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Results for “Antigenic Modulation”

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PubMed1996

Naturally processed T cell epitopes from human glutamic acid decarboxylase identified using mice transgenic for the type 1 diabetes-associated human MHC class II allele, DRB1*0401.

The identification of class II binding peptide epitopes from autoimmune disease-related antigens is an essential step in the development of antigen-specific immune modulation therapy. In the case of type 1 diabetes, T cell and B cell reactivity to the autoantigen glutamic acid decarboxylase 65 (GAD65) is associated with disease development in humans and in nonobese diabetic (NOD) mice. In this study, we identify two DRB1*0401-restricted T cell epitopes from human GAD65, 274-286, and 115-127. Both peptides are immunogenic in transgenic mice expressing functional DRB1*0401 MHC class II molecules but not in nontransgenic littermates. Processing of GAD65 by antigen presenting cells (APC) resulted in the formation of DRB1*0401 complexes loaded with either the 274-286 or 115-127 epitopes, suggesting that these naturally derived epitopes may be displayed on APC recruited into pancreatic islets. The presentation of these two T cell epitopes in the islets of DRB1*0401 individuals who are at risk for type 1 diabetes may allow for antigen-specific recruitment of regulatory cells to the islets following peptide immunization.

Alleles↗

PubMed2005

Drug-induced immunophenotypic modulation in childhood ALL: implications for minimal residual disease detection.

Assessment of minimal residual disease (MRD) by flow cytometry is considered to be based on the reproducibility of the leukemic immunophenotype detected at diagnosis. However, we previously noticed modulation of surface antigen expression in acute lymphoblastic leukemia (ALL) during the early treatment. Hence, we investigated this in 30 children with B-cell precursor ALL consecutively enrolled in the AIEOP-BFM ALL 2000 protocol. Quantitative expression of seven antigens useful in MRD monitoring was studied at diagnosis and compared to that measured at different time points of remission induction therapy. Downmodulation in the expression of CD10 and CD34 occurred at follow-up. By contrast, upmodulation of CD19, CD20, CD45RA, and CD11a was observed, while the expression of CD58 remained stable. Despite this, we could unambiguously discriminate leukemic cells from normal residual B cells. This holds true when bone marrow (BM) samples from similarly treated T-ALL patients, but not from healthy donors, were used as reference. Our results indicate that immunophenotypic modulation occurs in ALL during the early phases of BFM-type protocols. However, the accuracy of MRD detection by flow cytometry seems not negatively affected if adequate analysis protocols are employed. Investigators should take this phenomenon into account in order to avoid pitfalls in flow cytometric MRD studies.

Antigens, CD↗

PubMed1992

Regulation of D-3 phosphoinositides during T cell activation via the T cell antigen receptor/CD3 complex and CD2 antigens.

An immediate consequence of T cell activation via the T cell receptor (TcR)/CD3 complex and CD2 antigen is the hydrolysis of phosphatidylinositol-(4,5)-bisphosphate and the generation of inositol-(1,4,5)-trisphosphate and diacylglycerol which then regulate intracellular calcium and protein kinase C. Changes in cellular levels of phosphoinositides phosphorylated on the D-4 and D-5 position during T cell activation have been well documented. Recently it has been proposed that phosphoinositides phosphorylated on the D-3 position of the inositol ring by a novel phosphoinositide (PI) 3 kinase may also be important in cell activation. In the present study we have examined the levels and regulation of D-3 phosphoinositides in T cells activated by the TcR/CD3 complex and CD2 antigens. The data show the existence of phosphatidylinositol-(3)-monophosphate [PtdIns(3)P], phosphatidylinositol-(3,4)-bisphosphate [PtdIns(3,4)P2] and phosphatidylinositol-(3,4,5)-trisphosphate [PtdIns(3,4,5)P3] in T cells. Activation of the TcR/CD3 complex or CD2 antigen results in modulation of PtdIns(3,4)P2 and a putative PtdIns(3,4,5)P3 in T cells but does not change levels of PtdIns(3)P. These data provide the first evidence that lipid products of a PI3 kinase exist in T cells.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1990

In vivo induction of Ia expression in murine cornea after intravitreal injection of interferon-gamma.

