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PubMed2003

Correlates of immunity for pneumococcal conjugate vaccines.

The purpose of the NIAID/FDA joint workshop, "correlates of immunity for pneumococcal conjugate vaccines (PCVs)," was to discuss the present understanding of protective immunity against invasive pneumococcal disease and identify in vitro measures that may represent immunologic correlates in future clinical trials. Animal and clinical data support functional antibody as the basis for protection, but IgG antibody concentration has conventionally been the principle immunologic parameter for non-inferiority comparisons. No consensus for a pre-defined threshold antibody level was reached. Affinity maturation may contribute to protection, but its role has not been established. Opsonophagocytic activity, avidity and immunologic memory are important secondary measures to characterise functional antibody and long-term protective responses. Immunologic memory may also be useful for evaluation of new vaccine serotypes. More definitive qualitative and quantitative immunogenicity criteria for use by National Control Authorities still need to be established.

Antibodies, Bacterial↗
PubMed1980

[Primary and secondary immune response of mice to polysaccharide antigens of meningococcal serogroups A and C].

The peculiarities of the primary immune response, the formation of immunological memory and the secondary immune response to serogroup A and C meningococcal polysaccharides were studied in 7 strains of inbred mice, hybrids F1 and in noninbred animals. The passive local hemolysis test and the passive hemagglutination test indicated that the intensity of immune response to A and C polysacchardies depended on the genotype of the animals: both antigens induced the most intense response in CBA and BALB/c mice. The primary immune response to the both antigens was characterized by a short latent period, a rapid (by days 4-5) increase in the amount of antibody-producing cells in the spleen and in antibody titer in the blood serum to the maximum level, and a pronounced decrease inantibody formation by days 6-7 followed by a gradual extinction of the response. A single injection of A and C polysaccharides in a dose of 0.5 microgram induced the formation of immunological memory in mice, persisting for at least 4 weeks and manifesting after reimmunization as the increased or more prolonged synthesis of IgM and IgG.

Animals↗
PubMed2004

Cassette-based presentation of SIV epitopes with recombinant gas vesicles from halophilic archaea.

In earlier studies we demonstrated recombinant gas vesicles from Halobacterium sp. NRC-1, expressing a model six amino acid insert, or native vesicles displaying chemically coupled TNP, each were immunogenic, and antigenic. Long-lived responses displaying immunologic memory were elicited without exogenous adjuvant. Here we report the generation and expression of cassettes containing SIV derived DNA. The results indicate a cassette-based display/delivery system derived from recombinant halobacterial gas vesicle genes is highly feasible. Data specifically support four conclusions: (i) Recombinants carrying up to 705 bp of SIV DNA inserted into the gvpC gene form functional gas vesicles; (ii) SIV peptides contained as part of the expressed recombinant, surface exposed GvpC protein are recognized by antibody elicited in monkeys exposed to native SIV in vivo; (iii) in the absence of adjuvant, mice immunized with the recombinant gas vesicle (r-GV) preparations mount a solid, titratable antibody response to the test SIV insert that is long lived and exhibits immunologic memory; (iv) recombinant organelles, created through the generation of cassettes encoding epitopes inserted into the gvpC DNA, can be used to construct a multiepitope display (MED) library, a potentially cost effective vehicle to express and deliver peptides of SIV, HIV or other pathogens.

Animals↗
PubMed1986

Immunomodulating properties of substances to be used in combination with liposomes.

Liposomes haptenated with tripeptide-enlarged dinitrophenyl (DNP) are known to act as thymus-independent antigens which induce a strong IgM response and only limited amounts of circulating IgG. When haptenated liposomes are used in vaccination studies, it is of practical importance to improve the immunogenicity of these complexes. Therefore, an evaluation was made of the potency of various substances to modulate the immune response in such a way that the total antibody production is increased, including a relative great increase of 2-mercaptoethanol (2-ME)-resistant antibodies and immunological memory is induced. The following substances were used: glycophorin A (GP-A), sialogangliosides (monosialo-, disialo- and trisialoganglioside), 6-0-stearoyl-MDP (MDP-SA) and lipid A (lip A). Lip A incorporated into liposomes was the only substance inducing considerable increases of both total and 2-ME-resistant haemagglutination (HA) titre after immunization. Depending on the dose tested, the sialic-acid-containing protein GP-A had a small and varying influence on the serum antibody response. Sialogangliosides transiently decreased in a dose-dependent manner the total antibody titre in serum. In contrast to lip A, the lipophilic bacterial adjuvant MDP-SA did not influence HA titres significantly. The number of plaque-forming cells (PFC) in the spleen was enhanced considerably after both primary and secondary immunization with liposomes containing lip A. The other substances tested induced only minor differences of the number of PFC. To some extent, lip A induced immunological memory. In conclusion, it can be stated that of the agents tested, only lip A is a potent and consistent stimulator of the humoral immune response to liposomes haptenated with DNP groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed2005

Selecting B cells and plasma cells to memory.

