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PubMed1980

The comparative selectivity of adjuvants for humoral and cell-mediated immunity. I. Effect on the antibody response to bovine serum albumin and sheep red blood cells of Freund's incomplete and complete adjuvants, alhydrogel, Corynebacterium parvum, Bordetella pertussis, muramyl dipeptide and saponin.

A comparison was made of seven recognized adjuvants, Freund's incomplete and complete, alhydrogel, Corynebacterium parvum, Bordetella pertussis, muramyl dipeptide and saponin, administered with BSA or SRBC by the S.C. route of immunization. Strong selectivity as well as differences in potency were revealed in relation to these two antigens. Only FIA, FCA, alhydrogel and MDP promoted the primary response to 50 microgram of BSA, and FIA was significantly superior to FCA. Immunological memory to a low dose (0.5 microgram) of BSA, which did not evoke a primary response with any adjuvant, was potentiated by alhydrogel and by MDP and, relatively poorly, by FIA. Radioimmunoelectrophoresis showed that potentiation of the response with MDP was confined to IgG1, whereas alhydrogel, FIA and FCA stimulated both IgG1 and IgG2. Saponin was outstandingly the best adjuvant for both primary and secondary haemagglutinin responses to SRBC. Of the others, alhydrogel for the primary, and alhydrogel and B. pertussis for the secondary were active to a lesser degree. The results show that the relative potency of adjuvants differs markedly according to the antigen used, and suggest that saponin may be a particularly effective adjuvant for antigens in cell membranes.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2000

The critical role of Th1-dominant immunity in tumor immunology.

To investigate the precise role of antigen-specific Th1 and Th2 cells in tumor immunity, we developed a novel adoptive tumor-immunotherapy model using OVA-specific Th1 and Th2 cells and an OVA gene-transfected tumor. This therapeutic model demonstrated that both antigen-specific Th1 and Th2 cells had strong antitumor activity in vivo with distinct mechanisms. However, immunological memory suitable for the generation of tumor-specific cytotoxic T lymphocytes was induced only when tumor-bearing mice received Th1 cell therapy, but not Th2 cell therapy. Thus it was strongly suggested that Th1-dominant immunity is critically important for the induction of antitumor cellular immunity in vivo. We also proposed that several immunomodulating protocols using interleukin (IL)-12, IL-12 gene, the natural killer T cell ligand alpha-galactosylceramide, or Th1 cytokine-conditioned dendritic cells might be useful strategies for the induction of Th1-dominant immunity essential for the development of tumor-specific immunotherapy.

Animals↗
PubMed1978

Studies on the immune response to fixed antigens. III. Induction of helper function for antibody-dependent cellular cytotoxicity responses.

Heavy trinitrophenylated sheep red cells (TNP128SRC) and glutaraldehyde-treated SRC (G-SRC) could not induce cellular cytotoxicity against 51Cr-SRC. In contrast, the native antigen SRC could stimulate a cytolytic response against the radiolabeled homologous target cell. However, fixed SRC could stimulate a priming function that accelerated and augmented the secondary cytotoxic response to SRC. Such fixed antigens could stimulate a delayed-type hypersensitivity (DTHS) response also. Thus, the immunologic memory to the chemically modified antigen, as well as the DTHS response, are completely dissociated from the primary cytotoxic responses. The primary and the secondary cytotoxic responses that were developed in the spleens of the injected mice were mediated by antibody-dependent cellular cytotoxicity (ADCC), since the active supernatant that was released from the spleen cells could lyse the target cells in the presence of normal splenocytes. The active supernatant was identified as antibody. We suggest that B effector cells cytolyzed the antibody-coated target cells. Normal cells from nude mice could mediate the cytolytic process as efficiently as spleen cells from other strains of mouse. The results are discussed in terms of selective stimulation of T cell subpopulations.

Absorption↗
PubMed2001

IgG2a-mediated enhancement of antibody responses is dependent on FcRgamma+ bone marrow-derived cells.