Intravitreal injection of interferon gamma (IFN-gamma) induces increased expression of Class II major histocompatibility complex (Ia) antigen expression on corneal endothelial cells and stromal fibroblasts. In contrast, IFN-gamma has no detectable effect on Ia antigen expression in epithelium. Induction of Ia antigen expression was rapid with increases detectable as early as 6-12 hours after a single injection of 1 x 10(5) units. Expression peaked at 24-48 hours and decreased to background levels by 120 hours. The Ia antigen expression increased in a dose-dependent manner, and IFN-gamma treatment also induced the synthesis of increased amounts of a 65-kilodalton (kD) protein in the cornea. Increased levels of this 65-kd protein are seen as early as 12 hours after treatment and can be induced with as little as 1 x 10(2) units of IFN-gamma. The function of the 65-kd protein is unknown. This model should be useful in studies on in vivo modulation of Ia antigen expression.

Animals↗

PubMed1997

Low multiplicity cytomegalovirus infection of human aortic smooth muscle cells increases levels of major histocompatibility complex class I antigens and induces a proinflammatory cytokine milieu in the absence of cytopathology.

BACKGROUND: Cytomegalovirus has been implicated in the development of allograft vasculopathy in heart transplant recipients. Given that allograft vasculopathy is a form of chronic rejection, it is conceivable that cytomegalovirus somehow alters the allogeneic response to the vasculature. Prior work has demonstrated that smooth muscle cells (SMCs) are highly permissive for cytomegalovirus and exhibit cytopathologic characteristics and alterations in MHC class I antigens in response to cytomegalovirus at a high multiplicity of infection (MOI). METHODS: To determine whether cytomegalovirus at low, more clinically relevant MOI, can alter SMCs phenotypically, human aortic SMCs were infected with approximately 1 plaque forming units/3000 cells of cytomegalovirus strain AD169. RESULTS: One week after infection, human aortic SMCs (compared with human foreskin fibroblasts) demonstrated no cytopathologic characteristics (n = 6), released reduced amounts of intact virion into the culture media (assessed by exposing naive monolayers of human foreskin fibroblasts to media and staining for cytomegalovirus immediate-early antigen, n = 3), yet had at least, if not greater detectable total cytomegalovirus vital DNA levels. Infected HASMCs uniformly increased their expression of MHC class I antigen by 55% +/- 21% above constitutive levels (assessed by flow cytometry (n = 5, p < 0.0001). Cytomegalovirus infection resulted in an increase in interleukin-6 mRNA expression compared to control (297 +/- 63 vs 188 +/- 50, respectively; p = 0.02, n = 6) and reduced the expression of transforming growth factor-beta mRNA (802 +/- 152 vs 1201 +/- 236, respectively; p = 0.05). CONCLUSIONS: These data suggest that low MOI of cytomegalovirus can infect SMCs without producing cell cytolysis and, in spite of this lack of overt infection, modulate cell surface antigens and cytokine mRNA levels that can influence allogeneic responses.

Antigens, Viral↗

PubMed2000

Effects of interferons alpha and gamma on cytokine production and phenotypic pattern of human bronchial epithelial cells.

Human bronchial epithelial cells are involved in airway immune mechanisms through secretion of cytokines and through cell-cell contacts with immunocompetent cells. The aim of our study was to assess the ability of interferon (IFN) alpha and gamma alone and in combination to modulate human bronchial epithelial cell (HBECs) release of the inflammatory cytokines IL-8 and IL-6 and fibronectin and to induce the surface expression of HLA-DR and ICAM-1 molecules involved in immune interactions with other cells. HBECs spontaneously secreted a limited amount of IL-8, which was significantly increased by IFN gamma. IFN alpha inhibited IFN gamma stimulated IL-8 secretion in a concentration-dependent manner. Further, IFN gamma induced IL-6 and fibronectin secretion, and this was also inhibited by IFN alpha. The expression of HLA-DR antigens was significantly increased by IFN gamma and partially inhibited by co-stimulation with IFN alpha. In contrast, IFN gamma also induced ICAM-1 expression by HBECs but co-stimulation with IFN alpha had no significant effect on the expression of this surface antigen. IFN alpha modulation of HBEC functions does not seem to be restricted to IFN gamma stimulation since either stimulatory or inhibitory effects of INF alpha on IL-8 production have been found in pilot experiments using IL-1 beta, TNF alpha, and TGF beta as stimuli. In summary, IFN-gamma induces a number of responses in HBECs including increased secretion of IL-6, IL-8 and fibronectin and increased expression of HLA-DR and ICAM-1. IFN alpha can inhibit all these except expression of ICAM-1 which is unaffected. IFN alpha can also interact with other inflammatory cytokines, but whether the effects are inhibitory or augmentive depends on the cytokines.

