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Data available in literature on immunomorphological aspects of the immunological memory formation are summarized. Features of B memory cells and mechanisms of their activation are analyzed. Relations between antigen localization in the lymphoid follicles, the formation of virgin centres there and induction of B memory cells and organs of the immune system in the immunological memory are discussed.
To assess persistence of anti-HBs and immunologic memory of non-responders after revaccination, 40 healthy non-responder children were given a three-dose recombinant hepatitis B vaccine revaccination randomly by intramuscular (10 microg per dose) or intradermal (2 microg per dose) route and followed up to five years. All 17 intramuscular and 22 of 23 intradermal children developed a seroprotective antibody response (anti-HBs>or=10 mIU/mL) after revaccination. Children of intramuscular group had significantly higher seroprotection rates and anti-HBs geometric mean titers than the intradermal group. At year 5, 50% of children in intramuscular group, but only 18.2% of intradermal group still maintained seroprotection (P=0.075). By the end of follow-up, a booster dose (5 microg) was given to those who had lost seroprotection. All the eight intramuscular children developed an anamnestic response with increase of anti-HBs level by 215 times, but two of the 18 intradermal children failed to produce seroprotective level. Three-routine-dose intramuscular revaccination was significantly more effective than low-dose intradermal revaccination with the same number of injections. No child seroconverted to HBsAg, and 11 had transient infections indicated by seroconversion to anti-HBc. These results demonstrated that non-responders could benefit from three doses intramuscular revaccination not only in high proportion of anti-HBs conversion but also in long-term persistence of seroprotection, and more importantly in preservation of the immunologic memory years after loss of protective anti-HBs.
T-cell immunological memory consists largely of clones of proliferating lymphocytes maintained by antigenic stimulation and the survival and proliferative effects of cytokines. The duration of survival of memory clones in humans is determine by the Hayflick limit on the number of cell divisions, the rate of cycling of memory cells and factors that control erosion of telomeres, including mechanisms that control telomerase.
The antibody immune response and development of immunological memory to Murobacterium bovis antigens were studied in experiments carried out on CBA and BALB/c mice. Optimal antigen does for primary immune responses were 1 mg of both live and killed bacterial cells. In contrast to the primary antibody production, formation of the immunological memory was found to depend greatly on the viability of M. bovis injected. The levels of circulating immune complexes increased during secondary antibody responses demonstrated only in mice primed with live mycobacteria but not with killed ones. Aggregation of a purified derivative of tuberculin protein by crosslinking polypeptides using chromium chloride resulted in a significant enhancement of their immunogenic properties providing the high level of immunological memory formation as well as production of the antibodies against M. bovis specific antigens.
The basic regularities of the formation and realization of immunological memory to staphylococcal corpuscular antigen were studied in adoptive transfer experiments on CBA mice. The capacity of spleen cells for generating anamnestic response to staphylococci in the body of irradiated syngeneic recipients appeared on day 3 after the immunization of donors. The formation of immunological memory to staphylococci in mice was shown to be directly related to the dose of the antigen. The study also revealed that intact splenocytes did not suppress the realization of immunological memory to staphylococci in the system of adoptive transfer. The conclusion of the absence of the "isogeneic barrier" for memory cells specific to staphylococcal corpuscular antigen was made.
Infection with the human immunodeficiency virus results in profound perturbations in immunological memory, ultimately resulting in increased susceptibility to opportunistic infections and acquired immunodeficiency syndrome (AIDS). We have used rhesus macaques infected with the simian immunodeficiency virus (SIV) as a model to understand better the effects of AIDS virus infection on immunological memory. Acute infection with SIV resulted in significant deficits in CD4+ helper responses to cytomegalovirus (CMV) as well as CMV-specific cytotoxic T-lymphocyte and neutralizing antibody responses. Reactivation of CMV was associated with high levels of SIV replication and suppression of both T-helper and cytotoxic responses to CMV. We have also studied the effects of SIV infection on T-cell turnover in non-human primates. T-cell turnover was evaluated using the nucleoside analogue bromodeoxyuridine (BrdU) in combination with five-colour flow cytometric analysis. T cells in normal animals turned over at relatively rapid rates, with memory cells turning over more quickly than naive cells. In SIV-infected animals, the labelling and elimination rates of both CD4+ and CD8+ BrdU-labelled cells were increased by two- to threefold compared with normal controls. Further analysis of immunological memory in non-human primates should offer the opportunity to extend immunological insights from murine models to the pathogenesis and prevention of AIDS.
