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PubMed2001

The immune system and gene expression microarrays--new answers to old questions.

The recent increase in availability of gene expression technologies has the potential to dramatically expand our understanding of cellular immunology in molecular detail. Expression levels of tens of thousands of genes can be measured in dozens of samples in only a few days, and this data can be integrated with sequence informatics to tentatively assign some (limited) functional information to a majority of these genes. In this review we discuss some initial applications of these new tools to the fields of lymphocyte and monocyte differentiation pathways, the tolerance or immunity decision process, and B cell transformation. These examples illustrate the power of unbiased, 'wide-net', approaches both to drive immunological research in previously unexpected directions and to confirm classic tenets of immunology.

Animals↗

PubMed1990

Immunohistochemical study of human placental stromal cells.

An immunohistochemical study of stromal cells in human placental villi was made using various polyclonal and monoclonal antibodies. This study demonstrated that almost all villous stromal cells expressed HLA-ABC, which is indicative of class I major histocompatibility complex, and vimentin, which is a mesenchymal marker, through the entire period of pregnancy. Some of these stromal cells were considered to be fetal macrophages having HLA-DR, which is a determinant of class II major histocompatibility complex, particularly in the second and third trimesters. Such macrophages also expressed CD-4 (Leu-3a and -3b) and 2H4, which are the cell membrane determinants of suppressor-inducer T lymphocyte; CD-2 (Leu-5b), which is a marker of pan-T cell; Leu-M3, Leu-M5 and Mac-1, which are the markers of monocyte and macrophage lineage; leukocyte common antigen, which is a marker of bone marrow derived cell; and alpha-antichymotrypsin, which is a glycoprotein associated with macrophages. Morphologically, villous macrophages consisted of heterogeneous phenotypes such as classic Hofbauer cells, fibroblast-like spindle cells with long cytoplasmic processes, and dendritic-shaped cells. These may have more complex features than previously considered and may have a greater initiating role in immunologic interactions between mother and fetus when compared with the very sparsely distributed T or B lymphocytes.

Antigens, Differentiation↗

PubMed2005

Effect of C-reactive protein on vascular cells: evidence for a proinflammatory, proatherogenic role.

PURPOSE OF REVIEW: C-reactive protein (CRP) is the prototypic downstream marker of inflammation. High levels of CRP predict future cardiovascular risk in apparently healthy men and women. Recent evidence from different cell types suggests that CRP is not only a risk marker but may also be a participant in atherogenesis. This review will focus on the effects of CRP on different cells involved in atherosclerosis. RECENT FINDINGS: CRP is shown to induce matrix metalloproteinase-1 (MMP-1) expression through the Fc gamma RII and extracellular signal-related kinase pathway in U937 cells. MMPs are implicated in plaque instability. A recent report shows that CRP does not induce tissue factor in human monocytes directly, disputing the previous concept that CRP induces tissue factor in monocytes. CRP is shown to upregulate interleukin-8 in human aortic endothelial cells via nuclear factor-kappa B. CRP promotes monocyte chemoattractant protein-1-mediated chemotaxis by upregulating CC-chemokine receptor 2 expression in human monocytes. Also CRP is shown to attenuate endothelial progenitor cell survival, differentiation, and function via inhibiting nitric oxide. Human CRP transgenic animal models show that CRP promotes atherothrombosis and increases plasminogen activator inhibitor-1. Also, the classic dogma that CRP is produced exclusively in liver is challenged by recent data on the extrahepatic production of CRP in different cells including atherosclerotic lesions. SUMMARY: All this recent evidence along with earlier reports support a role for CRP in atherosclerosis.

Animals↗

PubMed1988

Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis.

TNF is a protein toxin which is secreted by activated macrophages and monocytes. Although the cytotoxic activity of TNF has been well documented, the mechanism of TNF-induced lysis is not well understood. The goal of this investigation was to determine whether TNF caused one of the classic forms of cell death, i.e., apoptosis, which is characterized by nuclear disintegration and cytoplasmic "boiling," or necrosis, which is characterized by the formation of a "balloon-like" plasma membrane and a lack of nuclear disintegration. Therefore, to distinguish apoptosis from necrosis, we have used time-lapse video microscopy to observe the death of several TNF-sensitive target cell lines while measuring the release of Na2(51)CrO4 and [3H]TdR from cytoplasmic and nuclear compartments, respectively. As targets we selected two spontaneously sensitive cell lines, F17 and L-M, and one resistant cell line, C3HA, which was sensitized by treatment with cycloheximide or by infection with the adeno-SV40 hybrid virus Ad2+ND2. We find that the type of cell death observed depends on the cell being tested. For example, in F17 cells we found that TNF treatment induced a classical form of apoptosis. In contrast, TNF induced a necrotic form of cell death in L-M cells, similar to the lysis induced by antibody and C. Finally, we found that sensitized C3HA cells displayed a novel cytolytic phenotype which resembled apoptosis but did not include DNA fragmentation. These results emphasize the complex nature of the TNF-induced cytotoxic response.

