transferred to calves could interfere with the antibody response to vaccination.

Animals↗

PubMed1994

An in vitro model for T cell-independent induction of humoral immunity. A requirement for NK cells.

We previously established an in vitro polyclonal model for membrane Ig-mediated Ig secretion by B cells in response to T cell-independent type 2 (TI-2) Ags, by using dextran-conjugated anti-IgD Abs (alpha delta-dex). We demonstrated that resting B cells activated with alpha delta-dex plus IL-2 secreted large amounts of Ig only in the presence of NK cells. In this report we show that, in contrast to small B cell-enriched spleen cells that require activation with the combination of alpha delta-dex and IL-2 for induction of Ig secretion, large B cells were induced to secrete Ig in response to alpha delta-dex, alone. These responses were inhibited by previous depletion of asialo-Gm-1+ cells from the B cell-enriched population, and restored both by the addition of freshly explanted NK cells and by in vitro-activated NK cells, suggesting a requirement for NK cells. Small alpha delta-dex-activated B cells could, however, also be stimulated to secrete Ig in the absence of added cytokines but only after the addition of in vitro-activated NK cells and not freshly explanted splenic NK cells. When highly purified large B cells, obtained by electronic cell sorting, were cultured with in vitro-activated NK cells, Ig secretion was induced even in the absence of any other added B cell stimulus. Because the splenic marginal zone has been implicated in humoral immune responses to TI-2 Ags, we further fractionated large B cells into marginal zone (MZB) and follicular (FB) B cells by electronic cell sorting. In vitro-activated NK cells stimulated large MZB, but not FB, cells to secrete Ig in the absence of exogenous stimuli. These data establish a T cell-independent model for induction of Ig synthesis in the absence of any added cytokine and demonstrate a role for freshly explanted NK cells in stimulating Ab production in response to TI-2 Ags. Further, they show that pre-activated NK cells can induce Ig secretion from pre-activated B cells even in the absence of any added stimuli. These data also underscore a special role for the MZB cell in these responses.

Animals↗

PubMed1977

Suppression of the humoral immune response by plasmacytomas: mediation by adherent mononuclear cells.

Mice bearing plasmacytomas have a severely impaired ability to mount a primary immune response; T cells from these mice, however, appear by both in vivo and in vitro criteria to function normally. This unusual pattern of immunodeficiency appears to be mediated by a regulatory cell found in the spleens and peritoneal cavities but not in the lymph nodes or thymuses of mice bearing plasmacytomas. The number of cells with suppressor activity in the spleens of plasmacytoma-bearing mice is directly proportional to the size of the subcutaneous tumor borne by the host. These cells are capable of suppressing antibody production in in vitro cultures of normal spleen cells but have no demonstrable effect on the ability of normal spleen cells to proliferate in vitro in response to phytohemagglutinin or 8-Br-guanosine-3', 5'-monophosphate (T and B cell mitogens, respectively). Characterization of the suppressor cell population on the basis of its cell surface properties, its radioresistance, its morphology, and its ability to adhere to various solid matrices suggest that these cells are adherent mononuclear cells. These data support the concept that plasma cell tumors indirectly induce an impairment in the humoral immune response of their hosts by stimulating the expression of regulatory functions in a population of splenic and peritoneal macrophages.

Animals↗

PubMed1998

Influence of HLA-DR2 phenotype on humoral immunity & lymphocyte response to Mycobacterium tuberculosis culture filtrate antigens in pulmonary tuberculosis.

