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PubMed2003

A transgenic mouse model genetically tags all activated CD8 T cells.

Identifying and characterizing Ag-specific CD8+ T cells are central to the study of immunological memory. Although powerful strategies such as MHC tetramers and peptide-induced cytokine production assays exist for identifying Ag-specific CD8+ T cells, alternate strategies that are not dependent upon a priori knowledge of the immunodominant and subdominant antigenic epitopes, as well as the MHC background of the animal are of obvious utility. In this study, we present a transgenic mouse model that uses Cre-loxP recombination to permanently mark all activated CD8+ T cells with beta-galactosidase. We used the lymphocytic choriomeningitis virus infection model to track the dynamics of the antiviral CD8+ T cell responses. We show that in this transgenic mouse model system, all of the antiviral effector and memory CD8+ T cells are contained within the beta-gal-marked CD8+ T cell population.

Animals↗
PubMed1975

The anamnestic response of the secretory immune system: A review.

Following topical immunization of the respiratory mucosa in man, persistence of antibody in the respiratory secretions can be demonstrated in some individuals for more than one year. The secretory response to replicating agents is generally more prolonged than the response to less persistent antigens. Repeat topical antigenic stimulation provokes a response which differs very little from the primary response in magnitude, duration or latency. Nevertheless, if more than 1 year following adequate primary intranasal immunization, at a time when secretory antibodies are no longer detectable, men are again vaccinated intranasally with a dose of formalin-inactivated rhinovirus vaccine which will not provoke a primary secretory immune response, some vaccinees will produce nasal antibody. Similarly in mice, a second topical immunization of the respiratory tract with a dose of tetanus toxoid which does not produce a detectable primary secretory immune response will cause 11S IgA antibodies to appear in bronchial and nasal washings. Thus, it is possible that the secretory immune system may possess certain attributes of immunologic memory as classifically defined by the responses of the internal immune system to repeated antigenic stimulation.

Animals↗
PubMed1985

Alloantigen-activated lymphocytes from mice bearing a spontaneous "nonimmunogenic" adenocarcinoma inhibit its growth in vivo by recruiting host immunoreactivity.

Nylon wool columns eluting lymphocytes from the spleen of mice bearing a clinically evident spontaneous, nonimmunogenic adenocarcinoma of recent origin (TS/A) do not display cytotoxic response, release of lymphokines, and proliferation in vitro against TS/A cells, nor do they inhibit TS/A tumor growth in a Winn-type neutralization assay in vivo. After 5-day co-culture with allogeneic spleen cells from mice differing at multiple minor histocompatibility antigens only, these lymphocytes are still noncytolytic against TS/A cells, whereas they release interferon-gamma, mediate delayed-type hypersensitivity (DTH) reactions, and inhibit TS/A tumor growth in the Winn assay. In the Winn test, alloactivated lymphocytes from TS/A tumor-bearing mice are more effective than those from normal mice on a per cell basis. The induction of this TS/A tumor inhibition ability depends on the presence in the cultures of Thy-1+ lymphocytes. The presence of Lyt-2+ lymphocytes is also important, whereas that of asialo GM1+ is not. The TS/A inhibition in vivo by alloactivated lymphocytes mostly depends on Thy-1+, Lyt-2- and asialo GM- lymphocytes, even though a few Thy- cells are also very efficient tumor inhibitors. The alloactivated lymphocytes inhibit TS/A tumor growth by recruiting the radiosensitive effector mechanisms of the recipient mice required for ultimate tumor rejection. TS/A tumor rejection leaves a specific DTH and an immunologic memory resulting in rejection of a second lethal TS/A challenge in a significant number of mice.

Adenocarcinoma↗
PubMed2004

Salivary antibodies induced by the seven-valent PncCRM conjugate vaccine in the Finnish Otitis Media Vaccine Trial.

We studied salivary antibodies induced by a seven-valent pneumococcal conjugate vaccine (PncCRM). Healthy Finnish children (n=115), a subcohort of the Finnish Otitis Media (FinOM) Vaccine Trial, were immunised either with the PncCRM or a control vaccine (hepatitis B) at the age of 2, 4, 6, and 12 months. Salivary IgG, IgA, IgA1, IgA2 and sIg for serotypes 6B, 14, 19F, and 23F were measured at 7 and 13 months of age, and IgG and IgA also at 4-5 years of age. The PncCRM could induce both salivary anti-Pnc polysaccharide IgG and IgA. However, by the age of 4-5 years IgA concentrations had increased in both groups and were similar. The increases in IgA concentrations were mostly of IgA1 subclass. The difference between the PncCRM and the control group was more notable for serotypes 6B, 14 and 23F than for serotype 19F. We could not find evidence for the development of mucosal immunologic memory after vaccination with the PncCRM.