The role of T and B cells in the immunological memory and prolonged antibody production in mice was studied; for this purpose CBA mice were immunized with SRBC in doses of 1 X 10(6) or 1 X 10(9) cells, decapitated 21--25 days later, and their spleen cells were treated with T or B antiserum and transferred in a dose 7 x 10(7) cells to syngeneic recipients treated with cyclophosphamide for suppressing their immunity. The treatment of the donor spleen cells with T or B antiserum resulted in a considerable decrease in the hemagglutinin level, as well as in the number of IgM- and IgG-forming cells. The transfer of T and B cells, mixed in equal amounts, to syngeneic recipients restored the immunological memory of the animals; in those cases when the mixture had the prevalence of T cells the restoration of the immunological memory was even more pronounced. The donor spleen cells treated with T or B antiserum, when tested for their ability to produce IgM- and IgG-forming cells in vitro (prior to their transfer to the recipient), showed a decrease in the production of IgM-forming cells (68%) and IgG-forming cells (74%) only under the action of B antiserum, whereas T antiserum had no influence on the production of IgM- and IgG-forming cells in vitro.
To test for immunologic memory after a single dose of meningococcal C conjugate (MCC) vaccine in toddlers, 226 children 12-18 months old were randomized to receive 1 of 3 MCC vaccines, with a C polysaccharide booster 6 months later. The protein conjugate was diphtheria mutant toxoid in 2 vaccines (MCC-CRM(197)) and was tetanus toxoid in the third (MCC-TT). One month after the MCC vaccines, 91%-100% of children had serum bactericidal antibody (SBA) titers > or =8, and 89%-100% had a > or =4-fold increase. Geometric mean titer (GMT) increased from <4 to 215 (95% confidence interval [CI], 166-279). MCC-TT induced higher SBA GMTs (P<.001) and higher proportions with SBA > or =8 (P=.02) than did the MCC-CRM(197) vaccines. By 6 months, GMTs had decreased to 55.1 (95% CI, 40-76), but IgG antibody avidity increased (P<.001). Induction of immunologic memory was confirmed by a GMT of 1977 (range, 1535-2547) after the polysaccharide booster and a further increase in avidity. This evidence justified the use of a single dose in a catch-up immunization program for children 1-18 years old.
Immunological memory is embodied in the rapid and enhanced immune responsiveness to previously encountered antigens. Classically, memory would depend on the presence of small resting long-lived specific lymphocytes which, through clonal expansion after priming with antigen, would be present at higher frequencies than in naive animals. Here we report that T-cell-reconstituted athymic mice, which lack recent thymic emigrants, mount a primary response to a T-cell-dependent antigen, but do not develop memory or the capacity to produce specific anti-TNP IgG1 antibodies during the secondary immune response. On the other hand, if thymocytes are continuously provided during the secondary response, a typical secondary immune response is achieved with high levels of specific IgG1. These results lead us to propose that the development of humoral immunological memory cannot be explained solely by the long life span of primed T lymphocytes, but is rather a dynamic state dependent on the continuous presence of recent thymic emigrants and qualitative functional differences in responder T cells.
The mechanisms by which immunological memory is maintained after infection or vaccination are still a matter of debate. Long-term survival of memory T cells does not require major histocompatibility complex (MHC) contact. We show here that compared with memory CD4+ T cells that maintain contact with MHC class II, memory CD4+ T cells deprived of MHC class II contact show distinct functional defects upon antigen re-encounter. Thus, in contrast to their survival, maintenance of the typical quality of memory T cells crucially depends on MHC-derived signals.