Association of HLA-DR2 genes/gene products has been shown with pulmonary tuberculosis (PTB) patients in India. In the present study, the influence of HLA-DR2 and non-DR2 genes/gene products on immunity to tuberculosis has been studied. Plasma samples of -DR2 positive patients (active and inactive TB) showed a higher antibody titre to Mycobacterium tuberculosis culture filtrate antigens than non-DR2 (-DR2 negative) patients. Immunoblot analysis revealed a trend towards an increased percentage of DR2 positive patients recognizing 38, 32/34 and 30/31 kDa antigens of M. tuberculosis than DR2 negative patients. A low spontaneous lymphoproliferative response (without antigen stimulation) was seen in HLA-DR2 positive active TB patients than HLA-DR2 negative patients. However, the antigen stimulated lymphocyte response was higher in the -DR2 positive patients (active and inactive TB) when compared to non-DR2 patients. Further, an inversional correlation between antibody titre and spontaneous as well as antigen induced lymphocyte response (measured by 3H thymidine uptake and expressed as counts per minute) was seen in HLA-DR2 positive active PTB patients than non-DR2 patients. The present study suggests that HLA-DR2 genes/gene products may be associated with a regulatory role in the mechanism of disease susceptibility to tuberculosis. The genes while augmenting the humoral immune response, they suppress the spontaneous and antigen induced lymphocyte response in -DR2 positive patients with active disease.

Adult↗

PubMed1976

Reduced humoral immune activity in long-lived old mice: an approach to elucidating its mechanisms.

Spleen cells from young (3-5 months) and old (22-27 months) mice were assessed in cultures, both in vivo and in vitro, for their anti-sheep RBC response separately and in mixtures. Pooled young spleens, pooled old spleens, and individual old spleens were analysed. The response of pure young spleen cells was always higher than that of pure old spleen cells (approximately 30 times). The responses of mixtures were either less than (i.e. reduced; frequency approximately 65%), comparable to (i.e. additive; frequency approximately 10%), or greater than (i.e. elevated; frequency approximately 30%) the sum of the responses given by equivalent numbers of pure young and pure old spleen cells. The reduced response was observed in mixtures containing cells from histologically normal old spleens, old spleens with tumours and old spleens with atrophic follicles. Additive and elevated responses were observed only in mixutres containing cells from histologically normal old spleens. The reduced response is explicable in terms of excessive numbers of suppressor cells in old spleens that can prevent young immunocompetent cells from responding maximally to the test antigen. The additive response can be accounted for by a reduction in number of immunocompetent cells in old spleens and/or a decrease in their functional efficiency. The elevated response can be explained by a reduction in number of at least one type of immunocompetent cell in old spleens that exists in excess in young spleens. These results indicate that there are several types of cellular changes responsible for the decrease in humoral immune activity in old mice. Pooling of old spleens, as was commonly done in the past, should therefore be discouraged. Not only might it selectively favour the expression of old spleens with an excess of supressor cells but it conceivably could result in an elevated response.

Aging↗

PubMed2000

TNF-alpha receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung.

Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose-dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-alpha and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. beta-Galactosidase expression in mice receiving intratracheal instillation of Adv/beta-gal (adenovirus construct expressing beta-galactosidase) was transient (less than 14 days), but a significant early increase of beta-galactosidase expression was seen in mice lacking either or both TNF-alpha receptors. Absence of TNF-alpha or the p55 receptor significantly attenuated the Ab response to both adenovirus and beta-galactosidase. Human IL-10 expression in the lung suppressed local TNF-alpha production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with beta-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-alpha signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with beta-galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with beta-galactosidase, and is nonimmunogenic in the lung.

Adenoviridae↗

PubMed1974

Mode of action of a supernatant activity from T-cell cultures that nonspecifically stimulates the humoral immune response.