Adenoviruses, Human↗

PubMed1994

Vitamin D and the hematolymphopoietic tissue: a 1994 update.

Monocytes/macrophages and activated (but not resting) lymphocytes as well as certain subsets of thymocytes express the VDR. This protein is indistinguishable from the classical 50-kDa VDR and is encoded by an mRNA with identical nucleotide sequence to that of the human intestinal VDR. Acting via the VDR, 1,25(OH)2D3 modulates the production of a plethora of monocyte, lymphocyte, and bone marrow stromal cell products, including several interleukins and other cytokines, as well as various oncogenes and transcription factors. However, these hormonal effects vary depending on the signals used to activate blood mononuclear cells; moreover, each of the effects of the hormone can be either attenuated, abolished, or even reversed from negative to positive in the presence of phorbol esters. Lymphocytes also express a previously unrecognized 80-kDa cytosolic protein that shares immunologic cross-reactivity with the VDR. This protein is induced on activation and is downregulated by 1,25(OH)2D3, whereas the VDR is upregulated by 1,25(OH)2D3. In contrast to the signal-dependent effects of the hormone on cytokine production and lymphocyte proliferation, the effects of 1,25(OH)2D3 on the 80-kDa protein and VDR are independent of the activation signals. This apparent mechanistic distinction raises the possibility that the signal-independent effects of 1,25(OH)2D3 on the 80-kDa protein and the VDR might be due to direct interactions of the 1,25(OH)2D3-VDR complex with specific response elements (negative and positive VDREs, respectively) on these two genes; as opposed to the signal-dependent effects that might be due to influences of the 1,25(OH)2D3-VDR complex on other transcription factors that are generated in response to the different activation stimuli. Consistent with the second part of this contention, we have recently found that 1,25(OH)2D3 regulates the 50-kDa DNA binding subunit of the pleiotropic transcription factor NF-kappa B and the 105-kDa precursor of this subunit; as well as other members of the rel-related family of proteins, including v-rel and its normal cellular homolog c-rel, in activated normal human lymphocytes. Besides its influence on immune cell products, 1,25(OH)2D3 is a potent agent for the differentiation of cells of the myeloid lineage. In addition, 1,25(OH)2D3 stimulates the fusion and differentiation of hematopoietic progenitors into osteoclasts, an effect which accounts for the potent role of the hormone in bone resorption.(ABSTRACT TRUNCATED AT 400 WORDS)

Adjuvants, Immunologic↗

PubMed1985

Immunoregulation by opioid peptides: I. Absence of classical opioid receptor on human mononuclear cells.

Potent effects of opiates and opioid peptides on the immune responsiveness of mononuclear cells have recently been described. The mechanism by which the effects are mediated was explored by examining the opioid receptor properties of these cells. Human mononuclear cells (B and T lymphocytes and monocytes) were examined for their ability to bind 3H-naloxone, a mu opioid ligand, and 3H-D-Ala2-D-Leu5-enkephalin, a delta opioid ligand. Both ligands bound to nonadherent cells as well as monocytes in a non-specific fashion and could not be competitively displaced by the addition of unlabeled compound. Cells which were stimulated in culture with mitogens did not develop receptors which bound either ligand in a specific fashion. Homogenization of human mononuclear cells prior to measuring binding significantly reduced non-specific binding of radioligands. Although under these conditions a limited amount of net specific binding was observed, this binding was not concentration dependent or saturable and varied considerably between individuals. These observations suggest that opioid effects on immune responsiveness are not mediated through a mononuclear opioid receptor.

B-Lymphocytes↗

PubMed1990

Antibiotics as biological response modifiers.