Humoral immunity appears to be based on immunological memory provided by memory plasma cells, which secrete protective antibodies, and memory B cells, which react to antigen challenge by differentiating into plasma cells. How these differentiation pathways relate to each other, how cells are selected into these memory populations, and how these populations are maintained remains enigmatic.

Animals↗
PubMed2004

A role for the granzyme B inhibitor serine protease inhibitor 6 in CD8+ memory cell homeostasis.

Generation and maintenance of protective immunological memory is the goal of vaccination programs. It has recently become clear that CD8+ memory T cells are derived directly from CTLs. The mechanisms underlying this transformation and the subsequent survival of memory cells are not completely understood. However, some effector molecules required by CTLs to eliminate infected cells have also been shown to control the number of Ag-specific cells. We report that memory cells express high levels of serine protease inhibitor (Spi) 6, an inhibitor of the effector molecule granzyme B, and that Spi6 can protect T cells from granzyme B-mediated apoptosis. In mouse models, both elevated expression of Spi6 and the complete absence of granzyme B in CD8+ T cells led to an increase in memory cells after infection with lymphocytic choriomeningitis virus. This was not the result of increased levels of antilymphocytic choriomeningitis virus CD8+ T cells during the expansion or contraction phases, but rather transgenic Spi6 directly influenced the survival of CD8+ memory T cells. We propose that expression of protective molecules, like Spi6, serves to shield metabolically active CD8+ memory T cells from their own effector molecules.

Animals↗
PubMed1998

An IgG3-IL-2 fusion protein recognizing a murine B cell lymphoma exhibits effective tumor imaging and antitumor activity.

Antibody (Ab)-based tumor therapeutics use the tumor-binding specificity of the Ab to target Fc functions or associated molecules to the site of the tumor. We have used an Ab-interleukin-2 (IL-2) fusion protein to deliver IL-2 to a murine B cell lymphoma (38C13). This anti-Id IgG3-CH3-IL-2, which recognizes the idiotype present on the surface of the lymphoma has a half-life in mice approximately 17-fold longer than the half-life reported for IL-2. Gamma camera studies showed that anti-Id IgG3-CH3-IL-2 localizes at the site of a subcutaneous tumor in mice. The anti-Id IgG3-CH3-IL-2 also shows enhanced antitumor activity compared with the combination of Ab and IL-2 administered together. However, the mechanism of antitumor activity appears to depend on the dose and the treatment schedule used. A single dose of fusion protein prevented tumor in only 50% of the animals, although all the survivors showed some evidence of immunologic memory. Although multiple doses are more effective in preventing tumor growth (87% survivors), they are ineffective in generating protective immunologic memory. Our results suggest that Ab-IL-2 fusion proteins will be useful in the diagnosis and treatment of human B cell lymphomas and other related malignancies.

Animals↗
PubMed2003

Toward a breast cancer vaccine: work in progress.

Advances in biotechnology and basic immunology have converged to create an unprecedented opportunity to use vaccines to harness the power of the immune system in the fight against breast cancer. Cancer vaccines have several therapeutic advantages over more traditional breast cancer treatment modalities. First, targeting the antitumor immune response to critical tumor-specific antigens defines a therapy with exquisite specificity and minimal toxicity. Second, immune-mediated tumor destruction occurs by mechanisms distinct from those underlying the efficacy of chemotherapy and hormone therapy. Thus, immunotherapy offers an approach to circumventing the intrinsic drug resistance that currently underlies therapeutic failure. Third, the phenomenon of immunologic memory endows immunotherapy with the potential for creating a durable therapeutic effect that is reactivated at the onset of disease relapse. Moreover, immunologic memory also underlies the potential future use of vaccines for the prevention of breast cancer. Early clinical trials have highlighted the promise of breast cancer vaccines, and have further defined the challenges facing translational scientists and clinical investigators. The judicious application of laboratory advances to clinical trial design should facilitate the development of immunotherapy as an additional major therapeutic modality for breast cancer, with the potential for breast cancer prevention as well as treatment.

Antibodies, Anti-Idiotypic↗
PubMed2000

Interleukin-1 and cutaneous inflammation: a crucial link between innate and acquired immunity.

