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Dietary fat affects immune response, production of antiviral factors, and immune complex disease in NZB/NZW mice.

Autoimmune-prone (NZB x NZW)F1 (B/W) mice fed three nearly isocaloric diets with varied fat content showed a marked difference in their spontaneous development of immune complex disease and their immune response. Those animals received the diets high in either unsaturated or saturated fats had more severe immune complex nephritis and died earlier than mice on the low-fat diet. Endogenous production of the mouse xenotropic virus was unaffected by dietary fats, but the serum lipoproteins associated with antiviral activity were increased to levels as high as 1:600,000 in the B/W mice on the high-fat diets. These lipoproteins may be partially responsible for the decreased mitogenic response of spleen cells from mice fed the two high-fat diets. The mice receiving a diet high in saturated fats produced substantially higher titers of natural thymocytotoxic autoantibody, an IgM class of antibody, than did the mice maintained either on the high-unsaturated-fat or low-fat diet. In contrast, the mice receiving the diet high in unsaturated fats made significantly greater levels of antibodies to double-stranded DNA, an IgG, than did the mice kept on the two other diets. These results suggest that the type of fat in the diet could affect the serum level of different immunoglobulin classes. The data provide further evidence that the amount of dietary lipids alone can influence cellular and humoral immune responses and the spontaneous development of immune complex disease.

Animals↗

Polyclonal antibodies from patients immunized with a globo H-keyhole limpet hemocyanin vaccine: isolation, quantification, and characterization of immune responses by using totally synthetic immobilized tumor antigens.

We have previously reported on a carbohydrate-based vaccine program for immunotherapy in cancer patients. One such vaccine, based on the globo H antigen conjugated to the protein keyhole limpet hemocyanin (KLH), has been in clinical evaluation. Although this and other carbohydrate vaccines have been shown to induce antibody responses, there are currently no quantitative data on the antibody levels achieved in immunized patients by these or other anti-cancer vaccines. We report herein an efficient route to complex synthetic oligosaccharides attached to an affinity matrix for identifying and isolating antibodies elicited against such a carbohydrate-based vaccine in humans. Pre- and postvaccination profiles from serum samples of patients immunized with globo H-KLH were compared. All anti-globo H antibody activity was efficiently separated from other serum constituents. The isolated antibodies were readily quantified, and their specificities were analyzed. Since no comparable data were available on antibodies resulting from the vaccination of other cancer patients, we compared the observed levels with those quoted in studies with bacterial polysaccharide vaccines that had been quantified. Remarkably, cancer patients immunized with globo H-KLH produce anti-globo H antibody levels often exceeding those formed by immunization with bacterial polysaccharides. In addition, substantial quantities of both IgG and IgM antibodies were elicited, clearly indicating a class switch to IgG. Taken together, these analyses serve to clarify several aspects of the immune response to the vaccine and give several new insights to the carbohydrate-based vaccination strategy. Furthermore, antibodies so isolated could well have applications in clinical therapy.

Antibodies↗

Induction of cellular immunity by immunization with novel hybrid peptides complexed to heat shock protein 70.

Heat shock proteins 70 (hsp70) derived from tissues and cells can elicit cytotoxic T lymphocyte (CTL) responses against peptides bound to hsp70. However, peptides can markedly differ in their affinity for hsp, and this potentially limits the repertoire of peptides available to induce CTL by the hsp immunization. Hybrid peptides consisting of a high-affinity ligand for the peptide-binding site of hsp70 joined to T cell epitopes by a glycine-serine-glycine linker were constructed. Immunization with hybrid peptides complexed to mouse hsp70 effectively primed specific CTL responses in mice and were more potent than T cell peptide epitopes alone with hsp70. In vivo immunization with hsp70 and hybrid peptides led to rejection of tumors expressing antigen with greater efficacy than immunization with peptide epitope plus hsp70. Induction of CTL responses occurred independently of CD4(+) T cells, suggesting that immunization directly primed antigen-presenting cells to elicit CD8(+) cytotoxic T cell responses without T cell help. Both peptide/hsp70 complexes and mouse hsp70 alone were able to induce cultures of mouse bone marrow-derived dendritic cells (DC) to release cytokines, including DC from endotoxin-resistant C57BL/10Sc mice. Thus, hsp70/hybrid peptide complexes can activate DC for cytokine release, providing a potential adjuvant effect that could bypass T cell help.

