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PubMed1996

Response of human immunodeficiency virus-exposed and -infected infants to Haemophilus influenzae type b conjugate vaccine.

OBJECTIVE: To evaluate the response of human immunodeficiency virus (HIV)-infected and -exposed infants to the primary series and booster dose of Haemophilus influenzae type b (Hib) conjugate vaccine. DESIGN: Retrospective study. PATIENTS AND SETTING: The HIV-exposed and -infected infants who were attending the Special Immunology Family Clinic at The Children's Hospital of Philadelphia (Pa). MAIN OUTCOME MEASURES: Geometric mean antibody titers (GMTs) to Hib polyribosyl ribitol phosphate capsular antigen were assessed after the primary series and again after the 15-month booster doses. In addition, the percentages of patients who responded with polyribosyl ribitol phosphate antibody levels greater than both 0.15 and 1.0 mg/L were compared between groups. RESULTS: After the 3-dose primary series, the GMTs were lower in the HIV-infected infants compared with those in the HIV-exposed, uninfected infants (0.86 vs 2.30, P = .02). Forty-six percent of the HIV-infected infants mounted a response ( > 1.0 mg/L) compared with that in 79% of the HIV-exposed infants (P = .05). Among the HIV-infected infants, there was no difference in the GMTs based on CD4+ cell counts or HIV-related symptoms. After the 15-month booster dose, the GMTs were not significantly different in the HIV-infected and -exposed infants. As a group, the HIV-infected infants responded to the booster dose with a 2-fold increase in the GMTs, and significantly more of these infants had antibody concentrations above 1.0 mg/L compared with their response to the primary series (62% vs 38%, P = .02). CONCLUSIONS: Most of the HIV-infected infants responded to the primary series of Hib conjugate vaccine with antibody concentrations greater than 0.15 mg/L, but the GMTs were significantly lower than those in the uninfected infants. The primary series of Hib conjugate vaccine appeared to be capable of inducing specific immunologic memory in the HIV-infected infants. The HIV-infected infants had a significant response to a booster dose of Hib conjugate vaccine, as measured by using the GMTs and the percentage of infants with antibody concentrations greater than 1.0 mg/L. The duration of protective titers will need to be followed in this population of patients who are at a high risk for serious bacterial disease.

Antibodies, Bacterial↗
PubMed1998

DNA immunization in relB-deficient mice discloses a role for dendritic cells in IgM-->IgG1 switch in vivo.

A single intraspleen inoculation of plasmid DNA coding for an immunoglobulin heavy chain gene initiates immunity and establishes immunologic memory against the antigenic determinants of transgenic immunoglobulins, somatic transgene immunization. During priming mice produce IgM but not IgG1 antibodies. Since IgM --> IgG1 class switch occurs spontaneously during the primary immune response to protein antigens we investigated possible mechanisms for failure of spontaneous isotype switch in vivo in this model of immunity. We found that inoculation of plasmid DNA in the form of a chimeric gene coding for granulocyte-macrophage colony-stimulating factor (GM-CSF) was able to drive IgG1 class switch readily after priming. Since GM-CSF activates cells of the dendritic lineage we tested the possibility that dendritic cells (DC) may be involved in regulating IgM --> IgG1 switch. To this end we used bone marrow chimeras constructed from mice carrying the null mutation for the relB member of the NF-kappaB/Rel family as these mice lack bone marrow-derived mature DC. RelB (-/-) mice and (-/-) bone marrow chimeras inoculated with DNA/GM-CSF did not produce IgG1 antibodies during the primary immune response. Since relB (-/-) bone marrow chimeras lack DC of donor origin but possess resident follicular dendritic cells we conclude that Ig class switch in vivo is regulated by the function of interdigitating dendritic cells (IDC). Thus, IDC may contribute to the qualitative aspects of the emerging immune response.

Animals↗
PubMed1976

Feasibility study of active immunotherapy in patients with solid tumors.

