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PubMed2006

DNA vaccination with CCL2 DNA modified by the addition of an adjuvant epitope protects against "nonimmune" toxic renal injury.

CC-chemokine-encoding DNA vaccine has been reported to be capable of inducing immunologic memory to corresponding pathogenic self CC-chemokines in animal models of autoimmune disease. This study investigated whether introduction of a foreign T helper epitope into monocyte chemoattractant protein 1 (CCL2) DNA vaccine could boost its immunogenicity by inducing strong neutralizing autoantibody against the pathogenic chemokine CCL2 sufficiently to be protective in a classically nonimmune model of disease, Adriamycin nephropathy (AN). Modification of the CCL2 DNA vaccine by replacing a surface loop region of CCL2 sequence with tetanus toxoid T helper epitope P30 elicited a strong self-specific CCL2 autoantibody production, as well as an IFN-gamma-producing T cell cellular response. The increased immunogenicity of modified CCL2 DNA vaccination but not unmodified CCL2 DNA vaccination was protective against functional and structural renal injury in rat AN. The protective effect of the modified CCL2 DNA vaccine was associated with blockade of glomerular and interstitial macrophage recruitment by neutralizing autoantibody against CCL2, which plays a critical role in eliciting renal injury in AN. Therefore, modification with a foreign T helper epitope breaks self-tolerance by inducing a cellular and humoral response against self-protein and provides a strategy to increase the potency of DNA vaccination sufficiently to afford protection in toxin-induced chronic renal disease.

Animals↗
PubMed2002

Immunity to systemic Salmonella infections.

Salmonella infections are a serious public health problem in developing countries and represent a constant concern for the food industry. The severity and the outcome of a systemic Salmonella infection depends on the "virulence" of the bacteria, on the infectious dose as well as on the genetic makeup and immunological status of the host. The control of bacterial growth in the reticuloendothelial system (RES) in the early phases of a Salmonella infection relies on the NADPH oxidase-dependent anti-microbial functions of resident phagocytes and is controlled by the innate resistance gene Nramp1. This early phase is followed by the suppression of Salmonella growth in the RES due to the onset of an adaptive host response. This response relies on the concerted action of a number of cytokines (TNFalpha, IFNgamma, IL12, IL18, and IL15), on the recruitment of inflammatory phagocytes in the tissues and on the activation of the recruited cells. Phagocytes control bacterial growth in this phase of the infection by producing reactive nitrogen intermediates (RNI) generated via the inducible nitric oxide synthase (iNOS). Clearance of the bacteria from the RES at a later stage of the infection requires the CD28-dependent activation of CD4+ TCR-alphabeta T-cells and is controlled by MHC class II genes. Resistance to re-infection with virulent Salmonella micro-organisms requires the presence of Th1 type immunological memory and anti-Salmonella antibodies. Thus, the development of protective immunity to Salmonella infections relies on the cross-talk between the humoral and cellular branches of the immune system.

Animals↗
PubMed2006

Meningococcal conjugate vaccines: efficacy and new combinations.