The mode of action of "allogeneic supernatant" (the culture supernatant of a 24-hr mixedlymphocyte reaction), has been studied. This factor stimulates the response of spleen cell cultures depleted in thymus-derived lymphoid cells (T-cells) to antigens that elicit a thymus-dependent response. We used a limiting dilution analysis, in which the frequency and size of response of individual bone-marrow-derived lymphoid cells (B-cells) could be measured. In confirmation of other reports, the occurrence of B-cells responding to antigen under different conditions was shown to follow a Poisson distribution in mouse spleen cell suspensions. Allogeneic supernatant increased responses to thymus-dependent antigens, both by increasing the frequency of B-cells whose response is initiated and by increasing the numbers of antibody-forming cells obtained from each responding B-cell. Two fractions were obtained by dialysis of the supernatant. The nondialyzable fraction contained factors able to increase both the frequency of B-cells responding to sheep erythrocytes, and the size of the responding unit. The dialysate contained factors that were only able to increase the numbers of antibody-forming cells obtained per responding B-cell from B-cells whose response had already been initiated by antigen-specific T-cells. Since the nondialyzable factors were active in the absence of detectable functional T-cells, it was concluded that these factors, produced by T-cells, might represent one mechanism whereby T-cells cooperate with B-cells in the initiation or development of a humoral immune response.

Animals↗

PubMed1986

T cells bearing unique membrane antigen and their regulatory role in humoral immune response in mice.

The mutant lpr gene causes a generalized massive T cell proliferation and an associated autoimmune disease in mice. The lpr T cells bear unusual membrane phenotypes and play a causative role in the pathogenesis of autoimmune disease through excess production of some lymphokines. Therefore, the "aberrant" T cells in lpr mice may be normal regulatory T cells in non-lpr-bearing mice, if nonproliferative. We thus attempted to produce a xenogeneic monoclonal antibody (ALP-1) directed against the lpr T cells. The ALP-1 monoclonal antibody reacted with the antigen Lp-1 distributing on about one half of the proliferating lymph node cells from MRL/Mp-lpr/lpr mice but not on the cells from non-lpr-bearing mice. Nevertheless, a significant number of Lp-1+ cells appeared in the lymph node and spleen cells from these normal mice after in vitro stimulation with mitogens. Functional studies revealed that either the treatment with ALP-1 plus complement of the antigen-primed splenic T cells from non-lpr-bearing mice or the addition of ALP-1 alone all but completely abolished the development of plaque-forming cells against sheep red blood cells in T-B cell coculture. Pretreatment of spleen cells with ALP-1 plus complement, however, did not affect other in vitro T cell functions such as mitogen-induced proliferative responses, interleukin 2 production, response in mixed lymphocyte culture (MLC) and the MLC-induced cytotoxic T cell activities. Thus, Lp-1+ T cells in normal mice are unique T cells that may play an important regulatory role in humoral immune response.

Animals↗

PubMedDate not supplied

Induction of humoral immune response and protective immunity in chickens against Salmonella enteritidis after a single dose of killed bacterium-loaded microspheres.

Formalin-inactivated Salmonella enteritidis phage type 4 strain 119/95 (SE) was encapsulated in biodegradable poly (DL-lactide co-glycolic acid) PLGA; (65:35) microspheres by a modified water-in-oil-in-water (w/o/w) double-emulsion solvent extraction/evaporation technique. These SE-loaded microspheres (SE-MS) were porous and spherical in shape with diameters of 0.4-10 microm and 20-80 microm in two preparations. SE-MS were subsequently used to vaccinate specific-pathogen-free chickens in a single dose in order to investigate the potency of a single-dose vaccination in inducing immune responses and protective immunity. In Experiment 1, 4-wk-old chickens that were vaccinated intramuscularly with 20-80-microm SE-MS generated long lasting (over 6 mo) and persistently high serum anti-SE immunoglobulin (Ig)G antibody response. In Experiment 2, 2-wk-old chickens were vaccinated orally with 0.4-10-microm or intramuscularly with 20-80-microm SE-MS and challenged with 10(9) colony-forming units of homologous SE strain at 6 wk postvaccination. When challenged intramuscularly, one each of the orally vaccinated (n = 10) and the intramuscularly vaccinated birds (n = 10) showed clinical signs and death, whereas all of the nonvaccinated control birds (n = 12) were sick and 11 of them were killed. When challenge was via oral route, 26.1% of cloacal swabs and 24.0% of organs (liver, spleen, and cecum) collected from orally vaccinated birds (n = 35) were positive for SE, comparable to 27.9% of feces and 18.7% of organs from the intramuscularly vaccinated birds (n = 35). These figures were significantly lower than those for nonvaccinated birds (n = 30) from which 59.3% of feces and 44.0% of organs tested SE positive (P < 0.05). The humoral immune response was also determined after vaccination with a single dose. The intramuscular vaccination elicited higher serum IgG response than oral administration, but the latter elicited a significant intestinal mucosal IgA antibody response. This is the first evidence that chickens vaccinated with killed SE-loaded PLGA microspheres, intramuscularly and orally in a single dose, developed systematic and local immune responses, thereby conferring protective immunity.