Adolescent↗
PubMed2002

Non-lethal viral challenge of influenza haemagglutinin and nucleoprotein DNA vaccinated mice results in reduced viral replication.

Influenza DNA vaccines have been widely studied in experimental animal models and protection documented after lethal viral challenge. In this study, we have investigated the humoral response after a non-lethal viral challenge of mice vaccinated with plasmids encoding the influenza haemagglutinin (HA) or nucleoprotein (NP) genes. BALB/c mice were immunized intramuscularly with three doses (100 microg) of HA, NP or backbone plasmid at 3-week intervals, or alternatively infected intranasally, before being challenged with homologous virus 13 weeks later. Mice were then sacrificed at weekly intervals and the antibody-secreting cell response was examined systemically (spleen and bone marrow) and in the respiratory tract (nasal associated lymphoid tissue (NALT) and lungs). Sera were collected after each dose of vaccine and at sacrifice and analyzed by ELISA, haemagglutination inhibition and virus neutralization assays. We found that previous viral infection apparently elicits sterilizing immunity. Vaccination with HA or NP DNA significantly reduced viral replication in the nasal cavity after viral challenge, however, increases in serum antibody titres were observed after challenge. Prior to challenge, specific antibody-secreting cells were observed in the systemic compartment after HA or NP DNA vaccination but were also found in the NALT after viral challenge. In conclusion, intramuscular DNA vaccination resulted in immunological memory in the systemic compartment, which was rapidly reactivated upon viral challenge.

Animals↗
PubMed1977

Studies on the immune response to fixed antigens. II. Optimal conditions for inducing and eliciting helper function by fixed antigens and the mechanism responsible for this effect.

Heavily trinitrophenylated sheep red blood cells (RBC) (TNP128SRBC) and glutaraldehyde-treated SRBC (G-SRBC) induced helper function. This helper function could accelerate anti-SRBC and anti-TNP secondary responses to subsequent challenge with TNP0.14SRBC in different strains of mouse. Preferential induction of helper function over primary antibody response was obtained with fixed antigens only. High doses of fixed RBC (4 X 10(7) or 4 x 10(8)/mouse) could induce optimal helper function and high doses of the challenger TNP0.14SRBC (4 X 10(7) or 4 x 10(8)/mouse) could optimally recall this function and stimulate secondary responses. G-SRBC was a better inducer of helper function than low doses of nonmodified SRBC. TNP128SRBC-primed mice produced a significant anti-SRBC response after subsequent challenge with TNP0.14 mouse RBC. Reverse help was suggested as one of the possible mechanisms of this response. Early helper function which developed four days after priming with TNP128SRBC or G-SRBC could be transferred to irradiated recipients with T, but not B, cells. Late immunologic memory which appeared 18 days after priming with TNP128SRBC could be transferred to irradiated recipients only with a mixture of T and B cells.

Animals↗
PubMedDate not supplied

Anamnestic response to a thymus-independent antigen, TNP-LPS in C57BL/6 and DBA/2 mice: dominance of the IgG secondary response of the C57BL/6 mice in the F1 hybrids.

The primary and secondary immune responses to a thymus-independent antigen, TNP-LPS, were investigated in C57BL/6, DBA/2 and (C57BL/6 x DBA/2)F1 mice. While there is no evidence that TNP-LPS induces immunological memory in DBA/2 mice, a definite priming effect has been observed in C57BL/6 mice. Memory is revealed by the appearrance of antibody-forming cells of the IgG isotype. The differentiation of B micron precursors into B gamma memory cells is a dominant phenotype, since it is also found in the F1 C57BL/6 x DBA/2 hybrids.

Animals↗
PubMed1975

Antigen presentation as a factor in the protective immune response to renal infection.

Host protection against renal infection may be augmented by active immunization against the causative organism. In these experiments we have investigated the effect of varying amounts and methods of presentation of bacterial antigen on the seconday immune response. Primary immunization with varying amounts of both killed and live antigen did not affect the nature of the secondary immune response although active renal infection did have a noticeable effect on the titre of serum antibody during the primary immune response. The experiments confirmed the presence of immunological memory to the somatic antigen of E. coli and showed that memory persisted for at least 6 months after primary immunization. Experiments have also been carried out which have demonstrated that memory to the somatic antigen of E. coli is carried by the B lymphocyte.