OBJECTIVE: Meningococcal disease continues to be a serious public health concern, being associated with high morbidity and mortality rates worldwide, particularly in Brazil. In addition to discussing recent changes in the global epidemiology of meningococcal disease, we also analyze the development and impact of new conjugate vaccines on the prevention of meningococcal disease, with emphasis on the different immunization strategies implemented with these vaccines. SOURCES OF DATA: MEDLINE databases were searched from 1996 to 2006, with emphasis on review articles, clinical trials and epidemiological studies. Information was also sought on the Centers for Disease Control and Prevention, Brazilian Ministry of Health and Centro de Vigilância Epidemiológica do Estado de São Paulo websites. SUMMARY OF THE FINDINGS: Five serogroups (A, B, C, W135 and Y) are responsible for virtually all cases of the disease worldwide, with marked regional and temporal differences. The new meningococcal serogroup C conjugate vaccines (MCC) offer unmistakable advantages over polysaccharide vaccines. MCC vaccines generate a more efficient and long-lasting antibody response, inducing immunologic memory and reduction of nasopharyngeal carriage. The immediate results of introducing these vaccines into immunization programs have been encouraging, with a dramatic reduction in the incidence of serogroup C disease, not only in vaccinated, but also in unvaccinated individuals (herd immunity). However, concerns have arisen regarding the long-term effectiveness of these vaccines, especially for infants vaccinated in the routine schedule. CONCLUSIONS: The reported waning of efficacy more than 1 year after routine infant immunization supports alternative schedules incorporating a booster dose of MCC vaccine given at 12-18 months of age, in order to maintain long-term protection. The recent licensure of the tetravalent meningococcal conjugate vaccine represents, at last, a real possibility of a broader protection against meningococcal disease, although the need to develop an effective vaccine against serogroup B remains.

Adult↗
PubMed2006

Immune mechanisms in drug allergy.

Clinicians had suspected for years that drug eruptions were probably mediated by immune mechanisms because their timing suggested sensitization and specific immunologic memory rather than direct toxicity. An immune response to medications was also demonstrated by positive skin tests and by several types of in vitro tests that evidenced immediate or delayed hypersensitivity. In the last decade several teams of researchers obtained in vitro drug-specific human T-cell clones, in a variety of clinical types of drug eruptions. These clones were produced from blood or skin mononuclear cells of patients with a history of drug reaction by stimulation in vitro with drug. They were either of CD4 or CD8 phenotypes. Drug specific clones were stimulated by the parent drug much more often than by reactive metabolites. That challenged the classical "hapten hypothesis" that the immune response was initiated by reactive metabolites combined to self proteins. The medication usually stimulated specific T-cells after non-covalent binding to major histocompatibility (MHC) molecules on antigen presenting cells. In toxic epidermal necrolysis, T-lymphocytes present at the site of lesions, exhibited a drug specific cytotoxicity against autologous target cells, or allogeneic cells that shared the same HLA than autologous cells. This MHC class I restriction and mediation of death by perforin/granzyme release, is the classical behavior of cytotoxic T lymphocytes, like those operating in the reject of a transplanted organ. MHC restriction could explain the key role of HLA genes as predisposing factors to severe drug reactions. A strong association between HLA and hypersensitivity to abacavir, SJS or TEN to carbamazepine or allopurinol has been recently demonstrated. Resemblance to graft rejection points to the possible therapeution value of immuno suppressive agents. Most drug eruptions appear to result from T-cell mediated delayed hypersensitivity. The secondary activation of different cascades of cytokines, may contribute to the heterogeneity of clinical presentations.

Cytokines↗
PubMed1994

Serological and clinical characteristics of measles vaccine failure in Japan.

In 1991, in Fukuoka, Japan, a measles outbreak occurred in which we observed 15 cases of measles vaccine failure (MVF). We examined these patients both clinically and serologically. Seven of them, with a response pattern of an early rise in and attainment of a high hemagglutination inhibition (HI) antibody titre, were considered to be secondary vaccine failures (EH group). Eight others showed a normal (relatively late rise and low titre) HI antibody response pattern and were considered to be primary vaccine failures (LL group). In both MVF groups, measles-specific IgM antibody was detected by enzyme immunoassay. The EH group had a milder rash than did the LL group and unvaccinated controls. We believe they had an immunological memory that modified the clinical manifestations of measles. Two cases of encephalitis were observed in the EH group; both patients recovered without sequelae. These data suggest that the mere presence or absence of IgM antibody is not sufficient to differentiate primary from secondary MVFs. A two-dose measles vaccination scheme should be recommended to secure a booster effect, because immunity is waning in the population in which the measles vaccination rate is not high enough and in which natural measles still exists.

Antibodies, Viral↗
PubMed2002

Staphylokinase-specific cell-mediated immunity in humans.

