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Molecular associations on the T cell surface correlate with immunological memory.

Different isoforms of CD45 are expressed on naive and memory CD4 T cells in the mouse, as revealed by an antibody to a set of isoforms of CD45 that utilize exon B, called CD45RB. Cloned TH1 and TH2 lines also differ for expression of isoforms detected by this antibody. Differential expression of CD45 isoforms correlates with different behavior of cell surface molecules involved in transmembrane signal transduction. On naive T cells, CD4, CD45 and the CD3/T cell receptor complex behave as independent entities. On memory T cells, these three molecules are stably associated on the T cell surface. Furthermore, on TH2 cells, which express intermediate levels of CD45RB, CD4 is stably associated with CD45 isoforms other than CD45RB, but this complex is not associated with the CD3/T cell receptor. These results lead us to propose that immunological memory in CD4 T cells consists of an altered structure of the T cell's specific signal transduction apparatus controlled by low-molecular weight CD45 isoforms. This altered receptor structure would allow the more sensitive triggering of the T cell characteristic of memory cells. The organization of multimolecular signal transduction systems may be a general means by which cells alter their physiological behavior, allowing the acquisition of new phenotypic characteristics.

Animals↗

Studies on antibody affinity at the cellular level. Correlation between binding properties of secreted antibody and cellular receptor for antigen on immunological memory cells.

Heterogeneity with regard to affinity of anti-hapten antibody was demonstrated at the cellular level in mice. The heterogeneity was shown at the level of single antibody-forming cells using hapten inhibition of hemolytic antibody plaque formation as a measure of affinity. The affinity increased with time after immunization. A high antigen dose initially resulted in relatively low affinity antibody production as compared to the affinity of the antibody production in animals immunized with a low dose. Affinity specialization of immunological memory cells was demonstrated, since it was possible to specifically fractionate such cells with regard to affinity on hapten-protein-coated plastic bead columns. High affinity memory cells showed a higher tendency to become retained in the columns than did low affinity memory cells. The data in a direct way demonstrate that memory cells carrying membrane-associated receptors of a certain affinity for the antigen are determined to release antibody of a similar affinity after stimulation with antigen.

Animals↗

Persistence of immunologic memory for 13 years in recipients of a recombinant hepatitis B vaccine.

All subjects in this clinical study gave informed written consent, and guidelines of the authors' institution regarding human experimentation were observed in the conduct of the study. A booster dose of vaccine given to 18 adolescents (immunized as children) and 7 older adults immunized 13 years earlier with a 3-dose course of recombinant hepatitis B vaccine induced a strong secondary antibody response, demonstrating that the vaccinees retained immunologic memory for HbsAG. Within one week, booster vaccination induced an 11 to 24-fold rise in the GMT of anti-HBs which continued, reaching 52 to 319-fold after 4 weeks. Significantly even the 5 individuals with less than 10 mIU/ml of anti-HBs prior to the booster all had impressive responses to the booster dose.

Adolescent↗

Antigen-driven T cell clones can proliferate in vivo, eradicate disseminated leukemia, and provide specific immunologic memory.

The aim of the current study was to determine the ability of antigen-driven cloned helper cell independent cytotoxic T lymphocytes (HITc) to proliferate and to survive in vivo and to mediate tumor therapy. The HITc clone utilized (denoted 1.B6) was specifically cytolytic to FBL-3, a syngeneic Friend virus-induced murine leukemia. Activation in vitro (48 hr) with FBL-3 induced secretion of interleukin 2 (IL 2), expression of IL 2 receptors (IL 2R), and in vitro proliferation. These cells could be "rested" for several weeks without stimulation, which resulted in reduced expression of IL 2R; however, restimulation with antigen resulted in reinduction of IL 2R and proliferation. The ability of cloned HITc to proliferate and to survive in vivo was examined in cyclophosphamide (CY) pretreated donor mice congenic for the Thy-1 gene. Adoptively transferred cloned HITc could be found in large numbers, and were widely distributed in vivo 1 wk after transfer. In tumor therapy, 1.B6 cells when injected into a site of tumor (i.p.) and used as an adjunct to CY were effective against disseminated FBL-3. In this circumstance, cloned 1.B6 cells could be recovered from cured mice 125 days after transfer and were shown to specifically lyse tumor and proliferate in vitro in response to FBL-3. Thus as an adjunct to CY, tumor-specific cloned HITc are capable of eradicating disseminated leukemia, persisting long-term in vivo, and providing specific immunologic memory.