Bronchi↗

PubMed2002

Lysine residues of Epstein-Barr virus-encoded nuclear antigen 2 do not confer secondary modifications via ubiquitin or SUMO-like proteins but modulate transcriptional activation.

Epstein-Barr virus nuclear antigen 2 (EBNA2) is essential for transformation through activation of viral and cellular genes. Within 487 residues, EBNA2 contains six lysine (K) residues (positions 335, 357, 359, 363, 366 and 480), which were mutated to arginine (R) residues, either individually or in combination, and tested for subcellular localization, mobility by SDS-PAGE and transactivation of three promoters. All mutants featuring the K(480)R mutation within the nuclear localization signal were partially cytoplasmic with a reduced level of transactivation of the latent membrane protein 1 (LMP1) promoter (-327 to +40). The K(366)R mutation also showed a decrease in transactivation of a promoter consisting only of 12 recombination signal-binding protein-Jkappa-binding sites, while all mutants with the K(335)R exchange showed a markedly elevated transactivation with the -327 to +40 construct and all mutants showed slightly reduced transactivation with a -634 to +40 LMP1 promoter. None of the mutants exhibited altered migration in SDS-PAGE, excluding secondary modification, i.e. through SUMO-like proteins.

Epstein-Barr Virus Nuclear Antigens↗

PubMed2000

Coimmunization with IFN-gamma or IL-2, but not IL-13 or IL-4 cDNA can enhance Th1-type DNA vaccine-induced immune responses in vivo.

As we explore the potential improvements to the current DNA vaccine strategies, it may be desirable to investigate methods to improve the level of resulting immune responses. One strategy is the use of cytokine cDNA as molecular adjuvants for DNA-based vaccines. Codelivery of these molecular adjuvants consisting of expression plasmid encoding for cytokines with DNA vaccine constructs is an effective method to modulate the magnitude and direction (humoral or cellular) of the immune responses. We have previously reported on the immunomodulatory effects of codelivering cDNA for interleukin-2 (IL-2) and IL-4 as molecular adjuvants for DNA-based vaccines. In this report, we extend these finding and compare the immunomodulatory effects of IL-2 and IL-4 with those of cDNA for prototypical Thl-type cytokine interferon-y (IFN-gamma) and Th2-type cytokine IL-13. We observed that distinct antigen-specific immune modulation can be achieved by the coinjection of IFN-gamma or IL-13 genes with DNA immunogen cassettes. We observed that IFN-gamma is a strong driver of Thl immune responses. Furthermore, in contrast to previous reports on their similarities in biologic activities, IL-13 and IL-4 cDNA coimmunizations modulated vaccine-induced immune responses differently in this model. Overall, these results further support the potential utility of this strategy as an important tool for the development of vaccines and immune therapies.

Adjuvants, Immunologic↗

PubMed2006

Antigenic profile of osteoblasts present in human bone tissue sections.

The antigenic profile of human osteoblasts was previously analyzed by our group using primary cultures as study samples. These studies suggested a novel functional approach to this cell population. Osteoblasts have a characteristic antigenic profile and share antigens in common with other cell populations that also originate in the bone marrow. Some of the detected antigens are constitutively expressed, while others are modulated by different factors and/or cytokines. The aim of the present study was to analyze the antigens present in osteoblasts in vivo, since the presence of certain biomolecules in fetal bovine serum may modulate the antigenic expression, compromising the results. For this purpose, human bone tissue sections were analyzed with a wide panel of mAbs and using the immunoperoxidase technique. CD10, CD44 and alkaline phosphatase antigens and IL-12, IL-18 and IFNgamma cytokines were detected in osteoblasts in the bone tissue. However, CD80 and HLA-DR antigens were not found in all samples and when present their expression was weak. The expression of CD54 antigen was moderate or weak. These results allow data obtained by the primary culture of osteoblast-like cells to be endorsed.

Adult↗

PubMed1996

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin.

OBJECTIVE: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. DESIGN AND METHODS: PBMC from HIV-1 infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-gamma, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. RESULTS: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-gamma, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiment indicated that antigen-stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. CONCLUSIONS: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

Antibodies↗

PubMed2001

Edible genetically modified microorganisms and plants for improved health.

The development of new strategies for the delivery of vaccine antigens or immune modulators to the mucosal tissue includes innovative approaches such as the use of genetically modified food microorganisms and plants. Even though the 'proof-of-concept' has recently been established for these two systems, key questions mainly related to efficacy and risk of breaking oral tolerance remain to be critically addressed in the immediate future.