Forty-five immunocompetent patients with solid tumors were immunized with BCG, PPD, and tumor cells. The methods were practical, but the morbidity was significant, including painful draining ulcerations at vaccine sites, possible enhancement of tumor growth in three patients, and the discovery at autopsy of systemic tuberculosis in one patient. Various facets of cellular immunity were altered, namely: 1) a majority of the patients developed enhanced cutaneous reactions to the microbial skin-test antigens (particularly tuberculin) and tumor cells; 2) nine patients developed the equivalent of delayed hypersensitivity reactions or flares at all previous PPD and BCG inoculation sites following subsequent injection of these agents, which supports the concept of immunologic memory for these target antigens; 3) lesions resembling those of "spontaneous" regressed moles (halo-nevi) were observed at previous vaccine sites in 20 patients and generalized depigmentation occurred in three patients; 4) foreign body giant cells in tumor metastasis remote from BCG-PPD-tumor vaccine sites may indicate a cross-reactivity of microbial and tumor antigens; and 5) intralesional inoculation of the nonspecific agents (BCG, PPD, Varidase, and Mumps) resulted in dense mononuclear cell infiltration and complete regression of most of the injected lesions. Destruction of single or multiple lesions by local injections of antigens did not provide either significant regression of uninjected lesions or clinical benefit.

Abscess↗
PubMed1979

Selectivity of the micro-leukocyte adherence inhibition assay in pancreatic cancer.

A modified leukocyte adherence inhibition assay was performed on white blood cells from patients with ductal pancreatic cancer, other malignancies, benign gastrointestinal diseases including pancreatitis, and healthy controls, using four different ductal pancreatic cancer membrane preparations and similar preparations from gastric and colorectal cancers. A mean adherence index of less than or equal to 0.2 was evidence that the leukocytes "recognized" the antigen(s). In 9 of 10 patients with localized pancreatic cancer, 13 of 15 leukocyte populations "recognized" the pancreatic cancer antigen(s) and not other tested antigen(s). Leukocytes from only 11 of 18 patients (17 of 29 assays) with metastatic pancreatic cancer "recognized" the pancreatic tumor antigen (and no other antigen). The inability to recognize the pancreatic tumor antigen(s) was not related to nutritional, biochemical or therapeutic status of the patient, but was related to the demonstration of a response to skin test antigens. In contrast, 3 of 35 leukocyte populations in 2 of 31 patients with malignancies other than pancreatic, 1 of 28 with benign gastrointestinal disease, and one of 38 healthy control populations "recognized" the antigen. The LAI is worthy of further study in the differential diagnosis of pancreatic cancer.

Adenocarcinoma↗
PubMed2006

Conjugate vaccines for preventing meningococcal C meningitis and septicaemia.

BACKGROUND: Meningococcal polysaccharide (MPLS) vaccines protect against Serogroup C disease, but do not produce an immune response in infants less than two years of age. This limitation can be overcome by linking C polysaccharide to carrier proteins ('conjugating'), to create meningococcal serogroup C conjugate (MCC) vaccines. In the absence of trial data, the immune response to vaccination has been considered to be a reasonable surrogate for vaccine protection. OBJECTIVES: To assess the immunogenicity, safety and efficacy of MCC vaccines for preventing meningitis and septicaemia. SEARCH STRATEGY: We searched the Cochrane Central Register Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005); MEDLINE (1966 to September, Week 1 2005); and EMBASE (1990 to June 2005) and references of studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) in humans comparing MCC vaccines against a control vaccine or none. In the absence of any trials on vaccine efficacy, population-based observational studies about effectiveness were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened the results of the literature searches, selected eligible studies, extracted the data and evaluated the quality of them. MAIN RESULTS: The studies showed that MCC vaccine was highly immunogenic in infants after two and three doses, in toddlers after one and two doses and in older age groups after one dose. In general higher titres were generated after MCC than after MPLS vaccines. Immunological hypo-responsiveness seen after repeated doses of MPLS vaccine may be overcome with MCC. Observational studies have documented a significant decline in meningococcal C disease in countries where MCC vaccines have been widely used. The timing of the vaccinations schedules, the specific conjugate used, and the vaccines given concomitantly or combined, may be important. AUTHORS' CONCLUSIONS: The MCC vaccine appears to be safe, immunogenic and able to induce immunological memory in all age groups. Observational studies strongly suggest that MCC is clinically effective.