This review suggests that infections are potent immunomodulators by causing significant alterations in one or more mediators of homeostasis and that an effective antibiosis may be a potent immunomodulator, albeit indirectly. When large numbers of microorganisms are killed, their enzymes and toxins are rapidly released and activate the immune system. The septic syndrome and the potentially progressive states of septic shock, acute respiratory distress syndrome and multiple organ system failure illustrate the biological response modulating (BRM) activity of both infection and antibiotic. Enhancement of phagocytosis and intracellular killing would be a useful immunomodulatory activity for antibiotics. Equally useful would be the capacity of the antibiotic to bind or inactivate bacterial lipopolysaccharide (LPS) to diminish monocyte release of tumour-necrosing factor (TNF) at a rate equal to or faster than the killing effect of the antibiotic on bacteria. For other types of immune deficiencies, such as are observed in HIV-positive patients with secondary bacterial, fungal and viral infections, modulation of viral receptors including HIV-R on CD4 lymphocytes accompanied by their up-regulation, enhancement of interferon (IFN) and natural killer (NK) function and inhibition of CD8 suppressor activity would be important activities. The classic example of polymyxin as an immunomodulating, albeit toxic, antibiotic offers a rational and definitive basis for the concept. In-vitro data on cefodizime, a third generation cephalosporin that achieves good tissue levels, are presented and show the ability of the intact antibiotic, as well as its immunomodulating side-chain, to down-regulate TNF and interleukin 1 (IL-1) released from human monocytes by lectin-activated lymphocytes, LPS and IFN.

Anti-Bacterial Agents↗

PubMed1994

cAMP modulates stress protein synthesis in human monocytes-macrophages.

The synthesis of heat-shock proteins (HSPs) and other stress proteins, including heme oxygenase (HO) and ferritin, is differentially induced by heat and oxidizing agents. In order to determine what role cAMP plays in those inductions in human monocytes-macrophages (m phi), we used cAMP activators or analogues alone or in combination with various stressful conditions. A stimulation in cAMP production did not per se affect stress proteins synthesis in m phi but modulated their induction in a differential way according to the stimulus. cAMP increased the synthesis of HSPs after heat shock. During erythrophagocytosis, whereas cAMP depressed the phagocytic process and the associated generation of superoxide anions, it enhanced the synthesis of HSPs, while inhibiting that of HO and ferritin. These results indicate that cAMP has a direct enhancing effect on the expression of stress proteins controlled by a classic heat-shock promoter, while decreasing their expression when induced by oxidative stress.

Cadmium↗

PubMed1996

Ion channel expression in PMA-differentiated human THP-1 macrophages.

Ion channel expression was studied in THP-1 human monocytic leukemia cells induced to differentiate into macrophage-like cells by exposure to the phorbol ester, phorbol 12-myristate 13-acetate (PMA). Inactivating delayed rectifier K+ currents, IDR, present in almost all undifferentiated THP-1 monocytes, were absent from PMA-differentiated macrophages. Two K+ channels were observed in THP-1 cells only after differentiation into macrophages, an inwardly rectifying K+ channel (IIR) and a Ca2+-activated maxi-K channel (IBK). IIR was a classical inward rectifier, conducting large inward currents negative to EK and very small outward currents. IIR was blocked in a voltage-dependent manner by Cs+, Na+, and Ba2+, block increasing with hyperpolarization. Block by Na+ and Ba2+ was time-dependent, whereas Cs+ block was too fast to resolve. Rb+ was sparingly permeant. In cell-attached patches with high [K+] in the pipette, the single IIR channel conductance was approximately 30 pS and no outward current could be detected. IBK channels were observed in cell-attached or inside-out patches and in whole-cell configuration. In cell-attached patches the conductance was approximately 200-250 pS and at potentials positive to approximately 100 mV a negative slope conductance of the unitary current was observed, suggesting block by intracellular Na+. IBK was activated at large positive potentials in cell-attached patches; in inside-out patches the voltage-activation relationship was shifted to more negative potentials by increased [Ca2+]. Macroscopic IBK was blocked by external TEA+ with half block at 0.35 mM. THP-1 cells were found to contain mRNA for Kv1.3 and IRK1. Levels of mRNA coding for these K+ channels were studied by competitive PCR (polymerase chain reaction), and were found to change upon differentiation in the same direction as did channel expression: IRK1 mRNA increased at least 5-fold, and Kv1.3 mRNA decreased on average 7-fold. Possible functional correlates of the changes in ion channel expression during differentiation of THP-1 cells are discussed.

Base Sequence↗

PubMed2006

Immunoglobulin g antibody-mediated enhancement of measles virus infection can bypass the protective antiviral immune response.

