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Secondary immune amplification following live poliovirus immunization in humans.

Eight subjects inoculated orally with live attenuated poliovirus were investigated to study the effects of live virus infection on human T-cell responses. Proliferation to poliovirus and unrelated recall antigens were measured serially over a 3-week period. Five of eight subjects inoculated demonstrated a clear anamnestic response to poliovirus, but three did not. Only the five subjects demonstrating an anamnestic response to poliovirus were found to have augmented secondary immune responses to two unrelated recall antigens (tetanus toxoid and reovirus) and in the autologous mixed lymphocyte response (AMLR). No consistent changes were found in circulating T-cell surface activation antigens whether or not the subjects responded to poliovirus. These studies suggest that an asymptomatic poliovirus infection associated with immunization in humans can induce nonspecific secondary immune amplification as measured by in vitro T-cell proliferative response. This amplification pathway is a potential mechanism for immune responses against antigens other than those of the infecting virus.

Administration, Oral↗

Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response.

Maintenance of protective humoral immunity depends on the generation and survival of antibody-secreting cells. The bone marrow provides niches for long-term survival of plasma cells generated in the course of systemic immune responses in secondary lymphoid organs. Here, we have analyzed migratory human plasma blasts and plasma cells after secondary vaccination with tetanus toxin. On days 6 and 7 after immunization, CD19(+)/CD27(high)/intracellular immunoglobulin G(high) (IgG(high))/HLA-DR(high)/CD38(high)/CD20(-)/CD95(+) tetanus toxin-specific antibody-secreting plasma blasts were released in large numbers from the secondary lymphoid organs into the blood. These cells show chemotactic responsiveness toward ligands for CXCR3 and CXCR4, probably guiding them to the bone marrow or inflamed tissue. At the same time, a population of CD19(+)/CD27(high)/intracellular IgG(high)/HLA-DR(low)/CD38(+)/CD20(-)/CD95(+) cells appeared in the blood in large numbers. These cells, with the phenotype of long-lived plasma cells, secreted antibodies of unknown specificity, not tetanus toxoid. The appearance of these plasma cells in the blood indicates successful competition for survival niches in the bone marrow between newly generated plasma blasts and resident plasma cells as a fundamental mechanism for the establishment of humoral memory and its plasticity.

Adult↗

Secondary immunization with a protein antigen (tetanus toxoid) in man. Characterization of humoral and cell-mediated regulatory events.

Tetanus toxoid (TET) was used as an immunogen to explore regulatory events occurring after secondary immunization in man. Changes in dose-response patterns, kinetics, and frequency of antigen-reactive cells in the peripheral blood, and the serum antibody titres were studied. The most striking feature of these studies was the finding that immediately after immunization, a brief period of decreased responsiveness preceded the expected amplification of antigen-specific humoral and cell-mediated responses. One day after immunization serum antibody levels declined to approximately half their initial values before the expected increase in titre. These results could not be explained by the formation of antigen-antibody complexes. Lymphoproliferative responses were also depressed 1 day after immunization but increased in both magnitude and sensitivity from 7 to 28 days after challenge. A decrease in thymidine incorporation evident at supraoptimal antigen concentrations also became progressively more prominent during this interval. Cell mixing experiments documented the presence of a radioresistant population present 1 day after immunization capable of suppressing TET-specific lymphoproliferative responses of autologous lymphocytes obtained before immunization. These suppressors are preferentially activated at high antigen concentrations. Limiting dilution analysis revealed a 30-fold increase in TET-reactive proliferating cells by 28 days after immunization. Expansion occurred first in cells recognizing high antigen concentrations and subsequently in cells recognizing lower doses. Taken together, these findings present a consistent if somewhat counterintuitive picture of some of the regulatory processes accompanying booster immunization. The earliest detectable event appears to be the application of an active suppressor mechanism, release from which signals initiation of those processes classically associated with an anamnestic response.

Adult↗

Secondary immune response in a vaccinated population during a large measles epidemic.