Spleen cells (SC) of mice immunized with sheep red blood cells contain factor that suppresses primary immune response and the formation of immunologic memory. During studies of antigen-specific suppression of the immunogenesis, it has been discovered that suppressor factor of SC non-specifically blocks the development of immunologic memory for the other antigen (rat red cells) without affecting primary immune response to this antigen administration. It is assumed that at an early stage the cells responsible for the formation of immunologic memory are more sensitive to the non-specific effect of suppressor factor than those involved in the generation of primary immune response.
Cells that carry immunologic memory of phiX 174 have been studied in the rat. Memory cells could not be detected in thoracic duct lymph before the 10th day after priming. Thereafter, they increased rapidly in number to reach a plateau by the 4th week. This long latency was not due to a protracted process of maturation of cells formed and delivered to the lymph during the early post-induction period because memory never appeared in rats immunized adoptively with cells obtained before the 11th day. The fact that phiX memory cells are resistant to inhibition by vinblastine also indicates that memory is carried by cells which are released from regionally stimulated lymphoid tissue only after they have ceased dividing and become functionally mature. Adoptively acquired memory decays rapidly at first, but slowly from the 2nd week after cell transfer. This suggests that two cell populations of differing half-life are involved. If two distinct populations are necessary to the full expression of phiX memory, both populations recirculate because the memory cells in lymph draining the sites of the primary response and those reaching the central lymph of adoptive hosts give parallel dose-response curves.
A mechanism is proposed which explains the perpetuation of B-cell immunological memory indefinitely without requiring the presence of long-living memory cells or persisting antigen. The salient feature of this model is that immunological memory can be perpetuated indefinitely through the mutual interaction of idiotypic and anti-idiotypic B cells. These cells mutually stimulate and clonally expand with either specific or bystander T-cell help. Because B cells can present antigen, they present 'apparently foreign' idiopeptides to T cells. The idiopeptides of de novo synthesized antibody is presented to CD8+ T cells that recognize the idiopeptide-presenting cell as targets and regulate their population. The recycling of immunoglobulins from surface to endosomal compartment of B cells leads to the presentation of idiopeptides by major histocompatibility complex (MHC) class II to CD4+ T cells. Even if the majority of the clonally expanded cells die because of lack of stimulation, cytotoxic T lymphocyte (CTL) lysis or for other reasons, the surviving cells will be able to carry forward the memory. This mechanism also provides a means for affinity maturation through idiotypic selection of somatically mutated high affinity cells or those from the naïve pool. We have termed these two types of complementary B cells as Burnet B cells: those which recognize the antigen or antigen mimic, and Jerne B cells, which can recognize the idiotypes of antibody and carry antigen mimics. The proposed hypothesis can explain differential duration of memory for different antigens, the shelf space paradox, affinity maturation, repertoire shift, etc.
OBJECTIVES: Hoping to increase hepatitis B (HB) vaccination of adolescents, we did the following: 1) studied if modified regimens of the recombinant HB vaccine, Recombivax HB (2 or 3 doses of 5 or 10 microg given over 4 or 6 months), induce protective anti-hepatitis B surface antibody [anti-HBsAb] levels (>/=10 mIU/mL) comparable to the recommended regimen (5 microg at 0 and 1, and 6 months); 2) measured early antibody response after a single dose; and 3) assessed immunologic memory after 2- and 3-dose regimens. DESIGN: One thousand twenty-six adolescents were randomized to 1 of 5 treatment groups (10 microg at 0 and 4 or 0 and 6 months; 5 microg at 0 and 6 or 0, 2, and 4 or 0, 1, and 6 months) in an open trial. Anti-HBsAb was measured in all participants just before and 1 month after the last dose, and at several other times in a subset of vaccinees. Anti-HBsAb response to a booster dose 2 years later was examined to assess immunologic memory in participants vaccinated with 5 microg at 0 and 6 or 0, 1, and 6 months. RESULTS: All regimens induced >/=10 mIU/mL of anti-HBs in >/=95% of vaccinees. Geometric mean titers ranged from 674.8 to 3049.4 mIU/mL. Geometric mean titers were higher with regimens using the following: 1) 10 versus 5 microg; 2) 3 versus 2 doses; and 3) vaccination intervals of 6 versus 4 months. After 6 months, 63.8% of vaccinees given one 10-microg dose had >/=10 mIU/mL of anti-HBsAb versus 41.6% after one 5-microg dose. Participants vaccinated with either two or three 5-microg doses retained robust immunologic memory. CONCLUSIONS: . The results of this study show that a 2-dose regimen of Recombivax HB is as immunogenic and induces immunologic memory as effectively as the recommended 3-dose regimen. A regimen of two 10-microg doses may be of significant benefit for vaccinees who are poorly compliant or deviate from the intended vaccination schedule.