Animals↗

Heterologous immunity in rodent malaria: comparison of the degree of cross-immunity generated by vaccination with that produced by exposure to live infection.

The degree of heterologous immunity occurring between the different rodent malarias was examined. Mice immunized with a killed vaccine consisting of formalin-fixed blood-stage parasites mixed with saponin, were challenged with homologous or heterologous parasites and the degree of protection assessed by monitoring the number of survivors and the duration and severity of parasitaemia. The results indicated that vaccination conferred strong cross-protection between two different Plasmodium yoelii lines and also some cross-protection between different species. The most significant inter-species cross-immunity was in P. berghei-vaccinated mice challenged with P. yoelii (33% survival rate) and in P. vinckei-vaccinated mice challenged with P. chabaudi (50% survival rate). The protection operated only in one direction since mice vaccinated against P. yoelii or P. chabaudi were fully susceptible to P. berghei and P. vinckei respectively, although extension of the survival time did occur in both cases. Significantly greater levels of homologous and heterologous immunity occurred in vaccinated mice which had cleared a primary homologous infection. All recovered animals were fully resistant to homologous secondary challenges. P. berghei-recovered mice had complete resistance to a secondary P. yoelii challenge, with partial resistance also to P. vinckei and P. chabaudi: P. vinckei-recovered mice were completely resistant to P. chabaudi challenge and showed partial resistance to P. berghei (50% survival rate). Conversely, no reduction in mortality occurred in P. chabaudi-recovered mice challenged with any heterologous parasite. Plasmodium yoelii-recovered animals were fully susceptible to P. vinckei but showed some resistance to P. berghei and P. chabaudi (33 and 17% survival respectively). Many lesser instances of cross-resistance were observed in the present study and are discussed in the text but they were not sufficiently powerful to reduce mortality. The present study provides the first reported comprehensive investigation on cross-resistance in rodent malarias generated by a killed vaccine. In addition this is the only complete cross-resistance study available which has concentrated exclusively upon highly lethal strains of each parasite species. Taken with the rechallenge experiments, the results extend, and to a certain point confirm, previous observations on cross-immunity in the rodent malarias. However, several of the present results conflict with previous reports and these are discussed in relation to the relevant literature.

Animals↗

Potent immune response against HIV-1 and protection from virus challenge in hu-PBL-SCID mice immunized with inactivated virus-pulsed dendritic cells generated in the presence of IFN-alpha.

A major challenge of AIDS research is the development of therapeutic vaccine strategies capable of inducing the humoral and cellular arms of the immune responses against HIV-1. In this work, we evaluated the capability of DCs pulsed with aldrithiol-2-inactivated HIV-1 in inducing a protective antiviral human immune response in SCID mice reconstituted with human PBL (hu-PBL-SCID mice). Immunization of hu-PBL-SCID mice with DCs generated after exposure of monocytes to GM-CSF/IFN-alpha (IFN-DCs) and pulsed with inactivated HIV-1 resulted in a marked induction of human anti-HIV-1 antibodies, which was associated with the detection of anti-HIV neutralizing activity in the serum. This vaccination schedule also promoted the generation of a human CD8+ T cell response against HIV-1, as measured by IFN-gamma Elispot analysis. Notably, when the hu-PBL-SCID mice immunized with antigen-pulsed IFN-DCs were infected with HIV-1, inhibition of virus infection was observed as compared with control animals. These results suggest that IFN-DCs pulsed with inactivated HIV-1 can represent a valuable approach of immune intervention in HIV-1-infected patients.

AIDS Vaccines↗

Long-term efficacy and immune responses following immunization with the RTS,S malaria vaccine.

The malaria sporozoite vaccine candidate RTS,S, formulated with an oil-in-water emulsion plus the immunostimulants monophosphoryl lipid A and the saponin derivative QS21 (vaccine 3), recently showed superior efficacy over two other experimental formulations. Immunized volunteers were followed to determine the duration of protective immune responses. Antibody levels decreased to between one-third and one-half of peak values 6 months after the last dose of vaccine. T cell proliferation and interferon-gamma production in vitro were observed in response to RTS,S or hepatitis B surface antigen. Seven previously protected volunteers received sporozoite challenge, and 2 remained protected (1/1 for vaccine 1, 0/1 for vaccine 2, and 1/5 for vaccine 3). The prepatent period was 10.8 days for the control group and 13.2 days for the vaccinees (P < .01). Immune responses did not correlate with protection. Further optimization in vaccine composition and/or immunization schedule will be required to induce longer-lasting protective immunity.