Animals↗
PubMed2004

A stochastic model of cytotoxic T cell responses.

We have constructed a stochastic stage-structured model of the cytotoxic T lymphocyte (CTL) response to antigen and the maintenance of immunological memory. The model follows the dynamics of a viral infection and the stimulation, proliferation, and differentiation of naïve CD8(+) T cells into effector CTL, which can eliminate virally infected cells. The model is capable of following the dynamics of multiple T cell clones, each with a T cell receptor represented by a digit string. MHC-viral peptide complexes are also represented by strings and a string match rule is used to compute the affinity of a T cell receptor for a viral epitope. The avidities of interactions are also computed by taking into consideration the density of MHC-viral peptides on the surface of an infected cell. Lastly, the model allows the probability of T cell stimulation to depend on avidity but also incorporates the notion of an antigen-independent programmed proliferative response. We compare the model to experimental data on the cytotoxic T cell response to lymphocytic choriomeningitis virus infections.

Antigens, Viral↗
PubMed1990

Verification of immune response optimality through cybernetic modeling.

An immune response cascade that is T cell independent begins with the stimulation of virgin lymphocytes by antigen to differentiate into large lymphocytes. These immune cells can either replicate themselves or differentiate into plasma cells or memory cells. Plasma cells produce antibody at a specific rate up to two orders of magnitude greater than large lymphocytes. However, plasma cells have short life-spans and cannot replicate. Memory cells produce only surface antibody, but in the event of a subsequent infection by the same antigen, memory cells revert rapidly to large lymphocytes. Immunologic memory is maintained throughout the organism's lifetime. Many immunologists believe that the optimal response strategy calls for large lymphocytes to replicate first, then differentiate into plasma cells and when the antigen has been nearly eliminated, they form memory cells. A mathematical model incorporating the concept of cybernetics has been developed to study the optimality of the immune response. Derived from the matching law of microeconomics, cybernetic variables control the allocation of large lymphocytes to maximize the instantaneous antibody production rate at any time during the response in order to most efficiently inactivate the antigen. A mouse is selected as the model organism and bacteria as the replicating antigen. In addition to verifying the optimal switching strategy, results showing how the immune response is affected by antigen growth rate, initial antigen concentration, and the number of antibodies required to eliminate an antigen are included.

Animals↗
PubMed2000

Development of oral vaccines for human use.

In developed and developing countries, oral vaccine formulations that elicit protection at mucosal surfaces are attractive vaccine candidates. Research has shown that vaccine delivery using either viral or non-viral vector delivery of heterologous proteins via the oral route is highly effective. Improvements in non-viral vector uptake, specific targeting, antigen presentation and antigen release times will be required to overcome differences in the immune response following delivery. In contrast, the use of plant and animal viruses as vectors provides an effective method for targeted gene delivery. Recently, recombinant plant viruses grown in plants or transgenic plants have been proposed as edible vaccines for human use. Food plants offer many advantages as affordable, oral vaccines, especially for use in developing countries. Further research is necessary to develop strategies to improve immunological memory following oral vaccination and to avoid immunological tolerance in the host.

Adenoviridae↗
PubMed1964

THE FORMATION AND PROPERTIES OF POLIOVIRUS-NEUTRALIZING ANTIBODY. II. 19S AND 7S ANTIBODY FORMATION: DIFFERENCES IN ANTIGEN DOSE REQUIREMENT FOR SUSTAINED SYNTHESIS, ANAMNESIS, AND SENSITIVITY TO X-IRRADIATION.