As our primary interface with the environment, the skin is constantly subjected to injury and invasion by pathogens. The fundamental force driving the evolution of the immune system has been the need to protect the host against overwhelming infection. The ability of T and B cells to recombine antigen receptor genes during development provides an efficient, flexible, and powerful immune system with nearly unlimited specificity for antigen. The capacity to expand subsets of antigen-specific lymphocytes that become activated by environmental antigens (memory response) is termed "acquired" immunity. Immunologic memory, although a fundamental aspect of mammalian biology, is a relatively recent evolutionary event that permits organisms to live for years to decades. "Innate" immunity, mediated by genes that remain in germ line conformation and encode for proteins that recognize conserved structural patterns on microorganisms, is a much more ancient system of host defense. Defensins and other antimicrobial peptides, complement and opsonins, and endocytic receptors are all considered components of the innate immune system. None of these, however, are signal-transducing receptors. Most recently, a large family of cell surface receptors that mediate signaling through the NF-kappaB transcription factor has been identified. This family of proteins shares striking homology with plant and Drosophila genes that mediate innate immunity. In mammals, this family includes the type I interleukin-1 receptor, the interleukin-18 receptor, and a growing family of Toll-like receptors, two of which were recently identified as signal-transducing receptors for bacterial endotoxin. In this review, we discuss how interleukin-1 links the innate and acquired immune systems to provide synergistic host defense activities in skin.

Antibody Formation↗
PubMed1986

The effect of maternal antigenic stimulation upon the active immune responsiveness of their offspring: suppression induced by soluble protein antigen, ovalbumin, in mice.

The active immune responsiveness of the offspring of pregnant mice stimulated with heterologous protein antigen was investigated by measuring the plaque-forming cells (PFC). Mice (C57BL/10;B10) immunized once in pregnancy with ovalbumin (OVA) in the form of Al(OH)3 gel (in alum) or in a soluble form (in saline) developed no anti-OVA PFC response. The anti-OVA PFC response suppression induced in the offspring was high in the offspring of alum-treated mothers and low in those of saline-treated mothers. The optimal dose of OVA in alum that induces the highest immunological memory in pregnant mice caused the complete suppression of PFC development in their offspring. The same dose of OVA in saline induced a negative immunological memory in pregnant mice and partial suppression in the offspring. On the other hand, mice primed prior to conception and boosted during pregnancy developed anti-OVA PFC in significant numbers, and only a partial suppression was established in their young. Based on these data, we discussed the possible mechanisms concerned with the specific suppression induced in the young B10 mice stimulated by OVA.

Animals↗
PubMed1975

Influence of repeated local stimulation on the splenic response to mucosal and parenteral immunization.

It has been suggested that a regional immune response may be induced by local administration of small doses of antigen, whereas larger doses are capable of inducing not only a local but also a systemic immune response. Except with fluorescence, the study at the cellular level and in the mucosa of specific antibody-producing cells appears difficult. The circulation in the body of lymphocytes from the lamina propria of the gut allows the detection of antibody-producing cells in extra-intestinal lymphoid tissues. The administration of 4 times 10-9 sheep red blood cells (SRBC) by gastric intubation to BALB/c mice (repeated daily for 4 days) was found to cause the appearance in the spleen of plaque-forming cells which predominantly belonged to the IgA class and whose numbers reached a maximum at about day 8 or 9 after the onset of the immunization. This observation is relevant to splenic colonies from cells that had received their antigenic stimulation in the gut wall and thence had seeded out in the body. Booster administration of SRBC performed 3 months after the first antigenic contact induced in the spleen an immunological response similar to that observed in newly primed mice and in no way suggestive of immunologic memory. A secondary response is completely absent when the second intragastric immunization is initiated 10 days after the end of the first. The parenteral administration of 2 times 10-8 SRBC to mice primed by the oral route 15 days earlier is followed by a marked hyporeactivity of the spleen. In any case, the IgA system appears endowed with only a minimum, if any, immunological memory to non-living antigen. In some conditions local immunological stimulation may even cause tolerance.

Administration, Oral↗
PubMed1997

In vitro responses of human CD45R0brightRA- and CD45R0-RAbright T cell subsets and their relationship to memory and naive T cells.