Animals↗

Immunotherapy of murine leukemia VI. Development of immunologic memory in mice protected against Friend leukemia virus-induced disease by passive serum therapy.

The resistance of DBA/2 mice to infection with a leukemogenic dose of Friend leukemia virus (FLV) as a result of the passive administration of chimpanzee anti-FLV serum is maintained for at least six months after infection and is accompanied by the continued synthesis of mouse anti-viral antibodies analogous to that previously found to be associated with short-term protection (approx. 30 days). Furthermore, the induction of immunologic memory in serum-protected mice is demonstrated by their long-term resistance to rechallenge with FLV of FLV-infected leukemic spleen cells, although cells of an established transplantable syngeneic FLV-erythroleukemia (FLC-745) are not rejected. In the course of these studies, a serum prophylaxis effect was defined in DBA/2 mice treated with the chimpanzee anti-FLV serum before, rather than after FLV infection. The prophylaxis effect is highly dependent on the time period between the last serum inoculation and virus challenge. The results indicate that the long-term resistance of therapeutically protected mice to subsequent virus or leukemic cell challenge is not due to the short-term prophylactic effect of serum treatment alone.

Animals↗

[Effect of suppressor cells on the formation of immunologic memory in mice of various strains].

The mice of different lines were immunized twice with low doses (10(6) of sheep red blood cells (SRBC) at a 7-day interval. The immune spleen cells (ISC) from syngeneic and allogeneic mice preliminarily (14 days before) given SRBC (5 . 10(8) were transplanted into the animals at varying times before or after primary antigen administration. It was discovered that the administration of the ISC from CBA and DBA/2 mice to syngeneic mice 1 or 2 days after the priming drastically lowers the production of antibody-forming cells in the recipients in response to the repeated antigen injection. The ISC from C57BL/6 mice provided low suppressor effect. ISC transplantation one, three or six days after the priming exerted no effect on the height of the secondary immune response. Suppression of antibody formation was also obtained in the allogeneic combinations CBA ISC leads to leads to C57BL/6 and DBA/2 ISC leads to CBA. It is concluded that the spleen cells from mice immunized with SRBC are capable to suppress the development of the immunological memory of SRBC.

Animals↗

Probing the cellular basis for immunologic memory: approaching functional distinctions between primed and unprimed B-cell populations.

The physiologic distinctions between secondary and primary lymphoid populations remain largely conceptual. Altered activation, differentiation, and compartmentalization properties likely underlie these differences, but little precise knowledge of how these parameters are affected by antigen priming exists. Because lymphoid populations are dynamic entities and priming is a temporal process, lineage and life span analyses of definable subpopulations are required for the design and interpretation of experiments to probe functional distinctions between primed versus unprimed B-cell populations. Subsequent studies, which address differences in activation requirements and collaborative potential of primed versus unprimed B-cells are further required to evaluate the cellular basis of immunologic memory. Recent advances in the ability to dissect lymphoid differentiation subsets and lineages, coupled with a rapidly expanding knowledge of molecules which mediate B-lymphocyte growth and differentiation, render these possibilities amenable to experimental analysis.

Animals↗

Inhibition of immunological memory and T-independent humoral responses by monoclonal antibodies specific for murine complement receptors.

The importance of the complement system for mounting an antibody response in vivo was investigated by down-regulating and blocking the complement receptors (CR) in mice with three different monoclonal rat antibodies (mAb): mAb 8C12 recognized the C3b-binding site of CR1, mAb 7G6 recognized another site of CR1 and the C3d-binding site of CR2 and mAb 7E9 again recognized other epitopes on CR1 and CR2. We have earlier shown that 7G6, is the only mAb that completely suppresses the primary antibody response to horse erythrocytes. This antibody was also shown to suppress induction of immunological memory and a secondary antibody response. In contrast to what seems to be the case for thymus-dependent antibody responses, all three mAb could inhibit the antibody response to a thymus-independent antigen, dextran B 1355S.