Mice received S. sonnei O-antigen at various concentrations (0.01-20,000 micrograms/ml) in drinking water. Systemic immunological memory, induced by feeding with O-antigen, was manifested by secondary immune response to parenteral boosting with homologous O-antigen or ribosomal vaccine. A pronounced priming effect was also produced by O-antigen at concentrations as low as 0.01 micrograms/ml after courses of feeding as short as 1-3 days. Even high doses of the antigen had no tolerogenic activity. The state of immunological memory was formed at least 12 days after the first feeding and lasted for a long period (at least 4 months after the last feeding). The specificity of immunological memory was proved in experiments with heterologous O-antigen (Salmonella typhimurium): the insignificant stimulating action of this antigen was revealed only when high concentrations of the antigen (1000 micrograms/ml) were used for feeding.
Contrary to what has been reported of thymus-independent antigens, we recently demonstrated that trinitrophenylated lipopolysaccharide (TNP-LPS), a class 1 thymus-independent antigen, elicited an anti-TNP anamnestic response in C57BL/6 mice. The question of whether or not class 2 thymus-independent antigens (DNP-Ficoll and DNP-dextran) could also induce immunological memory in this mouse strain was examined. Evidence induce immunological memory in this mouse strain was examined. Evidence is presented that priming with either of these class 2 thymus-independent antigens resulted in the induction of memory B lymphocytes. However, while the memory cells generated by these two antigens were able to be activated by TNP-LPS, they were not triggered by class 2 thymus-independent antigens. Genetic analysis of the capacity of different mouse strains to mount a secondary response to TNP-LPS revealed that major histo-compatibility-associated genes did not play an essential role, but that IgH-V or closely linked gene(s) controlled the immunological memory to TNP-LPS. These findings are discussed in terms of regulatory phenomena which govern the expression of memory response to thymus-independent antigens.
The role of antibodies and antigen deposition for the development of immunological memory has been incompletely investigated. We addressed whether long-term protection and T-cell memory can be stimulated against a genital tract infection with human Chlamydia trachomatis serovar D in B-cell-deficient (muMT) mice. At 6 months following a primary infection with C. trachomatis, both muMT and wild-type (WT) mice exhibited strong and comparable protection against reinfection. Evidence of long-lasting CD4+ T-cell memory was found in both muMT and WT mice, typified by comparable delayed-type hypersensitivity (DTH) reactions against chlamydial antigens. No bacterial or chlamydial DNA was found in the genital tract of muMT memory mice, suggesting that immunological memory was maintained in the absence of antigen. Whereas few T cells were present in the genital tract of memory mice, rapid recruitment of CD4+, and some CD8+, T cells into the genital tract tissue was observed after challenge with live bacteria. Accumulation of T cells in the genital tract was preceded by a short transient infection of similar magnitude in both muMT and WT memory mice, arguing against a long-term protective role of local antibodies. The rapid recruitment of CD4+ T cells into the genital tract was associated with a transient detection of interferon-gamma (IFN-gamma) mRNA in the genital tract in chlamydia-immune memory mice, which was not found in naïve, challenged mice. Thus, long-term protection in the genital tract against C. trachomatis infection is conveyed by IFN-gamma-producing CD4+ memory T cells, which appear to be maintained in the absence of antibodies and local antigen deposition.
In inbred CBA and CBA/N mice immunological memory was induced by subcutaneous injection of Mycobacterium bovis (BCG). Experiments with adoptive transfer of spleen T cells and ionomycin-resistant T cells (memory cells) between CBA and CBA/N mice in various combinations showed that immunological memory was not formed in CBA/N mice, but can be induced by adoptive transfer of cells from CBA mice.