Humans↗
PubMed1993

Limiting dilution analysis of interleukin-2-producing T cells responsive to recall and alloantigens in human immunodeficiency virus-infected and uninfected individuals.

Peripheral blood mononuclear cells (PBMC) from individuals who were seropositive for the human immunodeficiency virus type 1 (HIV), and most without symptoms (HIV+) were compared with PBMC from healthy HIV-seronegative (HIV-) individuals for in vitro generated T helper cell (Th) responses. Th function in bulk culture and limiting dilution analysis was assessed by IL-2 production following stimulation with influenza A virus (FLU) or irradiated allogeneic PBMC (ALLO). We observed that the frequencies of FLU- and ALLO-stimulated Th cells were not appreciably different in the PBMC of HIV- individuals, and that they were also not different in the PBMC of those HIV+ individuals who responded to both FLU and ALLO in bulk culture. However, there was a severe drop in the Th frequency to FLU in HIV+ individuals who were unresponsive to FLU but responsive to ALLO by bulk culture. The PBMC of HIV+ individuals who were unresponsive by bulk culture to both FLU and ALLO exhibited a drastic reduction in the Th frequencies for both stimuli. These results demonstrate a concordance between Th functional analysis performed by limiting dilution and bulk culture. The results also indicate that the early selective loss in Th function to recall antigens is not likely to be due simply to a difference in frequencies of FLU- and ALLO-stimulated Th cells present prior to the onset of Th dysfunction.

Cell Line↗
PubMed1994

Comparing macrophages and dendritic leukocytes as antigen-presenting cells for humoral responses in vivo by antigen targeting.

Immunotargeting is a novel technique whereby antigen is directed against antigen-presenting cells (APC) by conjugation to specific monoclonal antibodies (mAb). In this study we have employed the technique to investigate the efficiency of macrophages as APC compared with constitutively major histocompatibility complex (MHC) class II-positive cells, i.e. dendritic leukocytes and B cells, in vivo. We first studied the organ retention of the radiolabeled conjugates by gamma counting, and their distribution within the draining lymph nodes by autoradiography. We could confirm that the conjugates reached the cells at which they were aimed. We then measured primary and secondary humoral responses. The results confirmed previous findings that targeting with mAb against MHC class II, i.e. to dendritic leukocytes, strongly enhanced the primary humoral response. In contrast, anti-IgD conjugates, directed against B cells gave only weak primary responses. Although conjugates directed against macrophages were retained for a longer time than the other conjugates, the primary humoral response was virtually abolished. The secondary responses, however, were at least as strong as those obtained in animals primed with control conjugates, whereas animals primed with anti-MHC class II conjugates showed little if any amplification of the secondary response. The discrepancies between the various conjugates could not be ascribed to TH1 versus TH2 responses as IgG1, IgG2a, IgG2b and IgE titers all co-varied in single animals. A possible explanation for the observed results is that macrophages fail to induce cytokine production for terminal differentiation of B cells to plasma cells, whereas conversely, upon presentation by dendritic leukocytes most stimulated B cells mature to plasma cells, leaving less progeny for immunological memory.

Animals↗
PubMed2005

Fc gamma RII-dependent sensitisation of natural interferon-producing cells for viral infection and interferon-alpha responses.

Natural interferon-producing cells (NIPC), also called plasmacytoid dendritic cells, are the most potent producers of IFN-alpha in response to viral and bacterial components, serving an important function in innate immune defences. The present work demonstrates that NIPC responsiveness can be primed by immunisation, increasing their capacity to produce IFN-alpha after viral infection. NIPC isolated from pigs immunised against classical swine fever virus (CSFV), a member of the Flaviviridae, were more receptive to viral infection and produced higher levels of IFN-alpha than NIPC from immunologically naive animals. This sensitisation of NIPC was maintained for at least 8 months after immunisation. IFN-alpha production was dependent on live virus and required replication, and the "immune" NIPC responded to lower infectious doses of virus. Co-localisation of the virus with Fc(gamma)RII (CD32) in polarised structures was observed with "immune" NIPC only. This Fc(gamma)RII-dependent virus capture and sensitisation of NIPC, evidently mediated through cytophilic CSFV-specific antibodies, was inhibited by non-specifically aggregated immunoglobulin as well as by pre-formed virus-antibody complexes. In conclusion, these results demonstrate that NIPC not only represent a major player in innate immunity but are also functionally linked to the immunological memory of the adaptive immune system.

