Expression of Th1 and Th2 type cytokines responding to HBsAg and HBxAg in chronic hepatitis B patients.

The cytokine pattern on viral antigen recognition is believed to exert a profound influence on the resolution of viral infections and viral clearance. This study was initiated to investigate whether a cytokine imbalance oriented toward Th2 type response plays a role in chronic hepatitis B. Cytokine profiles of peripheral blood mononuclear cells associated with chronic hepatitis B were analysed by RT-PCR. Upon HBsAg stimulation, expression of IFN-gamma, IL-2, IL-4, and IL-10 was detected in 41%, 8%, 41%, and 50% of the patients, respectively. Among these cytokines, the expression of IFN-gamma was associated with high levels of serum AST/ALT. However, we could not prove that Th2 type cytokines had a protective effect on hepatocytes. Upon HBxAg stimulation, there was no recognizable association of cytokine patterns with AST/ALT levels. In conclusion, production of a Th1 cytokine, IFN-gamma, by HBsAg-reactive cells was associated with hepatocyte damage in chronic hepatitis B, while no counteracting effect of Th2 cytokines produced by those cells was observed.     

Different cytokine profiles of peripheral blood mononuclear cells from patients with persistent and self-limited hepatitis C virus infection

An imbalance between T helper cell Th1 and Th2 like cytokines has been described in several chronic infectious diseases. In an attempt to characterise the mechanism responsible for viral persistence in hepatitis C virus (HCV)-related chronic infection, we analyzed Th1 cytokines (IL-2, IL-12, IFN-gamma) and Th2 cytokines (IL-4, IL-10) production by phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC) derived from ten patients with viremic chronic hepatitis C, five healthy HCV seropositive individuals and four HCV seronegative individuals. Cytokine production was determined by enzyme-linked immunosorbent assay (ELISA) after 72 h of stimulation. The results showed that the production of IFN-gamma by PHA-stimulated PBMC was decreased in patients with hepatitis C infection (P=0.05). IL-4 production was not detected in both patients and controls, while no difference was observed for IL-2, IL-10 and IL-12 production between patients and controls. Furthermore, IL-12 and IFN-gamma production was weaker in patients with viremic chronic hepatitis C than in subjects who were able to clear the virus (P=0.01; P=0.03, respectively). These results clearly indicate that a defect both in IL-12 and IFN-gamma production may contribute to the persistence of HCV infection.     

Liver nonparenchymal cells involved in hyporesponsiveness induced by portal vein injection of alloantigen

INTRODUCTION: Intrahepatic injection of alloantigen prolongs allograft survival and inhibits T-lymphocyte release of both IL-2 and IFN-gamma but not IL-4. This suggests that intrahepatic processing of antigen lead to a predominance of Th2 cell population with inhibition of Th1 cell type. This study examines the effects of hepatic nonparenchymal cells (NPCs) on T cell function and cytokine mRNA expression profiles. MATERIALS AND METHODS: Following portal vein (p.v.) injection of allogeneic splenic mononuclear cells (SMNC) in mice, heterotopic cardiac allograft survival and donor-specific immune responses were assessed. The cytokine profiles were evaluated in heart grafts and spleens from transplanted mice, or in recipient lymphocytes stimulated in vitro with alloantigen. The immunoregulatory role of NPCs from p.v. injected mice was evaluated. RESULTS: Transplanted mice with prolonged graft survival demonstrated increased IL-4, TGF-beta and IL-10 and/or decreased IFN-gamma and IL-2 mRNA expression within the spleen and the transplanted graft. This correlated with increased antigen-specific IL-4, IL-10 and TGF-beta expression in lymphocytes isolated from the p.v. injected mice. In mixed lymphocyte cultures using NPC from p.v. injected mice as regulatory cells, there was decreased proliferation of lymphocytes from the p.v. injected mice in response to allogeneic stimulation, associated with increased IL-4, TGF-beta and IL-10 production and decreased IFN-gamma and IL-2 production. The regulatory effects of the NPC was reversed by prostaglandin E inhibitor. CONCLUSIONS: Interactions between allogeneic lymphocytes and NPCs results in an impaired Th1 response and preferential shift towards a Th2 cytokine response which may regulate allograft rejection.     