Antibodies (Ab) administered in complex with antigens (Ag) have the capacity to regulate the out-coming specific immune response. Primary immunization with complexes of bovine serum albumin-2,4,6-trinitrophenyl (BSA-TNP) and immunoglobulin (Ig)G2a anti-TNP induced a significant enhancement of IgG1 and IgG2a BSA-specific Ab response compared to immunization with the Ag alone. Enhancement was absent in nude mice, demonstrating the requirement of T cells for this regulation. Secondary immunization with BSA alone in mice previously primed with BSA-TNP/IgG2a led to a dramatic increase of Ab production, showing that immune complexes are efficient inducers of immunological memory. IgG-mediated enhancement of Ab responses has previously been shown to be impaired in mice lacking FcgammaRI, FcgammaRIII and FcepsilonRI owing to gene targeting of the common FcRgamma subunit (FcRgamma-/-). Here we show that enhancement after immunization with BSA-TNP/IgG2a complexes is restored in irradiated FcRgamma-/- recipients transferred with wild-type (FcRgamma+/+) bone marrow (BM) cells. In contrast, no enhancement is seen in FcRgamma+/+ irradiated animals reconstituted with FcRgamma-/- BM cells. We conclude that IgG2a-mediated enhancement of Ab responses is dependent on the presence of FcgammaRI and/or FcgammaRIII on BM-derived cells and that the presence of these receptors on the radioresistant follicular dendritic cell is not essential.

Animals↗
PubMed1999

Long term immune response of universal hepatitis B vaccination in infancy: a community-based study in Taiwan.

OBJECTIVES: To evaluate the long term immunity provided by a universal hepatitis B vaccination program in infancy and the booster effect on school age children who had no protective antibody titers to hepatitis B surface antigen. METHODS: We conducted a community-based seroepidemiologic study of 1337 healthy 7-year-old children in Taiwan one decade after the implementation of a mass hepatitis B vaccination program. A booster vaccination was suggested for noncarrier children who did not have protective titers of surface antibody. Serologic responses and infection rates were compared with those of the nonboostered children. In a nonselected group of 39 volunteer noncarrier vaccinees, quantitative serologic response was determined before, 1 month after a booster vaccination and 1 year later. RESULTS: A total of 572 children (42.8%) had low concentrations of surface antibody, and 9 were hepatitis B surface antigen carriers (0.7%). Eighty-two percent of "nonprotected" vaccinees showed immunologic memory to a booster dose and developed protective antibody titers 1 month later; 60.6% maintained protective titers 1 year later. The frequency of new hepatitis B virus infection was similar for those who received a booster and those who did not as investigated by the core antibody seroconversion during 1-year follow-up. However, the risk was low, with annual incidences of <1% in both groups, and none became chronic carriers. CONCLUSION: According to these data a universal vaccination program in infancy provides adequate protection against hepatitis B virus infection for school age children and a booster vaccination is not recommended.

Child↗
PubMed1981

Theoretical and practical considerations in the application of killed poliovirus vaccine for the control of paralytic poliomyelitis.

This paper contains a summary of the principles upon which the preparation and use of killed poliovirus vaccine (KPV) are based, as well as a summary of earlier and more recent work suggesting the feasibility of formulating a KPV preparation that would be fully and durably effective in a one- or two-dose regimen. The essential factor in the preparation of such a vaccine is the inclusion of a sufficient mass of the immunizing antigen, for each of the three antigenic types of poliovirus, to induce the formation of humoral antibody and/or immunologic memory after the first dose. The results of a series of studies carried out in West African and Scandinavian countries are summarized, which suggest that such a vaccine should contain 40, 8, and 32 D-antigen units for types I, II and III, respectively. If the D-antigen unit measurement is to be used as a guide to KPV standardization, the details of the method of manufacture are important; in this regard, the method of vaccine preparation used at the Rijks Instituut voor de Volksgezondheid should serve as a reference standard for the preparation of vaccines expected to produce the effects described.

Antibody Formation↗
PubMed2000

A targeted DNA vaccine encoding fas ligand defines its dual role in the regulation of experimental autoimmune encephalomyelitis.