Antigens, Bacterial↗

PubMedDate not supplied

[Cytotoxic T lymphocytes: role in immunosurveillance and in immunotherapy].

Experiments in mice and recent human clinical studies have clearly shown the contribution of CD8+ T lymphocyte in the control of tumor development. CD8+ T lymphocytes are a constitutive component of the immune response during the development of cancer. In murine models, the efficiency of various cancer vaccines mainly depends on their ability to induce CD8+ T lymphocytes. Clinical responses in immunotherapy treated cancer patients have been associated with the presence of antitumor specific CD8+ T lymphocytes. In spontaneous regressive melanomas, intratumor antigen specific CD8+ cytotoxic T cells were expanded suggesting their involvement in the tumor shrinkage. Administration of antitumor specific cytotoxic T clones in mice resulted in antitumor responses which directly demonstrated the therapeutic efficiency of these cells. However, in most cases during cancer progression, the presence of antitumor CD8 T lymphocyte is not associated with clinical responses. Intrinsic functional abnormalities of these cells or a defect of CD8+ T cell migration to the tumor may in part explain their failure to inhibit tumor development. On the other hand, tumors also develop immune escape mechanisms (down modulation of tumor antigens, secretion of immunosuppressive factors, expression of anti-apoptotic molecules by the tumors, or pro-apoptotic factors inducing T cell death) to resist to the CD8+ T cell attack. To circumvent these tumor escape mechanisms, efficient cancer vaccines will have to recruit CD8+ T cells associated with other immune effectors.

Animals↗

PubMed1995

Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.

We have previously demonstrated that human peripheral blood low density mononuclear cells cultured in granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 develop into dendritic cells (DCs) that are extremely efficient in presenting soluble antigens to T cells. To identify the mechanisms responsible for efficient antigen capture, we studied the endocytic capacity of DCs using fluorescein isothiocyanate-dextran, horseradish peroxidase, and lucifer yellow. We found that DCs use two distinct mechanisms for antigen capture. The first is a high level of fluid phase uptake via macropinocytosis. In contrast to what has been found with other cell types, macropinocytosis in DCs is constitutive and allows continuous internalization of large volumes of fluid. The second mechanism of capture is mediated via the mannose receptor (MR), which is expressed at high levels on DCs. At low ligand concentrations, the MR can deliver a large number of ligands to the cell in successive rounds. Thus, while macropinocytosis endows DCs with a high capacity, nonsaturable mechanism for capture of any soluble antigen, the MR gives an extra capacity for antigen capture with some degree of selectivity for non-self molecules. In addition to their high endocytic capacity, DCs from GM-CSF + IL-4-dependent cultures are characterized by the presence of a large intracellular compartment that contains high levels of class II molecules, cathepsin D, and lysosomal-associated membrane protein-1, and is rapidly accessible to endocytic markers. We investigated whether the capacity of DCs to capture and process antigen could be modulated by exogenous stimuli. We found that DCs respond to tumor necrosis factor alpha, CD40 ligand, IL-1, and lipopolysaccharide with a coordinate series of changes that include downregulation of macropinocytosis and Fc receptors, disappearance of the class II compartment, and upregulation of adhesion and costimulatory molecules. These changes occur within 1-2 d and are irreversible, since neither pinocytosis nor the class II compartment are recovered when the maturation-inducing stimulus is removed. The specificity of the MR and the capacity to respond to inflammatory stimuli maximize the capacity of DCs to present infectious non-self antigens to T cells.

Antigens↗

PubMed2004

Immunomodulating effects of "tien-hsien liquid" on peripheral blood mononuclear cells and T-lymphocytes from patients with recurrent aphthous ulcerations.