Staphylokinase is a highly fibrin-specific clot-dissolving agent that constitutes a promising drug for clinical development. It is of bacterial origin, and the majority of patients develop neutralizing Ab after its administration. Several antigenic regions, recognized by these Ab, have been identified, but the underlying immunogenic features of staphylokinase remain unknown. In this study, we show that staphylokinase is a T cell-dependent Ag, and that an immunological memory may be acquired, even without administration of staphylokinase. Thrombolysis with staphylokinase provokes the proliferation of staphylokinase-specific T lymphocytes, which remain elevated over 10 mo posttreatment. Interestingly, analysis of a large number of staphylokinase-specific T cell clones isolated from 10 unrelated donors revealed only six distinct immunogenic regions in the molecule. Moreover, five of the six regions are recognized by T lymphocytes from several individuals, indicating that these regions are not restricted to a single HLA-DR allele. Therefore, these new insights can guide the design of variants with a lower immunogenic profile in humans.

Adult↗
PubMed2003

Murine neonatal lymphocytes show rapid early cell cycle entry and cell division.

Neonatal animals are highly susceptible to infectious agents. At least part of this susceptibility is due to the virtual absence of immunological memory in newborns. One of the hallmarks of memory is the rapidity of the response. We show in this study that neonates may make up for their lack of memory, at least in part, by the rapid entry of large proportions of naive lymphocytes into the cell cycle. Following activation, greater percentages of both CD4(+) and CD8(+) neonatal, as compared with adult, lymph node cells showed early cell cycle entry; this was assessed by propidium iodide staining, CFSE labeling profiles, [(3)H]thymidine uptake, and up-regulation of early activation markers. This rapid cycle entry was observed following polyclonal activation with anti-CD3 or with PMA and ionomycin and in both C57BL/6 and BALB/c mice. Stimulation with specific peptide also elicited more rapid proliferative responses from neonatal vs adult TCR transgenic CD4(+) cells. In addition, more rapid cycle entry was observed in vivo, in lymphopenic RAG2(-/-) hosts. For both CD4(+) and CD8(+) cells, this phenomenon was observed out to 3 wk of life, although the differences between neonatal and adult cells became smaller with increasing time postbirth. These properties of peripheral neonatal T cells appeared to be inherited from their thymic precursors, because CD4(+)8(-) single-positive cells in the neonatal thymus also showed more rapid cycle entry, compared with their counterparts in the adult thymus. Interestingly, rapid early cycling was also observed among activated neonatal B cells, compared with adult B cells. Thus, early cell cycle entry by large proportions of cells may allow the naive lymphocyte population to efficiently mobilize responses against the broad range of pathogens first encountered in neonatal life.

Aging↗
PubMed2005

Targeted delivery of the ErbB2/HER2 tumor antigen to professional APCs results in effective antitumor immunity.

Activation of T cells by professional APCs that present peptide epitopes of tumor-associated Ags is critical for the induction of cell-mediated immunity against tumors. To facilitate targeted delivery of the ErbB2 (HER2, neu) tumor Ag to APCs in vivo, we have generated chimeric proteins that contain the extracellular domain of CTLA-4 for binding to B7 molecules on the APC surface, which is genetically fused to a human ErbB2 fragment as an antigenic determinant. Bacterially expressed CTLA-4-ErbB2 fusion protein and a similar molecule harboring in addition the translocation domain of Pseudomonas exotoxin A as an endosome escape function displayed specific binding to B7-expressing cells, followed by protein internalization and intracellular degradation. Vaccination of BALB/c mice with the fusion proteins resulted in the induction of ErbB2-specific CD8(+) T cells and CTL-dependent protection from subsequent challenge with ErbB2-expressing but not ErbB2-negative murine renal carcinoma cells. In a therapeutic setting, injection of CTLA-4-ErbB2 protein vaccines caused rejection of established ErbB2-expressing tumors. Thereby, immunological memory was induced, leading to long-term systemic immunity and protection against rechallenge several months later. Our results demonstrate that these chimeric protein vaccines are effective tools for the induction of ErbB2-specific, T cell-mediated immunity.