The cellular basis of immunological memory, particularly with respect to T cells is not understood. In humans, monoclonal antibodies to CD45 have been used to identify memory (CD45R0) and naive (CD45RA) T cells. However, this identification has been called into question by various studies which suggest that high molecular weight CD45 isoforms may be re-expressed by previously activated cells. In the present study, using cultures which supported responses of naive T cells, we examined the responses of purified CD45R0brightRA- or CD45R0(-)-RAbright T cell subsets. The former subset was found to respond preferentially to recall antigens with minimal responses apparent to neo-(or non-recall)-antigens. The inverse pattern was found for CD45R0-RAbright T cells, which converted to CD45R0brightRA- after stimulation with a neo-antigen. Moreover, the two populations of T cells exhibited distinct response kinetics with a faster response evident from the CD45R0brightRA- T cells compared to the CD45R0-RAbright subset. The poor responses of CD45R0-RAbright T cells to recall antigens compared to neo-antigens suggests that this putative naive population is specifically depleted of reactive T cells following an encounter with antigen. We propose that T cell priming results in the stimulation of many CD45R0-RAbright T cells with various T cell receptor specificities from which memory T cells are selected for survival. If re-expression of higher molecular weight isoforms does occur in humans in vivo, our results suggest that R0 expression would be retained (CD45R0+RA+). Alternatively, if primed CD45R0-RAbright T cells exist, they are not prevalent in peripheral blood and thus may be sequestered within lymphoid tissues. Our data support the view that in human peripheral blood, CD45R0bright and CD45RAbright expression identify memory and naive CD4+ T cells, respectively.

Adult↗
PubMed2006

Cell-autonomous CCL5 transcription by memory CD8 T cells is regulated by IL-4.

Immunological memory is associated with the display of improved effector functions. The maintenance by CD8 memory cells of high levels of untranslated CCL5 mRNA allows these cells to immediately secrete this chemokine upon Ag stimulation. Untranslated mRNA storage is a newly described process supporting the immediate display of an effector function by memory lymphocytes. We have tested the capacity of different cytokines to regulate the memorization of CCL5 by memory CD8 T cells. We found that IL-4 treatment of murine CD8 T cells impairs immediate CCL5 secretion capacity by inhibiting CCL5 mRNA transcription through a STAT6-dependent pathway. The inhibition by IL-4 is reversible, as memory CD8 T cells reconstitute their CCL5 mRNA stores and reacquire their immediate CCL5 secretion capacity when IL-4 is withdrawn. This recovery is cell autonomous because it proceeds in culture medium in the absence of exogenous growth factors, suggesting that CCL5 expression by memory CD8 T cells is a default process. Overall, these results indicate that the expression of CCL5 is an intrinsic property acquired by memory CD8 T cells that is regulated by environmental factors.

Animals↗
PubMed1994

Macrophage activation: a riddle of immunological resistance.

Various lines of defense against infection are present in all living creatures. The balance between symbiosis and parasitism is determined by the mechanisms through which the host resists infection and by the extent of injury induced by the parasite: both factors contribute to disease. Lines of host defense can be arbitrarily divided into three components: 1) barrier functions of skin and mucous membranes and their innate physical and secretory antimicrobial components; 2) elements of host defense that do not necessarily require prior exposure to an infectious agent or immunologic memory (mast cells, granulocytes, macrophages, NK cells, gamma/delta T cells); and 3) immune responses directed against specific epitopes on the infectious agent induced by prior exposure and immunologic memory (alpha/beta T cells, B cells). Analysis of such host defense mechanisms repeatedly documents tremendous redundancy and overlap between these lines of defense. Further, there is open communication, so that a change at any one level ripples throughout the system. Acquired nonspecific resistance to infection is an example of such a ripple. Host response to one infection alerts the immune system, so that the general level of resistance to other infectious agents is increased. This response is initiated by an immune response (third line of defense) but effected by nonspecific elements (second line of defense). The survival value of such responses is obvious. There are numerous examples in both mouse and man of the operation of these systems in response to infection. Further, the menus of antimicrobial components available to both mouse and man for resistance to infection are very similar, but not identical. Indeed, it is said that the genetic basis for differences between mice and man revolve around a difference of less than 10% in DNA sequences. But there are differences! Mouse macrophages produce IFN-beta in response to infection, human cells produce IFN-alpha. Mouse macrophages effect antimicrobial activity principally through induction of NO synthase and the generation of toxic nitrogen oxides. This pathway has yet to be described with human macrophages. In both man and mouse, F. tularensis is an obligate intracellular parasite of macrophages that requires an essential component provided by the cell for its replication. That mouse and man are not so different is well illustrated by the effector mechanisms induced by IFN-gamma for antimicrobial activity against F. tularensis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1997

Somatic transgene immunization with DNA encoding an immunoglobulin heavy chain.