Recurrent aphthous ulcerations (RAU) represent a common oral mucosal disease with altered humoral and cellular immunities. In our institution, an immunomodulating agent, levamisole, is used to treat RAU with satisfactory therapeutic effect. Tien-Hsien liquid (THL) is an extract of Chinese medicinal herbs with immunomodulating effects. To test whether THL has immunomodulating effects on antigen-stimulated proliferation response (PR) of peripheral blood mononuclear cells (PBMC) and T-cells isolated from RAU patients and to test whether THL is a potential drug for treating RAU, PBMC or T-cells isolated from RAU patients were incubated with lipopolysaccharides (LPS) from Escherica coli, phytohemagglutinin (PHA), staphylococcal enterotoxin B (SEB), glutaraldehyde-inactivated tetanus toxoid (TT), glucosyltransferase D (GtfD), or antigens of Streptococcus mutans in the presence or absence of THL. We found that THL significantly increased the LPS-stimulated PR of PBMC from active RAU patients, the GtfD-stimulated PR of PBMC and of T-cells from inactive RAU patients, and the S. mutans-stimulated PR of PBMC from inactive RAU patients. However, THL could also significantly reduce the SEB-stimulated PR of PBMC and of T-cells from active RAU patients and S. mutans-stimulated PR of T-cells from active RAU patients. These results suggest that THL can modulate the antigen-stimulated PR of PBMC and T-cells from RAU patients. Therefore, it may be a potential immunoceutical agent for treatment of RAU.

Cell Culture Techniques↗

PubMed2003

Dichotomy between Lactobacillus rhamnosus and Klebsiella pneumoniae on dendritic cell phenotype and function.

The reaction of the intestinal immune system to intestinal bacteria shows striking differences between various bacterial strains. Whereas Klebsiella pneumoniae induces a fierce proinflammatory reaction, the probiotic strain Lactobacillus rhamnosus has clear anti-inflammatory effect in gastrointestinal disease and allergy. The molecular basis for this dichotomy is poorly understood but is likely to involve different modulation of antigen-presenting dendritic cells (DC) by L. rhamnosus and K. pneumoniae. Hence we evaluated phenotypic and functional characteristics of DC matured in the presence of L. rhamnosus and K. pneumoniae. Monocyte-derived immature DC were cultured in the presence of live bacteria to obtain mature DC. Both micro-organisms induced maturation of immature DC as shown by CD83 and CD86 expression, but receptors involved in activation of Th1 cells were expressed predominantly on DC exposed to K. pneumoniae. In contrast to K. pneumoniae, maturation with L. rhamnosus resulted in lower TNF-alpha, IL-6, and IL-8 production by immature DC and lower IL-12 and IL-18 production by mature DC. Moreover, L. rhamnosus led to the development of T cells without a typical Th phenotype whereas K. pneumoniae induced a Th1 immune response, dependent mainly on IL-12 production. Thus our results strongly support the concept that differential modulation of DC explains the differences in the immune response to various bacterial strains and indicates that K. pneumoniae induces Th1 immune responses via DC.

Antigens, CD↗

PubMed1988

SSA/Ro antigen expression in simian virus 40-transformed human keratinocytes.

SSA/Ro antigen is a soluble cellular component to which antibodies are frequently produced in patients with Sjögren's syndrome and systemic lupus erythematosus. Its exact location within the cell has yet to be determined. In this study we report the expression of SSA/Ro antigen in simian virus 40 (SV40)-transformed keratinocytes. The locations of SSA/Ro, U1RNP, and DNA antigens were studied by indirect immunofluorescence using monospecific antibodies. SSA/Ro antigen was detected in both the nucleus and cytoplasm of SV40-transformed keratinocytes tested with three monospecific sera. Primary cultured keratinocytes derived from adult human skin showed localized immunofluorescent staining within the nucleus. When Ca++ concentration of the medium was switched to 0.05 mM, these cells expressed cytoplasmic SSA/Ro antigens within 48 h. Depletion of the antibody activity with insolubilized human spleen extract abolished the staining. Surface expression of this antigen could not be detected in either primary or transformed cells. Localization of U1RNP and DNA was not altered. These results indicate that expression of SSA/Ro antigen in human keratinocytes is modulated by SV40 infection and that this antigen is expressed to a greater degree in cells that are less differentiated, transformed, or proliferating.

Autoantigens↗

PubMed1981

Accessory cell function of rabbit alveolar macrophages.