This study used naked DNA vaccination to induce breakdown of tolerance to self and thus elicit immunological memory to native, membrane-bound Fas ligand (FasL). Upon induction of experimental autoimmune encephalomyelitis (EAE), this memory was turned on to provide protective immunity. FasL-specific autoantibodies isolated from protected animals differentially downregulated the in vitro production of TNF-alpha, but not IFN-gamma, by cultured T cells. These autoantibodies were highly protective when they were administered to rats at the onset of EAE. In contrast, administration of these FasL-specific Ab's to EAE rats after the peak of the acute phase of disease prevented spontaneous recovery from disease. This extended illness is partially explained by inhibition of mononuclear cell apoptosis at the target organ, which resulted in increased accumulation of T cells and macrophages at the site of inflammation. Hence, FasL exerts two distinct, stage-specific regulatory functions in the control of this T-cell mediated autoimmune disease of the central nervous system.

Animals↗
PubMed1976

Specific allograft reactivity in the sea star Dermasterias imbricata.

Transplantation studies with the sea star Dermasterias imbricata revealed that this echinoderm rejected most first-set allografts after prolonged chronic reactions. All control autografts remained intact and fully viable. The greatly accelerated rejection of subsequent second- and third-set allografts demonstrated that these reactions were not only highly specific, but that these animals possess at least short-term immunological memory. The specific nature of the allograft response was confirmed by the prolonged survival of unrelated third party allografts placed at the same time as second- or third-set allografts. Animals in these experiments were maintained in sea water at temperatures of 14-16 C. Since this low temperature is required for successful maintenance of this species, temperature-dependence studies could not be undertaken. The rejection reaction was characterized by loss of pigmentation, edematous swelling, and necrosis. Histologically, the allograft tissue was heavily infiltrated by lymphocyte-like cells and phagocytic cells, causing disruption of the normal cytoarchitecture of the dermis. Deposits of fibrous material were also in evidence. Autografts, on the other hand, remained fully viable with no signs of rejection. We conclude that this asteroid, a representative of the echinoderms, has a well-developed, cell-mediated immune response analogous to that of vertebrates.

Animals↗
PubMed1987

Prior exposure to subimmunogenic amounts of some bacterial lipopolysaccharides induces specific immunological unresponsiveness.

Pretreatment (priming) of BALB/c mice with a low (subimmunogenic) dose of Escherichia coli O113 lipopolysaccharide (LPS) generates immunological memory 7 to 30 days later; the direct (immunoglobulin M) plaque-forming cell (PFC) responses produced after subsequent immunization with an optimal dose are 4 to 20 times greater than those of unprimed mice. By contrast, priming with a low dose of E. coli O55 LPS, followed by immunization with an optimally immunogenic dose 2 to 30 days later, resulted in a significantly reduced antibody response. Similar results were obtained with Serratia marcescens LPS. Dose-response studies indicated that such unresponsiveness is antigen specific and could be induced with subimmunogenic amounts of LPS. Priming reduced the magnitude of the PFC response to all immunizing doses of LPS tested. Unresponsiveness is not due to (i) an alteration in the time course of the PFC response or to (ii) a change in the isotype of the anti-LPS antibody produced after priming and immunization.

Animals↗
PubMed2006

Differential usage of cellular niches by cytomegalovirus versus EBV- and influenza virus-specific CD8+ T cells.

Immunological memory provides long-term protection against reinfection or reactivation of pathogens. Murine memory T cell populations may be compressed following infections with new pathogens. Humans have to retain memory T cells directed against a variety of microbes for many decades. Under these circumstances, the effect of pathogens that mount robust T cell reactivity on the pre-existing memory directed against unrelated microbes is unknown. In this study, we studied peripheral blood memory CD8+ T cells directed against different viruses following primary CMV infection in renal transplant recipients. The entrance of CMV-specific CD8+ T cells expanded the Ag-primed CD8+ T cell compartment rather than competing for space with pre-existing memory T cells specific for persistent or cleared viruses. Neither numbers nor phenotype of EBV- or influenza-specific CD8+ T cells was altered by primary CMV infection. CMV-specific CD8+ T cells accumulated over time, resulting in increased total CD8+ T cell numbers. Additionally, they acquired a highly differentiated cytolytic phenotype that was clearly distinct from EBV- or influenza-reactive T cells. Thus, the human immune system appears to be flexible and is able to expand when encountering CMV. In view of the phenotypic differences between virus-specific T cells, this expansion may take place in cellular niches different from those occupied by EBV- or influenza-specific T cells, thereby preserving immunity to these pathogens.