Animals↗
PubMed1994

Blood-to-lymph migration of small lymphocytes through the liver of the sheep.

The process of lymphocyte migration is required for the systemic dissemination of immunological memory and immune surveillance. We report here experiments to quantitate the normal traffic of lymphocytes that occurs from blood to lymph through the liver and hepatic node in the sheep. Comparisons were made with known lymphocyte homing pools. Individual afferent hepatic lymphatics had cell outputs of 1.4 +/- 0.1 x 10(6) cells/hr, suggesting that the total combined lymphocyte output from the liver was no greater than about 1 x 10(7) cells/hr. The lymphocyte output in efferent hepatic lymph was 6.2 +/- 0.4 x 10(7) cells/hr, comparable to the cell outputs recorded from other lymph nodes of similar size. When the specificity of lymphocytes homing through the liver or hepatic node was examined, we found similarities to both the peripheral lymph node and intestinal lymph node homing patterns. Migration into afferent hepatic lymph was found to be different from that into intestinal or subcutaneous efferent lymph, and the kinetics of migration into hepatic afferent lymph was faster than that observed into efferent compartments. Intravenously injected endotoxin was found to alter the normal lymph flow through the liver tissue and the hepatic node; it appeared to enhance the migration of macrophages out of the liver by way of the afferent lymph. These studies suggest unique features of lymphocyte traffic through the liver and the need for further experiments on hepatic lymphocyte traffic, particularly in pathological states with substantial mononuclear cell infiltration.

Animals↗
PubMed2006

Personalized immunotherapy for the treatment of non-Hodgkin's lymphoma: a promising approach.

The efficacy of immunotherapeutic strategies for the treatment of lymphoid malignancies has been demonstrated in recent years. In patients with B-cell lymphomas, particularly indolent lymphoma, the use of passive immunotherapy, such as the anti-CD20 monoclonal antibody rituximab, has made an impressive impact on patient outcome. Personalized immunotherapy, a method that triggers the immune system to mount a response against tumor cells, has shown promising results in early clinical trials in hematologic malignancies. This therapeutic modality appears safe, with the most common adverse events being transient, local reactions at the site of injection. Furthermore, personalized immunotherapy has the potential to generate immunologic memory, which could provide prolonged remission. Currently, 3 large phase III studies are evaluating the efficacy and safety of personalized immunotherapy in patients with follicular lymphoma. It is hoped that the results of these studies will lead to the incorporation of this promising approach into the standard treatment of patients with lymphoma.

Antineoplastic Agents↗
PubMed2001

Superantigen enhanced protection against a weak tumor-specific melanoma antigen: implications for prophylactic vaccination against cancer.

B16F10 melanoma is a tumor derived from C57BL/6 mice that has been found to be poorly immunogenic and highly aggressive. Here we have shown that vaccination of mice with irradiated B16F10 cells followed by treatment with a combination of staphylococcal enterotoxins A and B (SEA/SEB) leads to significant and specific protection against subsequent challenge with viable B16F10 cells (at least 25-fold greater than a lethal dose). Also, 75% of mice surviving over 150 days remained tumor-free after rechallenge with viable B16F10 cells, evidence of the development of strong immunologic memory. Additional studies showed increases in CD4(+) and CD8(+) T-cell populations, cytotoxic T-lymphocyte activity and interferon-gamma production, all of which may contribute to enhanced survival. Furthermore, failure to produce protection in either CD4(-/-) or CD8(-/-) T-cell knockout mice is evidence that CD4(+) and CD8(+) T cells play an essential role in induction of immunity. These results show that superantigen administration subsequent to vaccination with inactivated tumor cells results in protective antitumor immunity. Thus, prophylactic vaccination against cancer is a feasible method for arming the immune system prior to the incidence of cancer.