The rates of secondary immune response (SIR) and secondary vaccine failure (SVF) during a measles epidemic (10,184 notifications) were evaluated. A patient with SIR was defined as a subject for whom all sera were immunoglobulin G (IgG) positive and IgM negative with a significant increase in complement fixation titer. A patient with SVF was defined as a vaccinated symptomatic subject showing a SIR. Sequential sera from 898 subjects were tested for measles antibody by enzyme-linked immunosorbent assay (IgG and IgM) and by complement fixation. Evidence of recent anti-measles virus specific immune response was found in 496 subjects (55.5%). The vaccination rate was estimated at 74.6% (99% confidence interval [CI], 67.9 to 80.7%). The number of exposed vaccinated subjects was estimated at 370 (74.6% of 496). The SIR rate was 4.03% (20 of 496) (99% CI, 2.1 to 6.9%) among subjects with immune response. These 20 subjects were 2 with measles (Centers for Disease Control's definition), 6 with measles with rash of unknown duration, 8 with presumed measles with either rash or fever, 3 asymptomatic subjects (2 with recent contact with a measles case), and 1 undocumented subject. Since 3 patients with SIR were asymptomatic and 2 others were documented as not vaccinated, there was a maximum of 15 probable occurrences of SVF among the 20 patients with SIR. The SVF rate among exposed vaccinated subjects was estimated at 4.05% (15 of 370) (99% CI, 1.9 to 7.5%). In conclusion, neither prior vaccination nor detectable SIR ensures protective immunity. Measles virus may induce asymptomatic SIR in IgG-seropositive subjects. SVF led to typical or modified measles but did not seem to have played an important role during this epidemic.

Adolescent↗

The development of specific antibody-containing cells in the spleen of rabbits during the secondary immune response against free or liposome-associated albumin antigen.

In order to study the distribution pattern of specific antibody-containing cells in the spleen of rabbits during the secondary immune response, rabbits were given two intravenous injections of either free or liposome-associated human serum albumin (HSA) within an interval of 2 months. Demonstration of specific antibody-containing cells was performed by incubation of sections of spleen with HSA-horseradish peroxidase (HRP) conjugates, followed by peroxidase cytochemistry. Specific anti-HSA antibody-containing cells were detected already within 2 days after booster and peak numbers were found 4 days after booster. The bulk of these cells localized in the coaxial lymphocyte sheaths surrounding the terminal arterioles in the spleen. Specific antibody-containing cells were also found in the follicles. Using a double immunoenzyme technique we demonstrated that a majority of the specific antibody-containing cells produced immunoglobulin G(IgG) antibodies. From the results, it is also concluded that, after a priming injection with liposome-associated HSA, liposomes do not further enhance the secondary immune response, when they are also used for the booster injection.

Animals↗

Secondary immune response in the middle ear: immunological, morphological, and physiological observations.

A model of secondary immune response in the middle ear (ME) was developed in the guinea pig. Animals were immunized intradermally with keyhole limpet hemocyanin (KLH) and challenged with KLH in the ME 8 weeks later. The ME displayed effusion, mucosal hyperplasia, mucosal edema, and leukocytic infiltration. These responses were maximal at 3 days postchallenge, and persisted for 2 to 3 weeks. High levels of antibody were observed in the ME effusions, and serum titers increased significantly. Immunohistochemical localization of antibody indicated that substantial free IgG was present in the submucosa, with much less in the mucosal epithelium. IgA plasma cells were observed in the submucosa at 1 week postchallenge, but no IgM was detected. In contrast to the response observed in sensitized animals, antigen presented to the ME of unimmunized control animals resulted in no effusion, minimal mucosal inflammation, and little or no antibody in either the ME or serum. However, substantial neutrophilic infiltration of the ME cavity was observed. The effusion and inflammation produced by secondary ME immune responses were not affected by tympanostomy tubes. Eustachian tube function as measured by a forced response test was not affected by ME immune response. This suggests that the immunologically induced effusion was not the result of eustachian tube obstruction. We postulate that increased vascular permeability in the ME mucosa, induced by chemical mediators, resulted in the transudation of serum.

Animals↗

Inverse social gradient of secondary immune response parameters in children.

BACKGROUND: In children, the prevalence of allergy increases with increasing socioeconomic status. If frequent immune response stimulation by infections protects against development of allergic diseases, then a social gradient in infections should exist. The aim of our study was to assess the relation between social class, immune parameters, and the prevalence of respiratory infections in children. METHODS: A cross-sectional survey examined children aged 5 to 14 years in 3 communities of Sachsen-Anhalt, Germany. Data of 1724 children were gathered by a parent-completed questionnaire and analyses of blood samples. Social class was defined by parental educational level. Immune parameters included serum immunoglobulin (Ig)G, IgA, and IgM; the C3c component of complement; and the total leukocyte count. The period prevalence of febrile colds and lifetime prevalences of physician-diagnosed bronchitis, tonsillitis, otitis media, and pneumonia were assessed from parents' reports. Adjusted odds ratios for the association between social class and belonging to the group of children with immune parameter levels in the upper 50th or 75th percentile or experiencing respiratory infections were calculated by logistic regression. RESULTS: Social class was inversely associated with secondary immune response parameters (IgG, IgA), whereas indicators of primary immune reactions and inflammation (IgM, C3c, leukocytes) were not related to social status. While an inverse social gradient was found for the period prevalence of febrile colds, the frequency of bronchitis, tonsillitis, and otitis media decreased with decreasing social class. CONCLUSIONS: Health inequalities exist in immune reactions and respiratory infections in children from different social classes. We hypothesize that in children from lower social classes, increased frequency of infections stimulated the secondary immune response and protected against more severe courses of respiratory infections.