Adolescent↗
PubMed2001

Experimental preemptive immunotherapy of murine cytomegalovirus disease with CD8 T-cell lines specific for ppM83 and pM84, the two homologs of human cytomegalovirus tegument protein ppUL83 (pp65).

CD8 T cells are the principal antiviral effectors controlling cytomegalovirus (CMV) infection. For human CMV, the virion tegument protein ppUL83 (pp65) has been identified as a source of immunodominant peptides and is regarded as a candidate for cytoimmunotherapy and vaccination. Two sequence homologs of ppUL83 are known for murine CMV, namely the virion protein ppM83 (pp105) expressed late in the viral replication cycle and the nonstructural protein pM84 (p65) expressed in the early phase. Here we show that ppM83, unlike ppUL83, is not delivered into the antigen presentation pathway after virus penetration before or in absence of viral gene expression, while other virion proteins of murine CMV are processed along this route. In cytokine secretion-based assays, ppM83 and pM84 appeared to barely contribute to the acute immune response and to immunological memory. Specifically, the frequencies of M83 and M84 peptide-specific CD8 T cells were low and undetectable, respectively. Nonetheless, in a murine model of cytoimmunotherapy of lethal CMV disease, M83 and M84 peptide-specific cytolytic T-cell lines proved to be highly efficient in resolving productive infection in multiple organs of cell transfer recipients. These findings demonstrate that proteins which fail to prime a quantitatively dominant immune response can nevertheless represent relevant antigens in the effector phase. We conclude that quantitative and qualitative immunodominance are not necessarily correlated. As a consequence of these findings, there is no longer a rationale for considering T-cell abundance as the key criterion for choosing specificities to be included in immunotherapy and immunoprophylaxis of CMV disease and of viral infections in general.

Adoptive Transfer↗
PubMed2001

Ultraviolet a radiation suppresses an established immune response: implications for sunscreen design.

The ultraviolet radiation present in sunlight is the primary cause of nonmelanoma skin cancer and has been implicated in the development of cutaneous malignant melanoma. In addition, ultraviolet is immune suppressive and the suppression induced by ultraviolet radiation has been identified as a risk factor for skin cancer induction. Ultraviolet also suppresses the immune response to infectious agents. In most experimental models, ultraviolet is applied to immunologically naive animals prior to immunization. Of equal concern, however, is the ability of sunlight to suppress established immune reactions, such as the recall reaction in humans, which protects against microbial infections. Here we demonstrate that solar-simulated ultraviolet radiation, applied after immunization, suppresses immunologic memory and the elicitation of delayed-type hypersensitivity. Further, we found that wavelengths in the ultraviolet A region of the solar spectrum were critical for inducing immune suppression. Ultraviolet A (320-400 nm) radiation was as effective as solar-simulated ultraviolet A + B (290-400 nm) in suppressing the elicitation of an established immune response. Irradiation with ultraviolet AI (340-400 nm) had no effect. Supporting a critical role for ultraviolet A in ultraviolet-induced immune suppression was the observation that applying a sunscreen that contained an ultraviolet B only filter had no protective effect, whereas, a sunscreen containing both ultraviolet A and ultraviolet B filters totally blocked ultraviolet-induced immune suppression. These data suggest that sunlight may depress the protective effect of prior vaccination. In addition, the observation that ultraviolet A is immunosuppressive indicates the need for ultraviolet A protection when designing sun protection strategies.

Animals↗
PubMed1994

Effect of carrier protein priming on antibody responses to Haemophilus influenzae type b conjugate vaccines in infants.