Animals↗
PubMed1988

T-cell-mediated inhibition of EBV-induced B-cell transformation: recognition of virus particles.

In order to analyze the components of EBV-specific immunological memory that contribute to the T-cell-mediated inhibition of EBV-induced B-cell transformation, we have investigated the growth inhibitory potential of T cells cultured for 3 days with B cells exposed to transforming and non-transforming EBV preparations. T cells cultured for 3 days with EBV-infected autologous B cells inhibited the transformation of newly infected B lymphocytes. T cells cultured with the virus, with autologous uninfected B cells, or in the presence of 10 micrograms/ml Con-A had a significantly weaker inhibitory capacity. The inhibitory capacity was induced by co-cultivation with B cells infected with the transforming B95-8 virus strain, with the non-transforming P3HRI virus strain, and also with UV-inactivated B95-8 virus. B-cells infected with transforming B95-8 virus induced the strongest growth inhibitory activity. Activation of the T cells was shown by their IL-2 production, proliferation, and generation of non-specific cytotoxicity. These results suggest that the initial event of the T-cell response in EBV-infected cultures is induced by antigens associated with the viral particles presented by B lymphocytes.

Antigens, Viral↗
PubMed2006

The evolution of immune mechanisms.

From early on in evolution, organisms have had to protect themselves from pathogens. Mechanisms for discriminating "self" from "non-self" evolved to accomplish this task, launching a long history of host-pathogen co-evolution. Evolution of mechanisms of immune defense has resulted in a variety of strategies. Even unicellular organisms have rich arsenals of mechanisms for protection, such as restriction endonucleases, antimicrobial peptides, and RNA interference. In multicellular organisms, specialized immune cells have evolved, capable of recognition, phagocytosis, and killing of foreign cells as well as removing their own cells changed by damage, senescence, infection, or cancer. Additional humoral factors, such as the complement cascade, have developed that co-operate with cellular immunity in fighting infection and maintaining homeostasis. Defensive mechanisms based on germline-encoded receptors constitute a system known as innate immunity. In jaw vertebrates, this system is supplemented with a second system, adaptive immunity, which in contrast to innate immunity is based on diversification of immune receptors and on immunological memory in each individual.Usually, each newly evolved defense mechanism did not replace the previous one, but supplemented it, resulting in a layered structure of the immune system. The immune system is not one system but rather a sophisticated network of various defensive mechanisms operating on different levels, ranging from mechanisms common for every cell in the body to specialized immune cells and responses at the level of the whole organism. Adaptive changes in pathogens have shaped the evolution of the immune system at all levels.

Adaptation, Biological↗
PubMed1998

Impact of aging on innate immunity.

Immune responses in higher organisms are triggered by the recognition of a limited diversity of microbiological products by cells of the innate or "natural" immune system. As a result, in addition to the direct protective effect of natural immunity, antigen-presenting cells, particularly dendritic cells, are activated to process and present an enormous number of peptide antigens to the T lymphocytes of the adaptive immune system. These, together with the B lymphocytes, then mediate specific immune responses and maintain acquired immunological memory. The aging immune system is less well able to cope with infectious disease than the youthful immune system; this review will briefly consider what is known of the age-associated alterations in innate immunity, and how these may also impact on adaptive immunity.

Aging↗
PubMed1982

Treatment of ongoing experimental myasthenia gravis with short term high dose cyclophosphamide.