Animals↗
PubMed2006

[Gut barrier in the critically ill patient: facts and trends].

The disturbances of gut barrier in critically ill patients may influence their outcome and prognosis. Experiments in animals show that fasting and stress collaborate to produce intestinal atrophy and translocation of microorganisms and toxins. This fact is one of the main arguments to promote the use of early enteral feeding in critically ill patients. However, the intestinal barrier behaves differently in humans than in animals. The human enteral cells have a good tolerance to fasting and stress, mucosal atrophy is mild and it is not always associated with changes in intestinal permeability. Moreover, the relationship between intestinal permeability with sepsis and bacterial translocation is controversial. This last phenomenon also happens in normal subjects and may be a mechanism to build immunological memory. One of the most important factors that influence bacterial translocation is the microorganism, that under stress conditions can adhere to the intestinal cell and penetrate the intestinal barrier. Splanchnic ischemia and reperfusion is one of the main pathogenic factors in the failure of intestinal barrier. Finally, the fact that the small bowel is an inflammatory target of extra intestinal injuries, explains several clinical situations. The pathophysiology of the intestinal barrier definitely requires more research.

Bacterial Infections↗
PubMed1999

Cutting edge: contrasting roles of TNF receptor-associated factor 2 (TRAF2) and TRAF3 in CD40-activated B lymphocyte differentiation.

In B lymphocytes, CD40 signals contribute to the activation of Ab secretion, isotype switching, T cell costimulation, and immunological memory. TRAF proteins appear to be important components of the CD40 signal transduction complex, but their roles in the activation of B cell effector functions are poorly understood. We examined the contributions of TNF receptor-associated factor 2 (TRAF2) and TRAF3 to CD40-activated differentiation in mouse B cells transfected with inducible TRAF and dominant-negative TRAF cDNAs. We find that binding of TRAF2 and TRAF3 to CD40 is not required for the induction of Ab secretion, but that both TRAF molecules can regulate the activation process. We demonstrate a negative regulatory role for TRAF3 and that this activity is dependent on the availability of an intact TRAF3-binding site in the cytoplasmic domain of CD40. In contrast, TRAF2 appears to play a positive role in B cell differentiation, and this activity is apparent even when its binding site on CD40 is disrupted.

Amino Acid Sequence↗
PubMed1999

Massive activation-induced cell death of alloreactive T cells with apoptosis of bystander postthymic T cells prevents immune reconstitution in mice with graft-versus-host disease.

After hematopoietic stem cell transplantation, the persistence and expansion of grafted mature postthymic T cells allow both transfer of donor immunologic memory and generation of a diverse T repertoire. This thymic-independent process, which is particularly important in humans, because most transplant recipients present severe thymus atrophy, is impaired by graft-versus-host disease (GVHD). The goal of this study was to decipher how GVHD influences the fate of grafted postthymic T cells. Two major findings emerged. First, we found that, after a brisk proliferation phase, alloreactive antihost T cells underwent a massive activation-induced cell death (AICD). For both CD4(+) and CD8(+) T cells, the Fas pathway was found to play a major role in this AICD: alloreactive T cells upregulated Fas and FasL, and AICD of antihost T cells was much decreased in the case of lpr (Fas-deficient) donors. Second, whereas non-host-reactive donor T cells neither upregulated Fas nor suffered apoptosis when transplanted alone, they showed increased membrane Fas expression and apoptosis when coinjected with host-reactive T cells. We conclude that GVHD-associated AICD of antihost T cells coupled with bystander lysis of grafted non-host-reactive T cells abrogate immune reconstitution by donor-derived postthymic T lymphocytes. Furthermore, we speculate that massive lymphoid apoptosis observed in the acute phase of GVHD might be responsible for the occurrence of autoimmunity in the chronic phase of GVHD.