OBJECTIVE: To assess the effect of priming with diphtheria and tetanus toxoid vaccine (DT) at 1 month of age on the anticapsular polyribosylribitol phosphate (PRP) antibody responses of infants vaccinated with Haemophilus influenzae type b polysaccharide-tetanus toxoid conjugate (PRP-T) or PRP oligosaccharide-cross-reactive mutant diphtheria toxin conjugate (HbOC). DESIGN: Randomized controlled trial with serum samples assayed blindly. PARTICIPANTS AND SETTING: Healthy infants enrolled in private pediatric practices; 94 (91%) of 103 infants had prevaccination and postvaccination serum samples available for analysis. INTERVENTIONS: Two groups received DT vaccination at 1 month of age and subsequent injections of PRP-T or HbOC conjugate vaccines at 2, 4, and 6 months of age. The control groups were not vaccinated with DT but received PRP-T or HbOC at the same ages as the carrier-primed groups. Infants in all groups were given a booster injection of unconjugated PRP at 12 months of age to assess induction of immunologic memory. MAIN OUTCOME MEASURE: Concentrations of serum antibody to PRP. MAIN RESULTS: The DT-primed infants given PRP-T had twofold to threefold higher geometric mean anti-PRP antibody responses after one (P < or = .01), two (P < or = .01), or three (P = .06) doses of conjugate vaccine than the infants of the unprimed group. The primed infants also had threefold higher memory antibody responses to the booster PRP injection given at 12 months of age (concentration of 24.4 vs 8.4 micrograms/mL in infants not primed with DT; P < .01). The DT-primed infants given HbOC had twofold to threefold higher antibody responses after one (P = .07) or two (P < .01) doses of conjugate vaccine than the unprimed HbOC group, but there were no significant differences after the third dose of conjugate vaccine or after the PRP booster injection. CONCLUSIONS: Vaccination with DT at 1 month of age increases the magnitude of the anti-PRP antibody responses to conjugate vaccination. With HbOC, the effect of carrier priming was present for up to 6 months of age, whereas in infants vaccinated with PRP-T, enhanced immunity was present for at least 12 months.

Antibodies, Bacterial↗
PubMed2001

Ehrlich ascites tumor cells expressing anti-sense glutaminase mRNA lose their capacity to evade the mouse immune system.

Glutaminase (EC 3.5.1.2) is a key enzyme in rapidly proliferating cells. Using anti-sense technology, an Ehrlich ascites tumor cell line (0.28AS-2) with reduced glutaminase activity has been obtained. We investigated the in vivo growth characteristics of the 0.28AS-2 cells. When injected i.p. into normal Swiss albino mice, the 0.28AS-2 cells were unable to grow. On the contrary, when injected into nude mice, they developed into solid tumors. Mice inoculated with 0.28AS-2 cells kept immunologic memory and rejected a second inoculation with parental Ehrlich ascites tumor cells. Expression of both polymorphic epithelial mucin-1 (MUC-1) and the enzyme N-acetyl-alpha-D-galactosaminidase, proteins implicated in host immune system escape, were markedly diminished in 0.28AS-2 cells. Study of the immune system response in mice inoculated with 0.28AS-2 cells revealed an increase in splenic CD18 cells and the presence of a large number of activated F4/80+ macrophages in the ascites cavity. These features, not observed in mice inoculated with parental Ehrlich ascites tumor cells, indicate that a distinctive, strong immune response occurred in animals inoculated with 0.28AS-2 cells. Our results suggest that inhibition of glutaminase expression using anti-sense technology induces phenotypic changes in Ehrlich ascites tumor cells that allow the development of an effective anti-tumor immune response, which makes the cells unable to develop in vivo tumors.

Animals↗
PubMed1995

Immunologic priming by one dose of Haemophilus influenzae type b conjugate vaccine in infancy.

Immunogenicity of one dose of Haemophilus influenzae type b (Hib) conjugate vaccine in infancy and its ability to induce immunologic memory was studied in infants immunized at 4 and 14 months with either PRP-OMP (Hib polysaccharide conjugated with Neisseria meningitidis group B outer membrane protein complex) or PRP-T (Hib polysaccharide-tetanus toxoid conjugate) and compared with three doses of the same vaccines at 4, 6, and 14 months. Each group received diphtheriatetanus-pertusis vaccine at 3, 4, and 5 months of age. At 7 months of age, both vaccines were immunogenic after one dose, even though higher antibody concentrations were achieved after two doses. A booster dose given at 14 months resulted in a high antibody concentration and a strongly IgG-dominated isotype distribution, speaking for a secondary-type response in all groups, including those who had received only one dose in infancy. Subsequent persistence of antibodies suggestive of full protection for up to 36 months was similar in all groups.

Age Factors↗
PubMed2001

On natural and artificial vaccinations.