We have treated animals with an ongoing autoimmune disease, experimental autoimmune myasthenia gravis (EAMG), using a strategy designed to eliminate the antibody-producing cells. During well-established EAMG, a single high dose of cyclophosphamide was given because of its known effectiveness against B-lymphocytes. To counteract the lethal effects of the drug, the rats were "rescued" by bone marrow cell transplantation. This treatment produced a rapid and sustained fall of antibody titers against both the immunizing antigen (Torpedo acetylcholine receptor) and the autoantigen (rat acetylcholine receptor). Immunologic memory, as measured by an anamnestic response to the antigen, was partially suppressed. Cyclophosphamide treatment produced improvement in the neuromuscular defect: treated animals had, on the average, twice as many acetylcholine receptors at neuromuscular junctions compared with untreated EAMG animals. This treatment method of short-term high doses of an immunosuppressive drug, such as cyclophosphamide, may eventually prove useful for human myasthenia gravis and other autoimmune diseases.

Animals↗
PubMed1998

Cytokine gene transfer in cancer therapy.

New strategies based on gene transfer technology are employed in cancer therapy. Cytokines are polypeptides involved in immunity and inflammation, and essentially control the magnitude of the immune response. Genetically modified tumor cells releasing various cytokines have been shown to enhance tumor immunogenicity and to induce the regression of preexisting tumors. In some instances, immunological memory has been generated to resist the subsequent challenge with unmodified, parental tumor cells. Cytokine gene transfer into antitumor effector cells, as well as antigen presenting cells, is also being investigated to augment antitumor immune responses.

Animals↗
PubMed1994

Difficulties in establishing a serological correlate of protection after immunization with Haemophilus influenzae conjugate vaccines.

In several studies the protective concentration of anti-Haemophilus influenzae type b (Hib) capsular polysaccharide (PS) antibodies has been concluded to be around 0.04 to 0.20 microgram/ml. After the Finnish Hib polysaccharide vaccine trial it was estimated that 1 microgram/ml has to be achieved to predict long term protection after vaccination. These estimates of protective anti-Hib PS antibody concentrations were based on the assumption that protection from invasive Hib disease is mediated by antibodies and the role of cell-mediated immunity is negligible. This assumption was justified since the Hib PS is a T cell-independent antigen. The matter becomes quite different when the character of the PS vaccine is altered by conjugating it to a protein carrier, so that it acquires the ability to stimulate T cells, and the immunological memory plays a role in the protection. The immunized infants are thought to be able to respond with a rapid and high antibody response after exposure to the organism. After immunization with conjugate vaccines, protection can be seen at a lower serum antibody concentration than after polysaccharide vaccine. In addition, higher avidity of anti-Hib PS antibodies is associated with the response to conjugate than PS vaccine, and there are differences between the conjugates. This might have an influence on the functional activity of the antibodies. Hib conjugate vaccines are also able to reduce the carriage rate of Hib. This should be kept in mind when estimating what is needed from protective immune response after immunization with Hib conjugate vaccines.

Adult↗
PubMed1996

Unique T cell antagonist properties of the exact self-correlate of a peptide antigen revealed by self-substitution of non-self-positions in the peptide sequence.

The role of self-peptides in shaping the T cell receptor (TCR) repertoire remains to be established. While TCR reactive to certain self-peptides are thought to be depleted in the thymus, the selection of TCR specificity for foreign peptide reactivity appears to require recognition of self-peptide(s) bound to the groove of thymic major histocompatibility complex (MHC) molecules. This dichotomy suggests that different TCR affinities, accessory signals, and/or different sets of self-peptides dictate the eventual fate of any given TCR-bearing clone. Recently, it has been established for several T cell epitopes that derivatives with substitutions in TCR-contact residues can antagonize the proliferation of T cell clones against the wild-type peptide antigen. Moreover, these altered peptide ligands have demonstrated activity in the positive selection of thymocytes with TCR reactive to the wild-type peptide antigen. We have investigated the specificity of T cell antagonism with step-wise substitution of self-amino acids into each nonconserved position of a 12-amino-acid foreign peptide antigen. Our data demonstrate that the ability to antagonize proliferation without competition for MHC binding is unique to the exact self-derivative, where all five of the self-substitutions are inserted. These properties may specifically allow certain self-peptides to downregulate T cell activation to the foreign ligand and/or provide a source of stimulation for immunologic memory.

Amino Acid Sequence↗