Animals↗
PubMed2000

Are booster immunisations needed for lifelong hepatitis B immunity? European Consensus Group on Hepatitis B Immunity.

Long-term protection against clinically significant breakthrough hepatitis B (HB) virus infection and chronic carriage depends on immunological memory, which allows a protective anamnestic antibody response to antigen challenge. Memory seems to last for at least 15 years in immunocompetent individuals. To date there are no data to support the need for booster doses of HB vaccine in immunocompetent individuals who have responded to a primary course. All adequately vaccinated individuals have shown evidence of immunity in the form of persisting anti-HBs and/or in vitro B-cell stimulation or an anamnestic response to a vaccine challenge. Nonetheless several countries and individuals currently have a policy of administering booster doses to certain risk groups. Boosters may be used to provide reassurance of protective immunity against benign breakthrough infection. For immunocompromised patients, regular testing for anti-HBs, and a booster injection when the titre falls below 10 mIU/mL, is advised. Long-term monitoring should continue, to confirm the absence of clinically significant breakthrough episodes of hepatitis B and to find out if a carrier state develops after 15 years. Also, non-responders to a primary course should continue to be studied.

Adolescent↗
PubMed1975

Immune inhibition of allogeneic lymphoma cells in the peritoneal cavity of mice.

Mice were sensitized with cells of normal spleen, transplantable syngeneic lymphomas, or allogeneic lymphomas differing for alloantigens specified by the major histocompatibility complex. From three to eleven days later, the allograft reactivity of these sensitized and appropriate control mice was evaluated in the peritoneal cavity by the disappearance of injected lymphoma cells or the inhibition of DNA synthesis. For the disappearance test, target cells were labeled with [125-I]-5-ido-2'-deoxyuridine before transfer. For the inhibition test, unlabeled target cells were transferred, but these cells were subsequently exposed to the DNA precursor [125-I]-5-iodo-2'-deoxyuridine. In both procedures, cells were recovered from the peritoneal cavity without killing the hosts to measure retained radioactivity. Both tests were immunogenetically specific in detecting secondary allograft reactions, but the disappearance test was less sensitive. By inhibition of DNA synthesis, it was possible to detect primary and secondary reactions, the latter three to eight days after sensitization. Alloantigens associated with the H-2K-Ir regions of Murine Linkage Group IX were more immunogenic than those associated with the Ss-H-2D-Tla regions in eliciting antilymphoma reactions, and female mice responded better than males. It was concluded that the peritoneal inhibition test is sensitive enough to monitor transplantation immunity in vivo and could be applied to animals bearing tumors in sites other than the peritoneum and undergoing chemotherapy.

Animals↗
PubMed1975

Immunosuppression by leukemia viruses. Effect of Friend leukemia virus on humoral immune competence of leukemia-resistant C57BL/6 mice.

Infection of genetically resistant C57BL/6 mice with Friend leukemia virus resulted in a marked but transient immunodepression of the humoral immune response to sheep erythrocytes. The primary immune response to sheep erythrocytes was depressed in mice infected 1 or 3 days before challenge immunization, but no suppression was observed when the interval was greater. The suppression coincided with the time of transient viremia in the mice. The secondary immune response to sheep erythrocytes was inhibited when virus was injected within a few days before booster immunization. Induction of immunologic "memory" to sheep erythrocytes was also blocked in C57BL/6 mice given virus before priming with the SRBC. The immunosuppressive activity appeared due to a marked but transient effect of the virus on antibody precursor cells, as ascertained by cell transfer experiments. These observations are pertinent to the general question to the cellular site of action of immunosuppressive tumor viruses and the relationship between immunosuppression and the neoplastic properties of the RNA viruses.