Animals↗

Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to induce immunologic memory.

BACKGROUND: Pneumococcal polysaccharide vaccines are not protective against the most common pneumococcal infections in infancy. The importance of pneumococcal diseases and emerging antimicrobial resistance emphasize the need for prophylaxis. METHODS: Pneumococcal conjugate vaccine, containing capsular polysaccharides from serotypes 6B, 14, 19F and 23F conjugated to diphtheria toxoid (PncD), was given to 75 infants at 2, 4 and 6 months of age. Three dosages (1, 3 or 10 microg of each) were used. A placebo group of 49 infants received physiologic saline. Children were given a booster dose of either polysaccharide or conjugate vaccine at 14 months of age; the placebo group received conjugate vaccine. Antibody concentrations were determined with an enzyme immunoassay. RESULTS: The highest dose induced the strongest response after primary immunization, but booster response was greatest in the group primed with the lowest dose. Polysaccharide and conjugate vaccines induced booster responses of the same magnitude. At 24 and 36 months of age the antibody concentrations were similar in children who had received the PncD in infancy and in children immunized at 14 months of age only. CONCLUSIONS: The PncD conjugate vaccine is immunogenic and able to induce immunologic memory.

Antibodies, Bacterial↗

Immunologic memory induced at birth by immunization with inactivated polio vaccine in a reduced schedule.

One hundred forty-one healthy newborns were immunized 24 hours after birth with one dose of inactivated polio vaccine (IPV) of enhanced potency. Following the administration of a second vaccine dose six months later, a considerable proportion of babies responded with neutralizing antibody (NA) to the three poliovirus types. The very rapid occurrence and high antibody titer were indicative of an anamnestic response. Twenty-one infants who still had NA less than 1:4 to one-more poliovirus types after the second vaccine dose responded with very high NA values 7-10 days after a supplementary dose of IPV. It appears that IPV of enhanced potency administered at birth is apt to induce immunologic memory, which should provide the basis for protection against paralytic poliomyelitis in case of exposure to wild poliovirus later in life.

Humans↗

Clonal deletion as the mechanism of abrogation of immunological memory following liver grafting in rats.

In the rat strain combination of DA into PVG, an orthotopic liver graft has the ability to abrogate an existing state of sensitization against donor (DA) antigens. Fifty-four percent of PVG rats sensitized against DA by skin grafting accepted a DA liver graft permanently, and about half of these became systemically tolerant of DA MHC antigens, as demonstrated by permanent acceptance of a subsequent (second-set) DA skin or heart graft. The cellular basis of this tolerant state was studied in vivo. An adoptive transfer assay provided evidence for functional deletion of DA-reactive cells responsible for graft rejection from the recirculating lymphocyte pool. There was no evidence of a role for suppressor T cells in maintaining tolerance. However, a graft-versus-host assay showed normal reactivity in thoracic duct lymphocytes from tolerant animals. Hence, specific clonal deletion is apparently responsible for the abolition of immunological memory by liver grafting, but is selective in respect of the sets of alloreactive lymphocytes affected.

Animals↗

IgA antibodies in the bile of rats. II. Evidence for immunological memory in secretory immunity.

The Peyer's patches of Wistar rats were injected with suspensions of either sheep red blood cells (SRBC) or killed Brucella abortus organisms in doses that were insufficient to induce the appearance of biliary antibodies. The rats were challenged after periods ranging from 1 week to 1 year with the same dose of antigen given by the same route, and their bile was monitored for the appearance of specific antibodies. The test animals produced biliary antibodies to a much higher titre, and usually more rapidly, than control rats which had received the total dose of antigen as a single injection. As in primary responses, the biliary antibodies produced by challenging the primed rats were predominantly from the IgA class. The ability to mount substantial biliary responses to suboptimal doses of antigen could be transferred from primed donor rats to unimmunized recipients by thoracic duct lymphocytes, but not humoral factors, collected between 3 weeks and 5 months after priming. Gamma-irradiation of the lymphocytes abolished this effect. These results suggest strongly that immunological memory exists in the IgA system and that it is mediated by circulating lymphocytes.