Alveolar macrophages (AM) are the first cells to contact inhaled antigen. Accessory cell function of AM would modulate the immunologic response to antigenic exposure. We sought to examine the capability of AM to act as accessory cells for proliferation of lymphocytes using conditions that are best suited for expression of this function. We used rabbit popliteal lymph node cells, both before and after depletion of macrophages by 2 successive Sephadex G-10 columns that decreased nonspecific esterase positive cells from 2.56 to < 0.1%, and abolished or markedly decreased concanavalin A-induced lymphocyte proliferation. AM were lavaged from rabbit lungs and treated with mitomycin C. We found that AM enhanced proliferation of 5 x 10(4) and 7 x 10(4) unseparated, lymph node cells 5- to 15-fold, but had no effect on 2 x 10(5) cells. The optimal ratio of macrophages to lymphocytes (AM:L) was between 1:2 and 2:1. An AM:L value of 4:1 suppressed proliferation. The addition of AM to macrophage-depleted lymph node cells enhanced proliferation of 5 x 10(4), 7 x 10(4), and 2 x 10(5) lymphocytes 15- to 50-fold (AM:L, 1:2 to 2:1). Excessive numbers of macrophages (AM:L, 4:1) suppressed proliferation 5- to 50-fold. Rabbit AM can act as accessory cells in assays of mitogen-induced lymphocyte proliferation with maximal effect at AM:L values of 1:2 to 2:1. Suppression can occur as a result of excessive numbers of macrophages.

Animals↗

PubMed2003

[Up-to-date understanding of tuberculosis immunity].

This symposium was organized to provide the up-to-date knowledge on tuberculosis immunity, especially on the understanding of cytokines or Th1 cells involved in pathophysiology/protective immunity and vaccine development. Dr. Kazuo Kobayashi (Osaka City Univ.) reported their findings on the immune response to bioactive lipid component from M. tuberculosis, trehalose-dimycolate (TDM) and sulfolipid (SL) in mice. Their unique and novel finding was that TDM is capable of inducing T-dependent immune response in euthymic mice. The specific immune response in TDM-immune mice was consisting of CD4+ cell response and expression of chemokines, inflammatory cytokines and then TH1-related cytokines. In contrast, SL did not show such an activity. TDM may be one of the protective antigens and may modulate the specific immune response of the host. Dr. Isamu Sugawara's group (JATA) has examined the involvement of various cytokines in the host response to aerosolic infection with virulent strain of M. tuberculosis by using cytokine-knockout mice. The single deletion of IFN-gamma or TNF alpha resulted in a severe lesion of multiple necrosis without granuloma, and cytokine mRNA level other than knocked out cytokine was normal, suggesting that IFN-gamma and TNF alpha are principally important cytokines. In knockout mice for IL-12 or IL-18, necrotic lesion was not induced after infection and the pathological change was not so significant as in IFN-gamma/TNF alpha knockout mice. By using IFN-gamma knockout mice, it became possible to generate a granulomatous lesion with central necrosis and cavity resembling the lesion in humans. These mouse model appeared to be useful in the analysis of pathophysiology of human tuberculosis. Dr. Kazuyoshi Kawakami (Ryukyu Univ.) reported the importance of TH1 cytokines in anti-tuberculous immunity. By using IL-12, IL-18 knockout mice or double knockout mice, it was shown that IL-12 exhibits more important role than IL-18 in the protection. A possible contribution of IL-23 was also suggested. In most of the clinical cases of tuberculosis, the production of IL-12, IL-18 and IFN-gamma is increased, however, the group of relatively lower cytokine production did not respond well to the treatment. In addition, the plasma level of one of the chemokines, IP-10, was shown to be an indicator for the severity of the disease. Thus, some cytokines appear to be employable for the novel treatment in the near future. Dr. Saburo Yamamoto (NIH) summarized the recent advance in the understanding of biological function of CpG motifs. Immunostimulatory DNA is effective in the modulation of TH1/TH2 polarity and the enhancement of protective immunity to M. tuberulosis in animals. CpG motif (immunostimulatory DNA) appears to exert its activity by signaling cascade via TLR9 resulting in NF-kappa B activation and cytokine gene expression. Analysis of basic mechanism of action by CpG motif should pave the way to the clinical application in the future. Dr. Masaji Okada (Kinki Chuo Hospital) reported the current situation in the development of novel vaccines against tuberculosis. They have extensively constructed and examined the efficacy of various types of vaccines including subunit, DNA and recombinant BCG vaccines. Various vector systems have been tested for DNA vaccine. As immunizing antigens, a-Ag, ESAT-6, HSP65, 38kD-lipoprotein and so on have been employed. A large body of experimental data are accumulating for final evaluation, and among them, it is noteworthy to mention that HSP65DNA + IL-12DNA was 100 times more effective than conventional BCG in animal model. Among subunit vaccines, Mtb72f vaccine appears to be one of the promising candidates. In addition to the trial with various candidates, they have established a new mouse model, SCID/human PBL. This model animal has been employed for the development of vaccine effective for the induction of ESAT-6-specific human T cells.

Animals↗