Adolescent↗

T cell immunity to measles viral proteins in infants and adults after measles immunization.

Vaccination of infants against measles remains of global importance, and proposed new vaccine strategies include the use of measles proteins or synthetic peptides as immunogens. We studied cell-mediated immunity to whole measles antigen and measles proteins in immune adults and infants after measles vaccine. Further, we measured CD8+ T cell responses to peptide pools corresponding to the nucelocapsid (N) measles protein in adults given measles vaccine. Cell-mediated immune responses to three of four measles proteins were equivalent to those against whole measles antigen in immune adults. Responses to the fusion (F) protein were lower in infants compared to whole measles antigen (p < or = 0.03). Infant responses to both whole measles antigen and the F protein were lower compared with these responses in adults (p < or = 0.001). CD8+ T cell responses to N peptide pools varied, and differed between immune HLA-A2-positive individuals compared with naive and HLA-A2-negative subjects after measles vaccination. The measles-specific T cell adaptive response of infants is limited compared to adults, including responses to the F protein.

Adult↗

Parasitic infection and the polarized Th2 immune response can alter a vaccine-induced immune response.

The AIDS epidemic in the Developing World represents a major global crisis. It is imperative that we develop an effective vaccine. Vaccines are economically the most efficient means of controlling viral infections. However, the development of a vaccine against HIV-1 has been a formidable task, and in developing countries chronic parasitic infection adds another level of complexity to AIDS vaccine development. Helminthic and protozoan infections, common in developing countries, can result in a constant state of immune activation that is characterized by a dominant Th2 type of cytokine profile, high IgE levels, and eosinophilia. Such an immune profile may have an adverse impact on the efficacy of vaccines, in particular, an HIV-1 vaccine. Indeed, the CD8 cellular immune response and the corresponding Th1 type cytokines that enhance the CD8 cellular immune response are important for clearing many viral infections. It is believed that an antigen specific CD8 cellular immune response will be an important component of an HIV-1 vaccine.

AIDS Vaccines↗

Humoral immune responses in healthy heterosexual, homosexual and vasectomized men and in homosexual men with the acquired immune deficiency syndrome.

In homosexual men, the acquired immune deficiency syndrome (AIDS) is associated with sexual promiscuity and the appearance of circulating immune complexes (CICs) and antibodies to spermatozoa which crossreact with lymphoid cells. A comparative study was initiated to determine whether similar humoral responses existed in 38 heterosexual men lacking sperm antibodies, 13 heterosexuals with sperm antibodies, 42 heterosexual vasectomized men, 22 healthy homosexual men, 26 homosexuals with lymphadenopathy and 16 with AIDS or Kaposi's sarcoma (KS). Sperm antibodies were detected in 12% of the vasectomized heterosexual men, 23% of the healthy homosexuals, 35% of the lymphadenopathy patients and 44% of the men with KS-AIDS. IgG reactive with peripheral blood T lymphocytes was present in only 3% of heterosexuals lacking sperm antibody and 5% of vasectomized men. In contrast, 23% of heterosexuals with sperm antibody, 36% of healthy homosexuals, 31% of men with lymphadenopathy and 62% of KS-AIDS patients were positive in this assay. Antibodies to the neutral glycolipid asialo GM1 were found in none of the vasectomized men, 3% of the heterosexuals without and 8% with sperm antibodies, 17% of healthy homosexuals and 38% and 31% in patients with lymphadenopathy or KS-AIDS, respectively. Lastly, the incidence of CICs, determined by the Raji cell assay, was 0% in vasectomized men, 3% in heterosexuals lacking sperm antibody, 31% in heterosexuals with sperm antibody, 69% in healthy homosexuals, 81% in lymphadenopathy patients and 87% in KS-AIDS. In the homosexuals with lymphadenopathy and KS-AIDS, levels of CICs, T cell-reactive IgG and asialo GM1 antibody were positively correlated (p less than 0.01). Sperm antibody levels were negatively correlated (p less than 0.01) with CICs levels and T cell reactive IgG in heterosexuals and lymphadenopathy and KS-AIDS patients. The results demonstrate that vasectomized men do not manifest at all, and that non-vasectomized heterosexuals with sperm antibodies manifest to a much lesser extent the range of humoral immune responses exhibited by the three homosexual groups. Thus, the route of sperm immunization and/or exposure to autologous vs. heterologous spermatozoa may be of critical importance for eliciting specific immune responses.