Adolescent↗

Role of CD154 in the secondary immune response: the reduction of pre-existing splenic germinal centers and anti-factor VIII inhibitor titer.

Using the murine model of hemophilia A, we have examined the role of CD154 in the secondary immune response to factor VIII (FVIII). We previously reported that repeated i.v. injection of FVIII in hemophilia A mice induces a T cell-dependent anti-FVIII antibody formation. Herein, blocking of CD154 by a monoclonal antibody in FVIII-primed hemophilia A mice resulted in the disappearance of pre-existing spleen germinal centers (GC) in the white pulp within 24 h of treatment. Moreover, further expansion of GC in response to FVIII challenge was completely inhibited. In parallel, anti-FVIII antibody titers were markedly reduced and T cell responses to FVIII were abolished. The rapid disappearance of the GC after anti-CD154 treatment was not accompanied by increased B cell apoptosis; instead B cells accumulated in the peripheral zone of the splenic white pulp. Interestingly, repeated exposure to FVIII with anti-CD154 antibody administration blocked anti-FVIII antibody formation but failed to induce long-lasting unresponsiveness. Our data demonstrate that the CD40-CD154 interaction is critical for B cell homeostasis and the secondary immune response to FVIII. For potential clinical application, the data also suggest that therapies targeting the CD154 molecule may be useful for the treatment of high titer FVIII inhibitors in hemophilia A.

Animals↗

Absence of interleukin-4 enhances germinal center reaction in secondary immune response.

The germinal center (GC) is a compartment for B cell differentiation and proliferation. Interleukin (IL)-4 has been considered essential for GC functioning. To define the role of IL-4 in GC reaction, immunohistology of draining lymph nodes (LNs) of IL-4 gene-targeted (IL-4(-/-)) mice was performed during secondary immune response. IL-4(-/-) mice were immunized with ovalbumin emulsified in Freund' complete adjuvant. Final antigen challenge was done 4 weeks later. IL-4(-/-) mice had a higher production of IgG2a and IgG2b and a lower production of IgG1 than those in wild-type (WT) mice. In comparison with WT mice, LNs of IL-4(-/-) mice on days 4 and 7 after final antigen challenge were larger and contained a markedly greater number of GCs, which showed marked size variations with a large number of small GCs and a small number of markedly large GCs. By day 14, the number of GCs decreased to the same level as that in WT mice. However, the LN size in IL-4(-/-) mice was still larger than that in WT mice due to the presence of markedly large GCs. Although well-developed complement receptor(+) follicular dendritic cell (FDC) networks were present in GCs of IL-4(-/-) mice, no FDCs of mature phenotype (CD23(+)) were observed in many of the small GCs. In conclusion, the absence of IL-4 enhanced GC reaction and specific antibody response of Th1-type. IL-4 may play an important role in inducing the appropriate magnitude of humoral immune response.

Animals↗

Cells involved in the immune response. XXIX Establishment of optimal conditions for the primary and secondary immune responses by rabbit lymphoid cells in vitro.

Attempts were made to initiate the primary and secondary humoral immune responses to sheep red blood cells (SRBC) in vitro as determined by the hemolytic plaque-forming cell (PFC) response, with cell suspensions prepared from a variety of lymphoid organs of the rabbit- thymus, bone marrow, spleen, appendix, sacculus rotundus, Peyer's patches, popliteal lymph node and circulating leukocytes. A number of different media and gaseous phases were utilized in order to establish the optimal conditions for the immune response in vitro. The induction of a secondary PFC response was consistently obtained with 'memory' spleen cells obtained from rabbits 3-6 months following intravenous immunization with SRBC but not with cells of any of the other lymphoid organs, and this response probably represents the activity of memory cells which reside in the rabbit spleen. A primary response was observed only with 'normal' spleen cells, and the medium which faciliated the response was different from that which facilitated the induction of the secondary response in vitro. It was also observed, using a medium in which normal spleen cells were incapable of generating PFC', that mixed cultures of normal spleen and normal appendix or bone marrow cells could give a marked PFC reponse in vitro. Whether the PFC response to SRBCs obtained with the lymphoid cells of normal, unimmunized rabbits represent a true primary response, a secondary response, or a response of a different nature as a consequence of continuous subthreshold immunization of the rabbit with enteric microorganisms which cross-react with the antigen, remains to be determined. However, out initial successes with cultures consisting of cells of at least two distinct lymphoid organs in cases where the cells of any one of these organs could not respond, suggest that interaction of at least two functionally distinct cells is required and that the repsonse observed in vitro is probably a primary immune response.