This review summarizes the general parameters of cell- and antibody-mediated immune protection and the basic mechanisms responsible for what we call immunological memory. From this basis, the various successes and difficulties of vaccines are evaluated with respect to the role of antigen in maintaining protective immunity. Based on the fact that in humans during the first 12-48 months maternal antibodies from milk and serum protect against classical acute childhood and other infections, the concept is developed that maternal antibodies attenuate most infections of babies and infants and turn them into effective vaccines. If this "natural vaccination" under passive protective conditions does not occur, acute childhood diseases may be severe, unless infants are actively vaccinated with conventional vaccines early enough, i.e., in synchronization with the immune system's maturation. Although vaccines are available against the classical childhood diseases, they are not available for many seemingly milder childhood infections such as gastrointestinal and respiratory infections; these may eventually trigger immunopathological diseases. These changing balances between humans and infections caused by changes in nursing habits but also in hygiene levels may well be involved in changing disease patterns including increased frequencies of certain autoimmune and degenerative diseases.

Animals↗
PubMed1984

Trypanosoma musculi and Trichinella spiralis: concomitant infections and selection for resistance genotypes in mice.

Trypanosoma musculi infections were given to mice of different strains before, at the same time, and after an infection with 400 Trichinella spiralis. Examined parameters of the host response to T. spiralis were worm rejection, antifecundity responses, development of immunological memory, and muscle larvae burden. After dual infection, each mouse strain showed characteristic effects on resistance to T. spiralis. This was due to a dynamic interaction between the genes controlling rejection of T. spiralis and those influencing T. musculi growth. C3H mice develop high trypanosome parasitemias. This impairs worm expulsion and the development of memory to T. spiralis when Trypanosoma infections take place on the same day or 7 days before. The C57B1/6 mouse develops low parasitemias and T. musculi infections on the same day, or 7 days before T. spiralis, delaying worm rejection only slightly despite the overall weak capacity of B6 mice to expel worms. NFR-strain mice are strong responders to T. spiralis and also develop low parasitemias. Trypanosome infections on the same day, or after T. spiralis, produce a delay in worm rejection; the former is comparable to C3H mice. However, NFR mice alone showed enhanced rejection of worm when T. musculi infections preceded T. spiralis by 7 days. An unusual feature of C3H mice was that T. musculi infections 7 days before T. spiralis increased antifecundity responses at the same time that worm expulsion was inhibited. Trypanosome infections can therefore modulate distinct antihelminth immune responses in different directions simultaneously. The different outcomes of dual infections compared with single infections provides another selective mechanism by which genetic polymorphisms can be established and maintained in the vertebrate host.

Animals↗
PubMed2006

Mechanisms of gastrointestinal CD4+ T-cell depletion during acute and early human immunodeficiency virus type 1 infection.

During acute and early human immunodeficiency virus type 1 (HIV-1) infection (AEI) more than 50% of CD4+ T cells are preferentially depleted from the gastrointestinal (GI) lamina propria. To better understand the underlying mechanisms, we studied virological and immunological events within the peripheral blood (PB) and GI tract during AEI. A total of 32 AEI subjects and 18 uninfected controls underwent colonic biopsy. HIV-1 viral DNA and RNA levels were quantified in CD4+ T cells derived from the GI tract and PB by using real-time PCR. The phenotype of infected cells was characterized by using combinations of immunohistochemistry and in situ hybridization. Markers of immunological memory, activation, and proliferation were examined by flow cytometry and immunohistochemistry, and the host-derived cytotoxic cellular response was examined by using immunohistochemistry. GI CD4+ T cells harbored, on average, 13-fold higher HIV-1 viral DNA levels and 10-fold higher HIV-1 RNA levels than PB CD4+ T cells during AEI. HIV-1 RNA was detected in both "activated" and "nonactivated" mucosal CD4+ T cells. A significantly higher number of activated and proliferating T cells were detected in the GI tract compared to the PB, and a robust cytotoxic response (HIV-1 specificity not determined) was detected in the GI tract as early as 18 days postinfection. Mucosal CD4+ T-cell depletion is multifactorial. Direct viral infection likely accounts for the earliest loss of CD4+ T cells. Subsequently, ongoing infection of susceptible CD4+ T cells, along with activation-induced cellular death and host cytotoxic cellular response, are responsible for the persistence of the lesion.

Acute Disease↗