Administration, Oral↗

PubMed2003

Peptide immunogens based on the envelope region of HIV-1 are recognized by HIV/AIDS patient polyclonal antibodies and induce strong humoral immune responses in mice and rabbits.

Peptide immunogens produced by novel synthesis techniques and based on envelope proteins have repeatedly proven successful in inducing anti-HIV and anti-SIV responses in addition to producing anti-peptide immunity [Vaccine 12 (8) (1994) 736; AIDS Res. Hum. Retroviruses 14 (9) (1998) 751; Vaccine (2002) 2680]. We report here the design and evaluation of synthetic peptide constructs mimicking the variability of the third variable (V3) loop, or representing the conservation of the CD4 region of HIV-1 envelope. Three peptides based on the V3 region of HIV-1 subtype C gp120 and designated multiple epitope immunogens (MEI) differ in that one was randomly branched containing a spacer (b-MEI-s), another conjugated to a tetrameric lysine core (MEIV3b(4)) and the third conjugated to poly-L-lysine (poly-L-MEI). The method of synthesis employed produced peptides that were either linear, dimeric or tetramerically branched thereby providing differing levels of conformation. In addition the peptides also differed in their levels of variability. A fourth peptide designated B138 was based on a conserved region of HIV-1 envelope. The aim of this work was to evaluate the effect of variability and level of conformation on the immunogenicity of variable region peptides (MEI's) when compared to that of a known immunogenic and conserved region peptide (B138). Anti-peptide humoral immunity induced in BALB/c mice and New Zealand White rabbits produced antigen-recognizing antibody titres of </=5000 in enzyme linked immunosorbent assays (ELISA) and stimulation indices (SI) of 7 in cell proliferation assays. Plasma polyclonal antibodies collected from HIV/AIDS patients (from South Africa, Botswana and Puerto Rico) recognized the peptide constructs at antibody titres of </=5000. As demonstrated by mouse, rabbit and human antibody and proliferation responses, the immunogenicity and antigenicity of the peptides varied, with MEIV3b(4) responding better than the other three, at times even surpassing the conserved region peptide B138.

AIDS Vaccines↗

PubMed1998

Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses.

The gene encoding the immunosuppressive cytokine viral interleukin-10 (vIL-10) was introduced into BALB/c (H-2d) vascularized cardiac allografts by perfusing the graft vasculature with DNA-liposome complexes, utilizing the experimental cationic lipid gamma AP DLRIE/DOPE and a plasmid encoding vIL-10 under the control of the HCMVie promoter. The DNA to lipid ratio and DNA dose were critical factors in obtaining optimal biologic effects. Gene transfer of vIL-10 with a 3:1 DNA to lipid weight ratio using 375 micrograms DNA significantly prolonged allograft survival in MHC-mismatched C57BL/6 (H-2b) recipients (16.00 days) compared with both unmodified allografts (8.14 days) and vIL-10 antisense controls (8.28 days). Enhanced graft survival was specific to vIL-10 expression since treatment with antisense plasmid or anti-vIL-10 monoclonal antibody (mAb) abrogated the effect. Prolonged survival was associated with a novel histology characterized by a moderate mononuclear infiltrate, edema, and diffuse fibrillar/collagen deposition in the interstitium. Despite these morphologic changes, myocytes remained viable and vessels were patent. Limiting dilution analysis revealed transient infiltration of IL-2 secreting, donor-reactive, helper T lymphocytes (HTL) and cytotoxic T lymphocytes (CTL) in vIL-10 expressing grafts on day 7, that decreased significantly by day 14. Similarly, vIL-10 gene transfer inhibited the accumulation of donor-specific HTL and CTL in the spleen, compared with antisense controls. Prolonged survival was also associated with a marked decrease in IgM and IgG alloantibody production, with little to no IgG isotype switching. These results show that viral IL-10 gene transfer inhibits graft rejection in a clinically relevant model by inhibiting donor-specific cellular and humoral immune responses.