Acquired Immunodeficiency Syndrome↗

Cross-clade immune responses after immunization with a whole-killed gp120-depleted human immunodeficiency virus type-1 immunogen in incomplete Freund's adjuvant (HIV-1 immunogen, REMUNE) in human immunodeficiency virus type-1 seropositive subjects.

Lymphocyte proliferation responses to gp120-depleted HZ321 virus (clade A) antigen were compared to BAL human immunodeficiency virus (HIV) virus antigen (clade B) responses, clade E HIV virus antigen responses, and purified native p24 antigen responses in 15 human immunodeficiency virus type-1 (HIV-1) seropositive subjects immunized with a whole-killed inactivated gp120-depleted HIV-1 antigen in Incomplete Freund's adjuvant (HIV-1 immunogen, REMUNE). A significant increase in lymphocyte proliferation to HZ321 antigen was observed after immunization with the HIV-1 immunogen (p = 0.02). A strong association was demonstrated between the HIV-1 immunizing antigen, HZ321, and native p24 antigen responses (r = 0.80, p < 0.0001). Furthermore, a strong association in terms of proliferative responses was demonstrated between HZ321 virus (clade A) responses and BAL virus (clade B) (r = 0.95, p < 0.0001) and clade E virus antigen (r = 0.92, p < 0.0001). Proliferative responses to HIV antigens also correlated with baseline CD4 counts. Taken together, these results support the specificity of immune responses induced by REMUNE (HIV-1 immunogen). The development of cross-reactive immune responses between clades and to the more conserved epitopes of the virus have implications in the development of therapeutic and prophylactic HIV vaccines.

AIDS Vaccines↗

Immune restoration under HAART in patients chronically infected with HIV-1: diversity of T, B, and NK immune responses.

The aim of the study was to follow prospectively the humoral, cellular and innate immune responses under HAART and to verify if a functional restoration of the B lymphocytes could be evaluated by measuring the anti-HIV-1 IgG antibodies avidity index (AI). Eleven HIV-1 infected and immunosuppressed patients were included in the study. Viral load, naive and memory B-cells, CD4 and CD8 T-cells and NK-cells counts, and anti-HIV-1 IgG AI were determined during the follow-up (18 months). Ten patients were sustained responders under HAART and showed a quantitative restoration of the CD4 T-cell counts (+269 x 10(6)/L). The AI decreased for ten subjects (-11%, p = 0.006) but very slowly and continuously. A quantitative restoration of the humoral immune response began, mainly concerning the naive B-cells (+110 x 10(6)/L). Apart from one patient, the CD8 T-cell subset approached the reference values of healthy subjects either by decreasing or increasing their cell levels. No homogeneous evolution was described concerning the NK-cell subset, apart from trend towards increasing in patients with opportunistic infection (range, +58 to +291 x 10(6)/L). Our study, which evaluated simultaneously for the first time to our knowledge the cellular, humoral and innate immune responses showed that HAART induced a large diversity of immune restoration patterns in responder patients. However, the AI measure appears to be a weak marker to evaluate an immune restoration in chronic HIV-1 infected patients under HAART.

Adult↗

Immune-related conditions and immune-modulating medications as risk factors for non-Hodgkin's lymphoma: a case-control study.