Antibodies to viral surface glycoproteins play a crucial role in immunity to measles by blocking both virus attachment and subsequent fusion with the host cell membrane. Here, we demonstrate that certain immunoglobulin G (IgG) antibodies can also enhance the entry of measles virus (MV) into monocytes and macrophages. Antibody-dependent enhancement of infectivity was observed in mouse and human macrophages using virions opsonized by a murine monoclonal antibody against the MV hemagglutinin (H) glycoprotein, polyclonal mouse anti-MV IgG, or diluted measles-immune human sera. Neither H-specific Fab fragments nor H-specific IgM could enhance MV entry in monocytes or macrophages, indicating involvement of a Fc gamma receptor (FcgammaR)-mediated mechanism. Preincubation with an anti-fusion protein (anti-F) monoclonal antibody or a fusion-inhibitory peptide blocked infection, indicating that a functional F protein was required for viral internalization. Classical complement pathway activation did not promote infection through complement receptors and inhibited anti-H IgG-mediated enhancement. In vivo, antibody-enhanced infection allowed MV to overcome a highly protective systemic immune response in preimmunized IfnarKo-Ge46 transgenic mice. These data demonstrate a previously unidentified mechanism that may contribute to morbillivirus pathogenesis where H-specific IgG antibodies promote the spread of MV infection among FcgammaR-expressing host cells. The findings point to a new model for the pathogenesis of atypical MV infection observed after immunization with formalin-inactivated MV vaccine and underscore the importance of the anti-F response after vaccination.

Animals↗

PubMed2004

Structural relationships and cellular tropism of staphylococcal superantigen-like proteins.

The staphylococcal superantigen-like proteins (SSLs) are a family of polymorphic paralogs encoded in the Staphylococcus aureus genome whose function is unknown. The crystal structure of SSL7 was determined and compared to that of SSL5 and that of a classical superantigen, streptococcal pyrogenic exotoxin. Although the overall architecture of the superantigen family is retained in both SSL7 and SSL5, there are significant differences in the structures which suggest that the characteristic major histocompatibility complex binding site of superantigens has been lost. To complement these data, the abilities of SSL7 and a closely related paralog, SSL9, to interact with cells of the immune system were investigated. In populations of human white blood cells, both SSLs interacted selectively with monocytes via specific saturable but separate binding sites, which led to rapid uptake of the SSLs. In addition, SSLs were rapidly taken up by dendritic cells, but not by macrophages, into the same endosomal compartment as dextran. The ability of these secreted proteins to target antigen-presenting cells may enhance a misplaced antibody response against the proteins, which may facilitate bacterial colonization rather than contribute to host protection. Like classical superantigens, therefore, SSLs may distract the host's immune system, but they may do so via entirely different molecular mechanisms.

Bacterial Proteins↗

PubMed1985

Antigen-induced monocyte procoagulant activity. Requirement for antigen presentation and histocompatibility leukocyte antigen-DR molecules.

The present study explores the interactions between lymphocytes and monocytes that are required for expression of procoagulant activity (PCA) by monocytes in response to purified protein derivative of the tubercle bacillus (PPD) or tularemia antigen. The PCA response was antigen specific: peripheral blood mononuclear cells (PBM) from donors sensitive to PPD or tularemia showed an increase in PCA only in response to the sensitizing antigen. The PCA was tissue factorlike in that Factors VII and X were required for expression of the activity, whereas Factor VIII was not. Maximum PCA developed only after 36 to 72 h. Fractionation of PBM into lymphocytes and monocytes after antigenic stimulation demonstrated that greater than 90% of the PCA was associated with monocytes. Isolated monocytes or lymphocytes incubated with sensitizing antigen had the same PCA as control cells. Purified lymphocytes that had been pulsed with antigen were unable to elicit a PCA response from monocytes to which they were added. However, adherent monocytes incubated with antigen, then washed free of unbound protein, were able to trigger lymphocytes to become stimulatory for PCA toward responding monocytes. The development of antigen-specific PCA in PBM could be blocked by including a monoclonal antibody to HLA-DR antigen in the incubation. The antibody had no effect on the clotting assay, on preformed PCA, cell viability, or on stimulatory antigen itself. These results indicate that elaboration of PCA by mononuclear cells may be an intrinsic part of the classical immune response to antigen, and may explain the presence of fibrin in immune lesions, as well as the occurrence of thrombotic complications in many immune disorders.

Antigen-Presenting Cells↗

PubMed1989

Inhibitory effects of E-5110 on interleukin-1 generation from human monocytes.