Transient 19S antibody formation was induced in rabbits by single or repeated stimuli with a small dose of poliovirus. Available evidence indicated that cessation of 19S synthesis was due to lack of continuous antigenic stimulation and not to loss of cells participating in antibody formation. "Immunological memory" in 19S antibody formation was demonstrable only within 2 to 3 days following discontinuation of synthesis but not thereafter. Following stimulation with a high dose of polio-virus both 19S and 7S antibodies were formed. The kinetics of their formation differed in several respects: (a) 19S antibody preceded 7S antibody by 1(1/2) days; (b) 19S antibody rose to peak titers at a rapid exponential rate within 1 week, while 7S antibody increased at a slow decelerating rate for 3 weeks; (c) 19S antibody formation was short-lasting while 7S antibody synthesis endured. A renewed formation of both antibodies occurred following restimulation with a high antigen dose. The secondary 19S and 7S antibody responses were similar to the respective primary responses, and the preexistence of 7S antibody synthesis did not detectably alter the secondary 19S response. Both 19S and 7S antibodies were formed and the kinetics of their formation was similar (a) for infectious and non-infectious (UV-) poliovirus antigen; (b) for the serologically unrelated poliovirus and Coxsackie B-4 virus; (c) when poliovirus was administered by different routes; (d) when 1-day-old or adult rabbits were immunized; (e) in antibody responses to poliovirus in rabbit, guinea pig, and man. Whole body x-irradiation 20 hours prior to antigenic stimulus (high dose) resulted in delayed but markedly prolonged 19S antibody formation and inhibition of 7S antibody synthesis. Thus, the formation of 19S and 7S antibody differed in (a) antigen dose requirements for induction and maintained synthesis; (b) kinetics; (c) retention of memory; and (d) sensitivity to prior x-irradiation. These differences are best explained on the assumption that the two antibodies are produced by different cells.

Animals↗
PubMed2006

Induction of secretory immunity and memory at mucosal surfaces.

Mucosal epithelia comprise an extensive vulnerable barrier which is reinforced by numerous innate defence mechanisms cooperating intimately with adaptive immunity. Local generation of secretory IgA (SIgA) constitutes the largest humoral immune system of the body. Secretory antibodies function both by performing antigen exclusion at mucosal surfaces and by virus and endotoxin neutralization within epithelial cells without causing tissue damage. SIgA is thus persistently containing commensal bacteria outside the epithelial barrier but can also target invasion of pathogens and penetration of harmful antigens. Resistance to toxin-producing bacteria such as Vibrio cholerae and enterotoxigenic Escherichia coli appears to depend largely on SIgA, and so does herd protection against horizontal faecal-oral spread of enteric pathogens under naïve or immunized conditions--with a substantial innate impact both on cross-reactivity and memory. Like natural infections, live mucosal vaccines or adequate combinations of non-replicating vaccines and mucosal adjuvants, give rise not only to SIgA antibodies but also to longstanding serum IgG and IgA responses. However, there is considerably disparity with regard to migration of memory/effector cells from mucosal inductive sites to secretory effector sites and systemic immune organs. Also, although immunological memory is generated after mucosal priming, this may be masked by a self-limiting response protecting the inductive lymphoid tissue in the gut. The intranasal route of vaccine application targeting nasopharynx-associated lymphoid tissue may be more advantageous for certain infections, but only if successful stimulation is achieved without the use of toxic adjuvants that might reach the central nervous system. The degree of protection obtained after mucosal vaccination ranges from reduction of symptoms to complete inhibition of re-infection. In this scenario, it is often difficult to determine the relative importance of SIgA versus serum antibodies, but infection models in knockout mice strongly support the notion that SIgA exerts a decisive role in protection and cross-protection against a variety of infectious agents. Nevertheless, relatively few mucosal vaccines have been approved for human use, and more basic work is needed in vaccine and adjuvant design, including particulate or live-vectored combinations.

Animals↗
PubMed1992

Selection of B cell clones and memory B cells.

During a humoral immune response, a variety of histological, cellular, and molecular changes occur within the immune system. In this review, we would like to summarize and integrate these changes with a view toward gaining insight into the process of clonal selection. We describe here how antigen receptor number limits the sensitivity of a B cell to transduce a signal in response to antigen. We have also seen that this limitation can be compensated for by expressing a higher affinity receptor for antigen. These data suggest that the down regulation of antigen binding receptors in germinal center cells might be designed to exploit anticipated increases in affinity that result from somatic hypermutation in these tissues. This hypothesis is consistent with observed biological changes that occur during an immune response and has bearing on both the mechanism of affinity maturation and generation of immunologic memory.

Animals↗
PubMed2004

The development of effector and memory T cells in cutaneous leishmaniasis: the implications for vaccine development.