In immunosuppressed or autoimmune disease states, disordered immune responses may lead to non-Hodgkin's lymphoma (NHL). In a US population-based case-control study of NHL (1998-2000), the authors collected personal histories of immune-related conditions and use of immune-modulating therapies as well as family histories of autoimmune conditions. The study included 1,321 NHL cases and 1,057 controls; only half received some questionnaire components. NHL was associated with Sjögren's syndrome (odds ratio (OR) = 13, 95% confidence interval (CI): 1.7, 100) and lupus (OR = 4.2, 95% CI: 1.2, 15). Two specific NHL subtypes were strongly associated with Sjögren's syndrome: salivary gland (OR = 290, 95% CI: 33, 2600) and marginal zone (OR = 75, 95% CI: 9.1, 610). NHL was less convincingly associated with receipt of an organ transplant (OR = 2.0, 95% CI: 0.4, 11). Other autoimmune conditions were too rare to evaluate or not associated with NHL. Corticosteroid use was unrelated to NHL (OR = 1.0, 95% CI: 0.8, 1.2), but methotrexate use was marginally associated (OR = 2.3, 95% CI: 0.7, 7.5). Family history of dermatomyositis was associated with NHL (7 cases vs. 0 controls, OR = infinite; two-sided p = 0.02), but dermatomyositis was absent in cases themselves. Family history of remaining conditions was unrelated to NHL. Results suggest that disordered immunity in some immune-related conditions can lead to NHL.

Adult↗

Regulatory T cells, a potent immunoregulatory target for CAM researchers: modulating tumor immunity, autoimmunity and alloreactive immunity (III).

Regulatory T (T(reg)) cells are the major arbiter of immune responses, mediating actions through the suppression of inflammatory and destructive immune reactions. Inappropriate T(reg) cell frequency or functionality potentiates the pathogenesis of myriad diseases with ranging magnitudes of severity. Lack of suppressive capability hinders restraint on immune responses involved in autoimmunity and alloreactivity, while excessive suppressive capacity effectively blocks processes necessary for tumor destruction. Although the etiology of dysfunctional T(reg) cell populations is under debate, the ramifications, and their mechanisms, are increasingly brought to light in the medical community. Methods that compensate for aberrant immune regulation may not address the underlying complications; however, they hold promise for the alleviation of debilitating immune system-related disorders. The dominant immunoregulatory nature of T(reg) cells, coupled with recent mechanistic knowledge of natural immunomodulatory compounds, highlights the importance of T(reg) cells to practitioners and researchers of complementary and alternative medicine (CAM).

Journal Article↗

Long-term immunity to poliovirus in children immunized with live attenuated and enhanced-potency inactivated trivalent poliovirus vaccines.

Eighty-six children who completed immunization with the two trivalent poliovirus vaccines, live attenuated (OPV) and enhanced potency inactivated (EIPV), in one of four schedules (OPV-OPV-OPV, EIPV-EIPV-EIPV, EIPV-OPV-OPV, and EIPV-EIPV-OPV) at 1 year of age were monitored serologically over the subsequent 4 years and challenged with OPV at 5 years of age. Each of the immunization groups exhibited an initial 10- to 100-fold decline in neutralizing antibody to poliovirus types 1, 2, and 3 during the first 2 years of follow-up; thereafter antibody titers stabilized. The EIPV-EIPV-OPV group maintained the highest antibody levels throughout the observation period, including the response to OPV challenge at 5 years of age. These data suggest that immunization with OPV, EIPV, and combinations of the two vaccines confers long-term immunity. Optimal systemic immunity was associated with two or more doses of EIPV.

Antibodies, Viral↗

Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger.

Stimulation of certain cytokine and pattern recognition receptors enhances adaptive immune responses, and in chronic situations, may play a role in the loss of self-tolerance. We hypothesized that in addition to upregulating positive immune receptors (i.e. co-stimulatory molecules), certain cytokine and pattern recognition signals might downregulate negative immune receptors, removing a potential barrier to lymphocyte responsiveness. The newly identified CD28 family member Programmed Death-1 (PD-1) is an inhibitory receptor involved in peripheral tolerance, as evidenced by the frank autoimmunity and autoantibody formation found in PD-1-deficient mice. Here we report that antigen-receptor induced PD-1 expression on murine B cells is markedly reduced by certain signals associated with immune system danger, including LPS, CpG oligodeoxynucleotides and several pro-inflammatory cytokines, through distinct signaling pathways. We further report for the first time that engagement of PD-1 inhibits cell cycle progression in primary B cells and that modulation of PD-1 expression by CpG or IL-4 significantly reverses such inhibition. Our data suggest a novel mechanism for enhancement of normal immune responses and disruption of normal tolerance mechanisms.