Effects of E-5110, a novel non-steroidal antiinflammatory drug, on interleukin-1 (IL-1) generation from human monocytes were studied in vitro. E-5110 reduced the amounts of extra- and intracellular IL-1 activity induced by lipopolysaccharide (LPS, 1 micrograms/ml) in a dose-dependent manner (1-10 microM). E-5110 also inhibited the IL-1 generation induced by antigen-antibody complexes, opsonized zymosan and silica particles. It was suggested that the inhibition of IL-1 generation by E-5110 was independent of the inhibitory effects on arachidonate cyclooxygenase and/or lipoxygenase because indomethacin, piroxicam, BW755C and AA861 had no effects on IL-1 generation. Hydrocortisone (IC50:0.084 microM), aurothioglucose (11.5 microM) and lobenzarit (75.0 microM), which are clinically effective antirheumatic drugs, also inhibited IL-1 generation, like E-5110 (1.21 microM). It is expected that E-5110 will be superior to classical non-steroidal antiinflammatory drugs in medical treatment of rheumatoid arthritis.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1988

Diagnostic significance of histiocyte-related markers in malignant histiocytosis and true histiocytic lymphoma.

Interrelationships of immunologic and enzymatic markers of histiocytes have been studied in malignant neoplasms of histiocytic/monocytic origin and in differential diagnostically relevant, large cell non-Hodgkin's lymphomas. Cryostat sections required for demonstrating cell surface antigens by monoclonal antibodies are inadequate for studying cellular detail, enzymatic maturation by alpha-naphthyl acetate esterase (ANAE), and demonstrating the classical cytoplasmic markers of histiocytes like lysozyme, alpha-1-antitrypsin (AT), and alpha-1-antichymotrypsin (ACT). These markers have been compared in gently fixed and vacuum paraffin-embedded material. The reactivity for monoclonal anti-human monocyte 1 (Mo 1) has also been preserved by this method. Malignant histiocytosis (MH) is characterized by a heterogeneous cell population. The mature, ANAE-positive cells with macrophage morphology usually show a diffuse cytoplasmic positivity for AT and ACT. Lysozyme is moderately positive to negative in these cells, but it is more efficient than these markers in revealing smaller cells resembling monocytes by focal positivity in the cytoplasm. The expression of Factor XIIIa (F-XIIIa) is connected with the phagocytic activation of histiocytic cells. F-XIIIa positive cells usually form a minority of the neoplastic population in MH, but the large cytophagocytic marcophages are invariably positive. Reactive macrophages in large cell non-Hodgkin's lymphomas are characterized by a coexpression of ANAE, AT, ACT, lysozyme, F-XIIIa and Mo 1. Typical cases of true histiocytic lymphoma (THL) are made up of a homogeneous population showing the above mature, phagocytizing phenotype. In MH, Mo 1 and ANAE recognize different subpopulations. The reciprocal relation of these markers is an abnormal phenotypic feature. The results presented in this article prove the diagnostic value of ANAE and lysozyme in confirming the histiocytic differentiation of malignant cells. Monoclonal anti-human monocyte 1 is useful for identifying the immature component in MH. Factor XIIIa can be considered a functional marker of mature phagocytic histiocytes and an aid in the diagnosis of THL.

Antigens, Differentiation, Myelomonocytic↗

PubMed1990

An improved in vitro assay to quantitate chemotaxis of rat peripheral blood large granular lymphocytes (LGL).

We have developed an improved method to study the directed migration, or chemotaxis, of rat peripheral blood large granular lymphocytes (LGL) in vitro. A modified Boyden chamber technique was used to measure chemotaxis of LGL through polycarbonate filters that had been coated with different basement membrane components. LGL were found to adhere to collagen types I and IV, laminin and fibronectin. However, only collagen type IV was not in itself chemotactic for LGL. Migrated cells could be identified both morphologically and phenotypically as LGL on collagen type IV-coated filters after incubation with a chemotactic stimulus. LGL were found to display chemotaxis to a number of different stimuli, including the classical chemoattractant agents N-formyl-methionyl-leucyl-phenylalanine, leukotriene B4, and complement fragments present in activated sera. However, the degree of response to these stimuli was much less than that of isolated peripheral blood neutrophils or monocytes. In contrast, all three cell types showed increased chemotaxis to the diacyl glycerol analog 1-oleoyl 2-acetyl glycerol (OAG), which induced a 4-14 fold stimulation of migration. Induction of chemotaxis of LGL by OAG was time and dose-dependent, as confirmed using checkerboard assays. In summary, we have developed a rapid, quantitative method to measure chemotaxis of LGL in vitro. This technique may now be utilized to identify naturally occurring chemoattractants for LGL and to study the intracellular and regulatory events associated with LGL migration.