A plasmid DNA containing a chimeric immunoglobulin heavy-chain gene with tissue-specific promoter and enhancer elements was used as a model system to study the events triggered by a single intraspleen DNA inoculation in adult C57Bl/6 mice. A single intraspleen inoculation was followed in a week by secretion of transgene immunoglobulins and production of immunoglobulin M (IgM) anti-immunoglobulins. Their kinetics of serum appearance were almost superimposable. While anti-immunoglobulin antibodies remained detectable for over 6 months, transgene immunoglobulins disappeared after 3-4 weeks. However, transgene mRNA was detected in the spleen for 4 months. A multiplex polymerase chain reaction (PCR) analysis on splenic genomic DNA 17 days after inoculation demonstrated that the transgene was integrated in the host chromosomal DNA. The nucleotide sequence of the rearranged VDJ region from splenic genomic DNA was identical to that of the parental plasmid DNA, hence ruling out that hypermutation had occurred. A booster injection of immunoglobulin encoded by the transgene on day 200 elicited a typical secondary immune response with IgG1 and IgG2b antibodies. These results demonstrate that a single inoculation of an immunoglobulin heavy-chain DNA targeted to spleen lymphocytes leads to spontaneous integration of the transgene into the host DNA, and that this is sufficient to initiate immunity and establish immunologic memory. Our data also show that minute amounts (<100 ng/ml) of an endogenously produced protein secreted in the microenvironment of a lymphoid tissue generate immunity and establish immunologic memory rather than tolerance.

Animals↗
PubMed2000

[Meningococcal disease in Africa--epidemiology and prevention].

Neisseria meningitidis is one of the most common causes of purulent meningitis all over the world. Large epidemics caused by meningococci have spread during the last decade throughout vast areas of Africa, also outside the region referred to as the classic "Meningitis Belt". Globally, this organism each year causes about 300,000 cases and 30,000 deaths; most of these are children. Meningococci of serogroup A cause a major part of these epidemics, and a remarkable feature of the epidemical situation is that the bacteria differ very little in antigenic properties as they belong to the same clonal group of meningococci. Immunization with safe and effective vaccines is the most efficient way of combatting these epidemics. The currently available polysaccharide vaccines against serogroup. A meningococcal disease do not induce long-term immunological memory and do not provide adequate protection of children below two years of age. There is an urgent need for a vaccine that induces long-term immunological memory in all age groups, so it can be included in the routine vaccination program. In contrast to serogroup C, the development of conjugate vaccines against serogroup A meningococcal disease has not yielded the positive results hoped for. The development of alternative protein-based vaccines therefore needs to be intensified.

Adolescent↗
PubMed1999

Long-term response to hepatitis B vaccination and response to booster in children born to mothers with hepatitis B e antigen.

Hepatitis B (HB) vaccine provides an uncertain duration of protection and the optimal timing of booster vaccine remains unclear. This study examined the immune response at 10 years of 118 children who had developed protective anti-HB surface (anti-HBs) levels after a primary series of HB immunizations in infancy. All of the children were born to hepatitis B e Antigen (HBeAg)-positive hepatitis B surface antigen (HBsAg) carrier mothers. HB markers in all subjects and cellular immune response in some were determined. A booster was given to all subjects after the collection of samples and another blood sample was collected 4 weeks later. The results showed that a total of 39 (33%) of the children were seronegative for anti-HBs. T-cell proliferative response to HBsAg was noted in 47% of children. On HBsAg stimulation, leukocyte samples from a significantly higher proportion of subjects produced cytokines (81% of T cells produced interleukin-2 [IL-2] and 100% produced IL-5). The booster dose of HB vaccine induced the production of a protective level of anti-HBs (>/=10 mIU/mL) in all subjects. Cellular immunity was augmented with a positive rate of 58%, 90%, and 100% for HBsAg-induced T-cell proliferation, IL-2 production, and IL-5 production, respectively. Although 14 (11.9%) of the subjects were HB core antibody positive at 10 years of age, no new HBsAg carrier was detected. The results of this study show that protection afforded by HB vaccination persisted to the age of 10 years in all vaccinees. Immunologic memory was detected in all subjects including those who had lost their anti-HBs seropositivity. These results suggest that no booster vaccination is needed before 10 years of age. The most sensitive marker of immunologic memory is IL-5 production of T cells. (HEPATOLOGY 1999;29:954-959.)

Child↗
PubMed1991

T cell memory is short-lived in the absence of antigen.

Immunological memory has generally been ascribed to the development of long-lived memory cells that can persist for years in the absence of renewed antigenic encounter. In the experiments reported here, we have adoptively transferred memory T cells in the presence and absence of priming antigen and assessed their functional survival. The results indicate that, in contrast to the traditional view, the maintenance of T cell memory requires the presence of antigen, suggesting that memory, like tolerance, is an antigen-dependent process rather than an antigen-independent state.

Animals↗