Animals↗

Murine immune responses and immunization against Polyplax serrata (Anoplura: Polyplacidae).

Mice with restricted grooming capabilities were infested with the solenophagous louse, Polyplax serrata (Burmeister). Louse burdens on Cox/Swiss and C3H/HeSN mice increased for approximately 1 mo, reaching burden/host weight ratios of 1.14 and 1.26 mg/g, respectively, followed by a steady decline. Fifty days after initial ectoparasite contact, both strains were resistant to lice. Resistance was anamnestic, lasting several months with second infestation weights reduced by 98 and 78% on Cox/Swiss and C3H/HeSN, respectively. Furthermore, mice were systemically resistant because infestations on naive body sites of resistant hosts were reduced by 59%. Host resistance was associated with the development of antilouse immune responses. After the first week of a primary infestation, the draining lymph nodes contained cells that proliferated in vitro to louse antigens. Skin responses to louse antigens were also detected: (1) delayed, (2) immediate and delayed, and (3) no significant reactivity on days 19, 34, and 54, respectively. The presence of systemic antilouse responses provided an immunologic basis for immunization against lice. Intradermal injections of soluble louse components reduced primary infestation weights by 62%. Immunized mice had immediate and delayed skin responses containing an inflammatory infiltrate 1 wk following immunization. This study, using the natural host of P. serrata, demonstrates an inducible, anamnestic immune component in louse resistance.

Animals↗

Reduced immune responses after vaccination with a recombinant herpes simplex virus type 1 vector in the presence of antiviral immunity.

Due to the continuous need for new vaccines, viral vaccine vectors have become increasingly attractive. In particular, herpes simplex virus type 1 (HSV-1)-based vectors offer many advantages, such as broad cellular tropism, large DNA-packaging capacity and the induction of pro-inflammatory responses. However, despite promising results obtained with HSV-1-derived vectors, the question of whether pre-existing virus-specific host immunity affects vaccine efficacy remains controversial. For this reason, the influence of pre-existing HSV-1-specific immunity on the immune response induced with a replication-defective, recombinant HSV-1 vaccine was investigated in vivo. It was shown that humoral as well as cellular immune responses against a model antigen encoded by the vaccine were strongly diminished in HSV-1-seropositive mice. This inhibition could be observed in mice infected with wild-type HSV-1 or with a replication-defective vector. Although these data clearly indicate that pre-existing antiviral host immunity impairs the efficacy of HSV-1-derived vaccine vectors, they also show that vaccination under these constraints might still be feasible.

Animals↗

Hepatitis B virus immunization with an adjuvant containing vaccine after liver transplantation for hepatitis B-related disease: failure of humoral and cellular immune response.

Long-term hepatitis B reinfection prophylaxis after liver transplantation with hepatitis B immunoglobulin (HBIG) and nucleoside analogues is expensive and inconvenient. Studies evaluating humoral immune responses to hepatitis B virus (HBV) vaccines showed conflicting results. Best results were achieved under continuous HBIG administration with an adjuvant-containing HBsAg vaccine. In the present study, 8 patients who had been HBsAg positive and HBV DNA negative prior to liver transplantation were immunized with HBsAg-vaccine containing the adjuvant 3-deacylated monophosphoryl-lipid-A. Vaccination was started after discontinuation of HBIG. Six vaccinations were administered at weeks 0, 2, 4, 12, 16 and 24. Humoral (anti-HBs titres) and cellular (enzyme-linked immunospot assay and fluorescence-activated cell sorting analysis) immune responses were studied. Only one of eight patients responded with a humoral immune response (maximum anti-HBs titre 561 U/l). In this patient, decrease of anti-HBs titre before vaccination was significantly slower than in the other seven patients and anti-HBs did not become negative before first vaccination. A T-cell response to HBsAg could not be detected in any of the patients. The responder was the only patient who showed a T-cell response to HBcAg. In conclusion, the adjuvant-containing vaccine did not induce a humoral or a detectable cellular immune response in most patients. Patient-related preconditions and concomitant HBIG administration should be further investigated as possible predictors for response.

Adjuvants, Immunologic↗