Animals↗

PubMed1999

Standardisation of a procedure for quantifying surface antigens by indirect immunofluorescence.

Quantitative indirect immunofluorescence (QIIF) methods used to measure absolute numbers of surface-expressed antigens have produced conflicting results [Marchant, A., Duchow, J., Delville, J., Goldman, M., 1992. Lipopolysaccharide induces up-regulation of CD14 molecule on monocytes in human whole blood. European Journal of Immunology 22, 1663-1665; Antal-Szalmas, P., van Strijp, J.A.G., Weersink, A.J.L., Verhoef, J., van Kessel, K.P.M., 1997. Quantitation of surface CD14 on human monocytes and neutrophils. Journal of Leukocyte Biology 61, 721-728.]. The aim of this study was to standardise a flow cytometric method using the quantitative indirect immunofluorescence kit (QIFIkit, Dako, Denmark) for quantifying surface-expressed bovine classical major histocompatibility complex (MHC) class I molecules. The importance of accurately titrating antibodies in this procedure and using live cell gates is already accepted. However, little work has been carried out in optimising cell washes to remove excess antibody, or to study the influence of cell numbers used in the assay. In addition, information on the binding properties of each antibody is required in order to make accurate measurements. This study demonstrates that a number of critical parameters must be established prior to using this method for accurate numerical assessment of cell surface-expressed molecules.

Animals↗

PubMed2000

The agent of human granulocytic ehrlichiosis induces the production of myelosuppressing chemokines without induction of proinflammatory cytokines.

Infection by human granulocytic ehrlichiosis (HGE) is characterized clinically by cytopenias out of proportion to the number of cells seen to be infected directly. To study the pathogenic role of inflammatory mediators in HGE infection, cytokine production by untreated and dimethyl sulfoxide-treated HL-60 cells, which demonstrate enhanced infection because of granulocytic differentiation, and by normal bone marrow cells was measured using modified sandwich ELISA assays on samples obtained sequentially after inoculation with the HGE agent. All infected cells produced physiological concentrations of CC (monocyte chemotactic protein-1, macrophage inflammatory protein-1alpha and -beta, and RANTES) and CXC (interleukin [IL]-8) chemokines in amounts significantly greater than those produced by uninfected controls. In contrast, infected cells did not secrete the classic proinflammatory cytokines IL-1, IL-6, or tumor necrosis factor-alpha. The striking production of chemokines, powerful leukocyte chemoattractants capable of suppressing hematopoiesis, by susceptible target cells, is likely to be of pathogenic importance both in the observed cytopenias and in mediation of inflammation and host defenses during infection.

Bone Marrow Cells↗

PubMed2000

DNA vaccines encoding interleukin-8 and RANTES enhance antigen-specific Th1-type CD4(+) T-cell-mediated protective immunity against herpes simplex virus type 2 in vivo.

Chemokines are inflammatory molecules that act primarily as chemoattractants and as activators of leukocytes. Their role in antigen-specific immune responses is of importance, but their role in disease protection is unknown. Recently it has been suggested that chemokines modulate immunity along more classical Th1 and Th2 phenotypes. However, no data currently exist in an infectious challenge model system. We analyzed the modulatory effects of selected chemokines (interleukin-8 [IL-8], gamma interferon-inducible protein 10 [IP-10], RANTES, monocyte chemotactic protein 1 [MCP-1], and macrophage inflammatory protein 1 alpha [MIP-1 alpha]) on immune phenotype and protection against lethal challenge with herpes simplex virus type 2 (HSV-2). We observed that coinjection with IL-8 and RANTES plasmid DNAs dramatically enhanced antigen-specific Th1 type cellular immune responses and protection from lethal HSV-2 challenge. This enhanced protection appears to be mediated by CD4(+) T cells, as determined by in vitro and in vivo T-cell subset deletion. Thus, IL-8 and RANTES cDNAs used as DNA vaccine adjuvants drive antigen-specific Th1 type CD4(+) T-cell responses, which result in reduced HSV-2-derived morbidity, as well as reduced mortality. However, coinjection with DNAs expressing MCP-1, IP-10, and MIP-1 alpha increased mortality in the challenged mice. Chemokine DNA coinjection also modulated its own production as well as the production of cytokines. These studies demonstrate that chemokines can dominate and drive immune responses with defined phenotypes, playing an important role in the generation of protective antigen-specific immunity.

Animals↗