Leishmania major infections induce the development of a CD4(+) T-helper 1 (Th1) response that not only controls the primary infection but also results in life-long immunity to reinfection. How that immunity is maintained is unknown, although because of the existence of infection-induced immunity, there has been an assumption that the development of a vaccine against leishmaniasis would be relatively easy. This has turned out not to be the case. One problem has been the finding that a large part of the immunity induced by a primary infection depends upon the presence of persistent parasites. Nevertheless, there are ample situations where immunologic memory persists without the continued presence of antigen, providing the prospect that a non-live vaccine for leishmaniasis can be developed. To do so will require an understanding of the events involved in the development of an effective protective T-cell response and, more importantly, an understanding of how to maintain that response. Here, we review work from our laboratory, describing how Th1 cells develop in L. major-infected mice, the nature of the memory T cells that provide protection to reinfection, and how that information may be utilized in the development of vaccines.

Animals↗
PubMed1991

Different profiles of the human immune response to primary and secondary immunization with an oral Salmonella typhi Ty21a vaccine.

Human immune response to a secondary immunization by the oral route was studied by enumerating specific antibody-secreting cells (ASC) in the peripheral blood, believed to reflect the local immune response in the mucosa. The volunteers had been immunized 1-2 years earlier with live Salmonella typhi Ty21a given orally as three doses of vaccine in enteric-coated capsules (3 x E); their ASC and serum antibody responses have been published. In the present study 17 of the same volunteers received one booster dose of the same vaccine (B-E). Specific ASC appeared in the blood of all volunteers after vaccination, peaked on day 5 and faded away thereafter so that on day 9 specific ASC were detected in only seven subjects. The ASC responses to the single booster dose were significantly higher than those to one dose in primary immunization and at least as high as those of the same volunteers to three doses in primary immunization. Serum antibody responses were not seen in any of the vaccinees after secondary immunization, whereas after primary immunization 60% of these subjects responded. This study shows the presence of immunologic memory also in respect of the human ASC response, and confirms the separate nature of ASC and serum response.

Administration, Oral↗
PubMed1993

Gamma interferon response in secondary Leishmania major infection: role of CD8+ T cells.

CD8+ T cells have been shown to contribute to the rapid resolution of secondary lesions developing in immune mice challenged with Leishmania major. In the present study, we assessed directly the participation of specific CD8+ T cells in the memory response induced in immune mice by reinfection. Lymphocyte populations from reinfected immune mice exhibit marked secondary gamma interferon (IFN-gamma) responses. The participation of IFN-gamma-producing CD8+ T cells in the memory response elicited by secondary infectious challenge was demonstrated in both genetically resistant immune CBA mice and genetically susceptible immune BALB/c mice that were rendered resistant by administration of anti-CD4 monoclonal antibody in the early phase of the primary infection. The protective function of CD8+ T cells in experimental murine cutaneous leishmaniasis might thus be explained in part by their ability to secrete IFN-gamma. In this context, the neutralization of IFN-gamma at the time of reinfection reduced the Leishmania-specific delayed-type hypersensitivity response, showing that this cytokine is involved in the recall of immunological memory to L. major in vivo.

Animals↗
PubMed1998

[Fatal course of measles infection in a patient with a low-grade malignant non-Hodgkin lymphoma].

HISTORY AND CLINICAL FINDINGS: A 35-year-old man, for 6 years known to have non-Hodgkin lymphoma (NHL) was admitted because of deteriorating general condition, drowsiness and 11 days of flu-like symptoms. A generalized rash had been noted 5 days after onset of symptoms. His 2-year-old son had fallen ill with measles a few days earlier. The patient had reportedly had measles as a child. On admission a generalized rash was found, he had a fever of 40.5 degrees C, tachypnoea, conjunctivitis and possible meningismus. INVESTIGATIONS: Lactate dehydrogenase activity was raised to 458 U/ml, and C-reactive protein to 240 mg/ml. Cerebrospinal fluid contained 8/3 cells and protein of 269 mg/l. The chest radiogram revealed opacification in the left upper lobe. Computed tomography of the skull demonstrated a pansinusitis. DIAGNOSIS, TREATMENT AND COURSE: As measles encephalitis seemed unlikely he was treated for the measles superinfection of bacterial pneumonitis (measles RNA in the bronchoalveolar lavage) and the sinusitis with broad-spectrum antibiotics. After initial improvement artificial ventilation had to be be gun on day 3 because of an acute respiratory distress syndrome, diagnosed both clinically and radiologically. Despite additional antiviral and intensive medical treatment he died on day 11. CONCLUSION: Patients with impaired immunocompetence due to NHL may lose their immunological "memory" for a previous measles infection. Prevention of exposure may therefore be necessary, in addition to early hyperimmunoglobulin administration.

Adult↗