Animals↗

PubMed2004

Low-level hepatitis C viremia and humoral immune response to NS4 in chronic hepatitis B virus-hepatitis C virus coinfection.

BACKGROUND: There is a limited amount of published data on the interference of hepatitis B virus (HBV) on hepatitis C virus (HCV). The aim of this study was to investigate the effect of concurrent HBV infection on serum titers of HCV RNA and HCV antibody profiles in chronic HCV infection. METHODS: The clinical and virological profiles (serum titers of HCV RNA, HCV genotypes and antibody profiles) of 25 patients with chronic HBV-HCV coinfection were compared with those of 25 age- and sex-matched patients with HCV infection alone. RESULTS: Among the 25 patients with HBV-HCV coinfection, only 3 were found hepatitis Be antigen (HBeAg) and HBV DNA positive by hybridization assays, and the other 11 were found HBV DNA positive by polymerase chain reaction. Genotype 1b was dominant in both HBV-HCV coinfection and HCV infection alone (64% versus 84%, P > 0.1). Patients with HBV-HCV coinfection had significantly lower alanine aminotransferase (ALAT) levels and inflammatory scores but higher fibrosis scores than those with HCV infection alone. Serum titers of HCV RNA were significantly lower in HBV-HCV coinfection than in HCV infection alone. The frequency and relative intensity of antibody response to core, E2/NS1, NS3, and NS5 showed no significant difference between the two groups, but antibody response to NS4 was diminished significantly in HBV-HCV coinfection. CONCLUSIONS: In HBV-HCV coinfection, serum levels of HBV DNA are usually low or undetectable. Concurrent HBV infection, however, could interfere with HCV replication and suppress antibody response to NS4. The biological significance of selective inhibition of humoral immune response to NS4 in HBV-HCV coinfection should be further studied.

DNA, Viral↗

PubMed2006

Deciphering CD30 ligand biology and its role in humoral immunity.

Ligands and receptors in the tumour necrosis factor (TNF) and tumour necrosis factor receptor (TNFR) superfamilies have been the subject of extensive investigation over the past 10-15 years. For certain TNFR family members, such as Fas and CD40, some of the consequences of receptor ligation were predicted before the identification and cloning of their corresponding ligands through in vitro functional studies using agonistic receptor-specific antibodies. For other members of the TNFR family, including CD30, cross-linking the receptor with specific antibodies failed to yield many clues about the functional significance of the relevant ligand-receptor interactions. In many instances, the subsequent availability of TNF family ligands in the form of recombinant protein facilitated the determination of biological consequences of interactions with their relevant receptor in both in vitro and in vivo settings. In the case of CD30 ligand (CD30L; CD153), definition of its biological role remained frustratingly elusive. Early functional studies using CD30L+ cells or agonistic CD30-specific antibodies logically focused attention on cell types that had been shown to express CD30, namely certain lymphoid malignancies and subsets of activated T cells. However, it was not immediately clear how the reported activities from these in vitro studies relate to the biological activity of CD30L in the more complex whole animal setting. Recently, results from in vivo models involving CD30 or CD30L gene disruption, CD30L overexpression, or pharmacological blockade of CD30/CD30L interactions have begun to provide clues about the role played by CD30L in immunological processes. In this review we consider the reported biology of CD30L and focus on results from several recent studies that point to an important role for CD30/CD30L interactions in humoral immune responses.

Animals↗