Animals↗

Photoperiod controls the induction, retention, and retrieval of antigen-specific immunological memory.

Changes in day length affect several measures of immunity in seasonally breeding mammals. In Siberian hamsters (Phodopus sungorus), short day lengths suppress specific secondary antibody responses to the keyhole limpet hemocyanin (KLH) antigen and enhance cutaneous delayed-type hypersensitivity (DTH) responses to dinitrofluorobenzene (DNFB). These experiments tested whether day length affects secondary antibody and DTH responses by altering immune function solely during the interval after the initial exposure to each antigen, solely during the interval after the second exposure, or during both stages of the respective immune responses. Adult male Siberian hamsters were exposed to either a long (16 h light/day; LD) or a short (8 h light/day; SD) photoperiod for 7.5 wk before receiving an initial exposure to each antigen (KLH injection, cutaneous DNFB treatment; separate groups of animals for each antigen). A subset of LD hamsters was transferred to the SD photo-period, and a subset of SD hamsters was transferred to the LD photoperiod. Other hamsters remained in LD or SD. Eight weeks later, all hamsters were challenged with a second subcutaneous injection of KLH or a second application of DNFB to the ear, and immune responses were measured. Exposure to SD during the primary antibody response did not affect secondary IgG responses, but SD exposure during the secondary response significantly suppressed IgG production independent of day length during the initial KLH treatment. In contrast, exposure to SD during the DNFB challenge enhanced the ensuing DTH response, but this enhancement depended on the photoperiod prevailing during the initial exposure. Exposure to SD during the sensitization stage did not enhance DTH in hamsters subsequently exposed to LD. The data suggest that short photoperiods have enduring effects on immune responsiveness and on the establishment and retention of immunological memory.

Animals↗

The importance of antineuraminidase antibodies in resistance to influenza A and immunologic memory for their synthesis.

Eight hundred and seventy-seven sera from 360 adults aged 18-50 who were under permanent observation from October 1980 to March 1981 have been studied by haemagglutination-inhibition (HI) and erythrocyte elution-inhibition (EI) tests--a simplified method of antineuraminidase antibody titration. It was demonstrated in some subjects infected with influenza A H1N1 and H3N2 viruses that the antibody rise was to one of the surface antigens only--haemagglutinin or neuraminidase. These subjects made up 5.2-25.8% of all examinees. The protective effect of antibodies to neuraminidase was similar to that of antihaemagglutinins. Interaction of both types of antibodies was observed in protection against the disease. Data have been obtained on the influence of antineuraminidase antibodies in decreasing the severity of natural infection with influenza A. A study of heterologous immunologic responses to haemagglutinin and neuraminidase among persons immunized with live influenza A H1N1 and H3N2 vaccines and among children naturally infected with influenza A H3N2 demonstrated the presence of immunologic memory for antineuraminidase antibody synthesis. Thus, the suggestion of a common antigenic structure for neuraminidase N1 and N2 is made.

Adult↗

Induction of immunologic memory by a lipopolysaccharide-protein complex isolated from Fusobacterium necrophorum: humoral response.

The serum antibody response in BALB/c mice to a lipopolysaccharide-protein (LPS-P) complex was monitored by the enzyme-linked immunosorbent assay, total and 2-mercaptoethanol-resistant hemagglutination, and radial immunodiffusion. Dose-response analyses demonstrated that suitable primary doses of LPS-P injected IV or IM induced substantial concentrautions of specific serum immunoglobulin (Ig) M and IgG. Moreover, these values were greatly enhanced with small-dose booster injections. Inoculation of mice with a suitable primary IM dose of aluminum hydroxide-precipitated LPS-P-induced specific IgM and IgG amounts that were detectable for 120 days. An enhanced secondary response to antigen booster injections was generated 105 days after primary inoculation, providing direct evidence that LPS-P can induce immunologic memory. Similar results were obtained for IV inoculations of LPS-P, although the primary IgG response was not as persistent. Seemingly, the memory response to LPS-P was largely dependent on the protein component of the molecule.