Animals↗
PubMedDate not supplied

[Listeria monocytogenes: a dangerous pathogen used as a vector for the new generation of vaccines].

Listeria monocytogenes (LM) has become a major pathogen of human foodborne illnesses eliciting meningitis, peritonitis, and abortions with a mortality rate of about 30%. During the course of the disease, LM infects a variety of tissues and cell types due to its capacity to induce its own phagocytosis even into non-phagocytic cells. For over 35 years LM continues to serve as a model to define general paradigms of immunology In this review we focus on the clinical characteristics of listeriosis, on the risk factors involved in the pathogenesis, and discuss the currently accepted approaches to prophylaxis and treatment. We report on novel strategies in vaccine development based on the LM-dependent delivering machinery for immune recognition and induction of immunological memory against desired antigens.

Animals↗
PubMed2000

Therapeutic efficacy of OX-40 receptor antibody depends on tumor immunogenicity and anatomic site of tumor growth.

The OX-40 receptor (OX-40R) is a cell surface glycoprotein of the tumor necrosis factor receptor family that is expressed primarily on activated CD4 T cells. Engagement of OX-40R by the OX-40 ligand (OX-40L) is known to costimulate the production of cytokines by activated T lymphocytes and to rescue effector T cells from activation-induced cell death. It was previously reported that in vivo ligation of OX-40R by administration of OX-40L:immunoglobulin fusion protein or OX-40R monoclonal antibody (mAb) resulted in a significant prolongation of survival of tumor-bearing mice in four histologically distinct solid tumors. In this study, we demonstrate that the therapeutic efficacy of OX-40R mAb was influenced by the tumor burden, the intrinsic immunogenicity of the tumor as well as by the histological site of tumor growth. Whereas subdermal and intracranial growth of weakly immunogenic MCA 203 and MCA 205 sarcomas and GL261 glioma were susceptible to the mAb treatment, established pulmonary MCA 205 metastases were refractory to the same regimen of treatment. Furthermore, the mAb administration had no impact on the growth of the poorly immunogenic B16/D5 mela noma. Tumor regression mediated by OX-40R mAb was dependent on the participation of both CD4 and CD8 T cells and as a result of tumor rejection, a long-term tumor-specific immunity was established. Analysis of tumor-infiltrating T cells revealed the presence of a far greater number of OX-40R+ T cells of both CD4 and CD8 phenotypes in the intracranial immunogenic GL261 glioma than that in the poorly immunogenic B16/D5 melanoma. These results suggest that ligation of OX-40R on activated T cells in situ in the tumor may provide a necessary costimulatory signal to augment immune responses leading to tumor regression and immunological memory.

Animals↗
PubMedDate not supplied

Ten-year serological follow up of hepatitis B vaccine recipients.

AIM: To determine long-term persistence of antibodies to hepatitis B surface antigen (anti-HBs) after vaccination against hepatitis B. METHODS: Thirty-four laboratory workers received hepatitis B vaccine in 1989 in a 0-1-6 month vaccination schedule. Group A (n = 16) received a booster at 3 years after vaccination whereas Group B (n = 18) did not. Anti-HBs was quantitated at 1 month and 1, 2, 3, 5, 6 and 8 years post-vaccination. RESULTS: At eight-year follow up, 10 of 15 subjects in Group A and 3 of 16 in Group B had protective levels of anti-HBs; in addition, two and four subjects, respectively, had detectable anti-HBs though below protective levels. At ten years, 9/15 and 3/16 were anti-HBs positive in Groups A and B, respectively. One subject in each group had rise in anti-HBs titer at 6-year follow up but both of them tested negative for IgG antibodies to hepatitis B core antigen (anti-HBc). A booster dose at 10 years to anti-HBs negative subjects led to an anamestic response in 3/4 and 8/10 persons in Groups A and B, respectively. CONCLUSION: Immunological memory after vaccination against hepatitis B is maintained for at least 10 years.

Adult↗