Animals↗

Suppression of the secondary immune response by specific antibody, when given together with the secondary antigenic stimulus.

It is generally believed that antibody-mediated immunosuppression can be only produced in non-primed individuals, and that this applies both to experimental animals and Rh-negative women at risk. However, in this paper it is reported that the additional injection of 0.2 ml of an antiserum to sheep erythrocytes (SE) together with a secondary antigenic stimulus of 10(8) SE into mice, primarily immunized by a tiny dose of 5 x 10(5) SE 28 days before, was capable of producing effective suppression of the secondary immune response.

Animals↗

Intrinsic differences in the proliferation of naive and memory human B cells as a mechanism for enhanced secondary immune responses.

Humoral immune responses elicited after secondary exposure to immunizing Ag are characterized by robust and elevated reactivity of memory B cells that exceed those of naive B cells during the primary response. The mechanism underlying this difference in responsiveness of naive vs memory B cells remains unclear. We have quantitated the response of naive and memory human B cells after in vitro stimulation with T cell-derived stimuli. In response to stimulation with CD40 ligand alone or with IL-10, both IgM-expressing and Ig isotype-switched memory B cells entered their first division 20-30 h earlier than did naive B cells. In contrast, the time spent traversing subsequent divisions was similar. Consistent with previous studies, only memory cells differentiated to CD38(+) blasts in a manner that increased with consecutive division number. These differentiated CD38(+) B cells divided faster than did CD38(-) memory B cell blasts. Proliferation of CD40 ligand-stimulated naive B cells as well as both CD38(+) and CD38(-) cells present in cultures of memory B cells was increased by IL-10. In contrast, IL-2 enhanced proliferation of CD38(-) and CD38(+) memory B cell blasts, but not naive cells. Thus, memory B cells possess an intrinsic advantage over naive B cells in both the time to initiate a response and in the division-based rate of effector cell development. These differences help explain the accelerated Ab response exhibited by memory B cells after secondary challenge by an invading pathogen, a hallmark of immunological memory.

ADP-ribosyl Cyclase↗

[Analysis of spleen polyribosomal RNA during primary and secondary immune responses].

Synthesis of polyribosomal RNA was studied in the cells of mouse spleen, primarily and secondarily immunized with rat erythrocytes. In development of the immune response there was observed an increase in the number of polyribosomes which could occur first of all on account of intensification of their synthesis and secondly on account of their stabilization with the new informative RNA. Polyribosomal RNA labeled with P32 was analyzed in polyacrylamide gel. Electrophoresis of polyribosome preparations treated with a 2% SDS was conducted. It was found that in the secondary immune response in the 18S--4S there were revealed two principal activity peaks; other iRNA, which participated in the cellular growth of the organ realizing the antibody production, were synthesized during the primary immune response.

Animals↗

The role of complement receptor positive and complement receptor negative B cells in the primary and secondary immune response to thymus independent type 2 and thymus dependent antigens.

Both complement receptor positive (CR+) and complement receptor negative (CR-) B cells have been shown to be involved in the primary immune response to PC-Hy (phosphocholine conjugated hemocyanin), a thymus dependent (TD) antigen which preferentially induces antibody secretion in Lyb-5+ B cells during a primary adoptive transfer assay. CR+ and CR- B cells also responded in a primary adoptive transfer assay to TNP-Ficoll, a thymus independent type 2 (TI-2) antigen which activates only Lyb-5+ B cells. When the secondary immune response to PC-Hy and TNP-Ficoll were analyzed, it was found that most of the immune memory to both antigens was present in the CR- B cell subset. The CR- B cell subset also dominated the secondary immune response to PC-Hy in immune defective (CBA/N X DBA/2N)F1 male mice. These data indicate that CR- B cells dominate the memory response in both the Lyb-5+ and Lyb-5- B cell subsets of normal and xid immune defective mice and suggest that Lyb-5+ and Lyb-5- B cells can be subdivided into CR+ and CR- subsets.