Animals↗

Short-term stress experienced at time of immunization induces a long-lasting increase in immunologic memory.

It would be extremely beneficial if one could harness natural, endogenous, health-promoting defense mechanisms to fight disease and restore health. The psychophysiological stress response is the most underappreciated of nature's survival mechanisms. We show that acute stress experienced before primary immunization induces a long-lasting increase in immunity. Compared with controls, mice restrained for 2.5 h before primary immunization with keyhole limpet hemocyanin (KLH) show a significantly enhanced immune response when reexposed to KLH 9 mo later. This immunoenhancement is mediated by an increase in numbers of memory and effector helper T cells in sentinel lymph nodes at the time of primary immunization. Further analyses show that the early stress-induced increase in T cell memory may stimulate the robust increase in infiltrating lymphocyte and macrophage numbers observed months later at a novel site of antigen reexposure. Enhanced leukocyte infiltration may be driven by increased levels of the type 1 cytokines, IL-2 and IFN-gamma, and TNF-alpha, observed at the site of antigen reexposure in animals that had been stressed at the time of primary immunization. In contrast, no differences were observed in type 2 cytokines, IL-4 or IL-5. Given the importance of inducing long-lasting increases in immunologic memory during vaccination, we suggest that the neuroendocrine stress response is nature's adjuvant that could be psychologically and/or pharmacologically manipulated to safely increase vaccine efficacy. These studies introduce the novel concept that a psychophysiological stress response is nature's fundamental survival mechanism that could be therapeutically harnessed to augment immune function during vaccination, wound healing, or infection.

Acute Disease↗

Augmentation of the antibody response in aged mice with an 8-derivatized guanosine nucleoside and its effect on immunological memory.

The injection of aged mice with 7-methyl-8-oxoguanosine (7m8oGuo) along with aggregated human gamma-globulin (AHGG) results in an enhanced anti-HGG antibody response. Aged mice injected with AHGG alone make only a feeble anti-HGG response. The enhanced response in aged mice was not significantly different from the response obtained in young-adult mice injected only with AHGG. However, the enhanced response obtained by injection of 7m8oGuo in young-adult mice was several orders of magnitude greater than that observed in the aged mice. Aged mice given a primary injection of AHGG alone failed to make a secondary response to AHGG given 90 days later, whereas aged mice injected with 7m8oGuo along with a primary injection of AHGG showed variable secondary antibody responses to AHGG. Two of seven mice showed high degrees of immunological memory equivalent to that seen in young-adult mice while others showed either meagre or no responses. The effect of 7m8oGuo appeared to be primarily on B cells, albeit the role of T cells cannot be ruled out.

Aging↗

Activation of CD4 T cells by somatic transgenesis induces generalized immunity of uncommitted T cells and immunologic memory.

Cellular immune responses were analyzed in vivo after a single intraspleen inoculation of DNA coding for a 12-residue Th cell determinant associated with a 12-residue B cell epitope, a process termed somatic transgene immunization. We show that CD4 T cells are readily activated and produce IL-2, IFN-gamma and IL-4, characteristics of an uncommitted phenotype. Linked recognition of the two epitopes coded in the same transgene promoted IgM-IgG1 switch and enhanced the total Ab response but had no effect on IgG2a Abs. Although originating in the spleen, T cell responsiveness was found to spread immediately and with similar characteristics to all lymph nodes in the body. A single inoculation was also effective in establishing long term immunologic memory as determined by limiting dilution analysis, with memory T cells displaying a cytokine profile different from that of primary effector T cells. These studies provide evidence that by initiating immunity directly in secondary lymphoid organs, an immune response is generated with characteristics that differ from those using vaccines of conventional DNA or protein in adjuvant administered in peripheral sites. Somatic transgene immunization can therefore be used to probe T cell responsiveness in vivo and represents a tool to further understanding of the nature of the adaptive immune response.

Animals↗