Animals↗

Anti-immunoglobulin antibodies. VI. Age-dependent isotype and auto anti-immunoglobulin variation during secondary immune response in 129 mice.

The secondary and tertiary immune responses to TNP-KLH and the autoanti-immunoglobulin response were studied in 1-, 3- and 6-month-old 129/J and 129/Sv mice. A profound inability of aging 129/Sv mice (lifespan: 9 months) to produce gamma 2a anti-TNP antibodies relative to their normal counterparts was observed. However, this markedly low response could not be related to clearance of antibody by RFs since all 129 mice studied produced significant amounts of RFs after immunization with this T-dependent antigen. Furthermore, the results of the plaque forming cell assays indicated that young (1 month old) 129/Sv mice have an accelerated immune response while older mice produce significantly low direct and indirect responses compared to the control groups. The data suggest a fundamental dysfunction of B and/or T cells in 129/Sv mice and that spontaneous production of RFs in older mice may affect the ability of B and T cells to cooperate in a secondary response.

Aging↗

Immunological memory in mice. II. Cell interactions in the secondary immune response studies by means of immunoglobulin allotype markers.

Congenic mice, differing genetically only at the loci coding for immunoglobulin H chain (or Fc) structures, have been used to study cell interactions in the 7S (gammaG(2a)) antibody response to sheep erythrocytes (SRBC), as detected by the Jerne plaque-forming cell (PFC) method. The interaction between thymus and bone marrow cells was studied in adult thymectomized irradiated recipients, protected with syngeneic bone marrow and injected with thymus cells from the partner congenic strain. All of the gammaG(2a) PFC detected in the spleens of these mice were of bone marrow allotype. Adoptive secondary immune responses were then studied to determine whether a similar interaction between memory cells and bone marrow derived cells could be detected. Primed spleen cells from the partner congenic strain, or a subpopulation of these cells obtained by BSA density gradient fractionation, were injected into irradiated recipients alone, or together with syngeneic nonimmune spleen or bone marrow cells. All gammaG(2a) PFC detected in these experiments were of primed cell allotype. There was no evidence that antibody forming cell precursors in normal spleen or bone marrow participate in the adoptive secondary immune response detected 7 days after transfer of primed spleen cells. This was true regardless of whether the bone marrow cells were injected at the time of transfer, or were injected 1-2 wk earlier and allowed to become established in the spleens of recipient mice. Although no specific cell interaction was seen, bone marrow (and, to a lesser degree, normal spleen) cells were found to have a nonspecific enhancing effect on the adoptive secondary response when they were injected together with the primed spleen cells. This enhancement was not evident if the bone marrow cells were injected 1 or 2 wk prior to primed cell transfer.

Animals↗

In situ observation of germinal center cell apoptosis during a secondary immune response.

Germinal centers are highly organized anatomic structures essential for the clonal expansion of germinal center (GC) B-cells and associated somatic hypermutation, isotype switching, selection of the high-affinity B-cells (affinity maturation), and elimination of irrelevant or autoreactive clones. The identification of cellular interactions and regulatory mechanisms controlling apoptosis within GCs is essential for a complete understanding of the cellular and molecular dynamics of the GC reaction. We performed a kinetic analysis of the apoptotic activity occurring within GCs of draining lymph nodes of mice immunized with sheep red blood cells (SRBC) after secondary stimulation. The apoptotic activity of GC cells can be divided into three distinct phases : 1) initial phase (within the first days after immunization), 2) reactive phase (from the 5th day to 15th day after secondary immunization), and 3) late phase (after the 15th day). Apoptosis decreased shortly after secondary immunization followed by an increase to peak after an additional 10 days. Finally, apoptosis of GC cells decreased to basal levels. Administration of apoptosis inhibitors decreased the amount of apoptosis during the reactive phase. These results suggest that the reactive phase may be the critical period in which clonal selection and cellular differentiation to antibody forming cells take place.

Animals↗

Relationship between behavioral selection and primary and secondary immune response in wild gray rats.

The main characteristics of primary and secondary immune response (number of antibody producing cells and the amount of produced antibodies) are reduced in rats selected by elimination of aggressive behavior in comparison with animals selected by stimulation of this behavior. In parallel, the reaction of the pituitary-adrenal system during immune response was modified in these rats. Presumably, the differences in immune reactions of rats selected by contrast behavior are determined by changes in reactivity of the pituitary-adrenal system to stress and immune stimulation during selection.

Aggression↗