Lack of evidence for the Th2 predominance in patients with chronic hepatitis C

A T helper (Th)1 to Th2 shift has been proposed to be a critical pathogenic determinant in chronic hepatitis C. Here, we evaluated mitogen-induced and hepatitis C virus (HCV) core antigen-induced cytokine production in 28 patients with biopsy-proven chronic hepatitis C. Flow cytometry demonstrated that after mitogenic stimulation the percentage of Th2 cells (IL-4 + or IL-13 +) and Th0 cells (IFN-gamma/IL-4 + or IL-2/IL-13 +) did not differ between patients and controls. In contrast, the percentage of Th1 cells (IFN-gamma + or IL-2 +) was significantly increased in CD4 +, CD8 +, 'naive'-CD45RA + and 'memory'-CD45RO + T-cell subsets from patients versus controls. Similar results were obtained by ELISA testing supernatants from mitogen-stimulated, unfractionated peripheral blood mononuclear cell (PBMC) cultures. Interferon-alpha treatment was associated with a reduction in the mitogen-induced Th1 cytokine response in those patients who cleared their plasma HCV-RNA. Analysis of cytokine expression by CD4 + T cells after HCV core antigen stimulation in a subgroup of 13 chronic hepatitis C patients demonstrated no cytokine response in 74% of these patients and an IFN-gamma-restricted response in 26%. Finally, no Th2 shift was found in lipopolysaccharide-stimulated monocytes. These data indicate that a Th1 to Th2 shift does not occur in chronic hepatitis C.     

Transient inhibition of Th1-type cytokine production by CD4 T cells in hepatitis B core antigen immunized mice is mediated by regulatory T cells

The non-cytopathic hepatitis B virus (HBV) can induce chronic infections characterized by weak and limited T cell responses against the virus. The factors contributing to the failure to clear HBV and subsequent development of chronic HBV infections are not clearly understood, but a strong interferon-gamma (IFN-gamma) response by CD4+ T cells against the nucleocapsid hepatitis B core antigen (HBcAg) of the virus appears to be important for viral clearance. The present study documents depressed numbers of CD4+ T cells secreting IFN-gamma and interleukin-2 (IL-2) in enzyme-linked immunospot assay (ELISPOT) assays restimulated for 24 hr with antigen following both primary and secondary immunizations of mice with recombinant hepatitis B core antigen (rHBcAg). The kinetics of these responses showed that the depression occurred following a peak response and lasted approximately 2 weeks before returning to the previous peak levels. The depression was abrogated by depletion of CD25+ cells prior to culture in the ELISPOT assay, suggesting inhibition by regulatory T cells. This inhibition of IFN-gamma and IL-2 production was also reversed by in vitro restimulation of the test cells for 48 hr rather than 24 hr in the assay. No such transient, reversible inhibition was detected in the production of IL-5, a Th2-type cytokine. The inhibition in cytokine production did not appear to correlate with the number of antibody-secreting cells or the isotypes produced. This delay by regulatory T cells of Th1-type cytokine production could contribute to viral persistence in chronic HBV infection by interfering with the critical role IFN-gamma plays in protection against viral infections.     

Modulation of experimental blood stage malaria through blockade of the B7/CD28 T-cell costimulatory pathway

Recent studies have implicated cytokines associated with CD4+ T lymphocytes of both T helper (Th)1 and Th2 subsets in resistance to experimental blood stage malaria. As the B7/CD28 costimulatory pathway has been shown to influence the differentiation of Th cell subsets, we investigated the contribution of the B7 molecules CD80 and CD86 to Th1/Th2 cytokine and immunoglobulin isotype profiles and to the development of a protective immune response to malaria in NIH mice infected with Plasmodium chabaudi. Effective blockade of CD86/CD28 interaction was demonstrated by elimination of interleukin (IL)-4 and up-regulation of interferon (IFN)-gamma responses by P. chabaudi-specific T cells and by reduction of P. chabaudi-specific immunoglobulin G1 (IgG1). The shift towards a Th1 cytokine pattern corresponded with efficient control of acute parasitaemia but an inability to resolve chronic infection. Moreover, combined CD80/CD86 blockade by using anti-CD80 and anti-CD86 monoclonal antibodies raised IFN-gamma production over that seen with CD86 blockade alone, with augmentation of this Th1-associated cytokine reducing levels of peak primary parasitaemia. These results demonstrate that IL-4 production by T cells in P. chabaudi-infected NIH mice is dependent upon CD86/CD28 interaction and that IL-4 and IFN-gamma contribute significantly, at different times of infection, to host resistance to blood stage malaria. In addition, combined CD80/CD86 blockade resulted in preferential expansion of IFN-gamma-producing T cells during P. chabaudi infection, suggesting that costimulatory pathways other than B7/CD28 may contribute to T-cell activation during continuous antigen stimulation. This study indicates a role for B7/CD28 costimulation in modulating the CD4+ T-cell response during malaria, and further suggests involvement of this pathway in other infectious and autoimmune diseases in which the Th cell immune response is also skewed.     

Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes

The majority of hepatitis C virus (HCV) infections become chronic, despite the presence of HCV-specific cellular and humoral immune responses. We have previously suggested that IL-10-secreting antigen-specific regulatory T cells may contribute to viral persistence, and demonstrate here that peripheral blood mononuclear cells (PBMC) from chronically HCV-infected patients secrete IL-10, but not IFN-gamma, in response to HCV nonstructural protein 4 (NS4). A neutralizing anti-IL-10 antibody restored this defective antigen-specific IFN-gamma production in vitro. Furthermore, PBMC from normal individuals secreted IL-10 in response to NS4, suggesting that cells of the innate immune system, in addition to T cells, produced IL-10 in the HCV-infected patients. Cell separation experiments revealed that the innate IL-10 was produced by blood monocytes, but not dendritic cells (DC). In addition, NS4 inhibited IL-12 production by PBMC in response to LPS and IFN-gamma, and Th1 responses to recall antigens in normal individuals. Furthermore, supernatants from NS4-stimulated monocytes inhibited LPS-induced maturation of DC and suppressed their capacity to stimulate proliferation and IFN-gamma production by allospecific T cells. Our data suggest that HCV subverts cellular immunity by inducing IL-10 and inhibiting IL-12 production by monocytes, which in turn inhibits the activation of DC that drive the differentiation of Th1 cells.     

Saponin adjuvant primes for a dominant interleukin-10 production to ovalbumin and to Trypanosoma cruzi antigen.

The adjuvant activity of saponin for T-cell responses was evaluated and compared with that of complete Freund's adjuvant (CFA) in two antigen systems: a lysate of the protozoa Trypanosoma cruzi and ovalbumin (OA). Strong delayed-type hypersensitivity and T-cell proliferate responses, comparable with those stimulated by CFA, were observed for both antigens following immunization with saponin as adjuvant. Upon in vitro secondary antigen stimulation, high interleukin-10 (IL-10) and low interferon-gamma (IFN-gamma) levels were observed in lymph node (LN) cell cultures from saponin-immunized mice in contrast with the high IFN-gamma and decreased IL-10 production by LN cells from CFA-immunized mice. Production of IL-10 and IFN-gamma in these conditions was CD4-activation dependent. Concanavalin A (Con A)-stimulated interleukin-4 (IL-4) production was higher in saponin-immunized mice than in CFA-immunized mice. IL-10 produced by LN cells from saponin-immunized mice suppressed IFN-gamma production and Con A-induced proliferation. Taken together, these data are consistent with in vivo stimulation of both T-helper (Th)1 and Th2-type cells by immunization with saponin; in vitro a Th2-type cytokine response with high IL-10 production predominates, indicating preferential priming towards a Th2-type response. Immunization with CFA induced a Th1-type cytokine response. To our knowledge this is the first report in which an adjuvant is shown to prime for a dominant IL-10 production.     

Effects of boar seminal immunosuppressive fraction on production of cytokines by Concanavalin A-stimulated spleen cells and on proliferation of B lymphoma cell lines

PROBLEM: The immunosuppressive fraction (ISF) of boar seminal vesicle fluid has recently been demonstrated to inhibit mitogen-stimulated proliferation of lymphocytes and antibody response to corpuscular and soluble antigens. The effects of ISF on in vitro and in vivo production of cytokines as well as its possible inhibitory effect on proliferation of B lymphoma cells remain to be elucidated. METHODS: The effect of ISF on proliferation of normal mouse spleen cells stimulated by Concanavalin A (Con A) and on mouse B lymphoma cells was measured by 3H-thymidine incorporation. Cytokines were determined in the supernatants of mouse spleen cells stimulated with Con A in the presence or absence of ISF by enzyme-linked immunosorbent assay (ELISA). In vivo cytokine production in the sera samples of mice treated with ISF and immunized with keyhole limpet hemocyanin (KLH) was followed by ELISA, too. RESULTS: We confirmed the inhibitory effect of ISF on Con A-stimulated lymphocyte proliferation. ISF affected cytokine production in the Con A-stimulated spleen cells: production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) was lowered, but production of IL-4, IL-6, and IL-10 was enhanced. Similarly, in the sera samples of mice immunized with keyhole limpet hemocyanin (KLH), IL-2 and IFN-gamma levels were decreased by ISF. ISF inhibited proliferation of Ag 8 and X 63-IL-2 B lymphoma cells as well. CONCLUSIONS: ISF inhibited production of T helper1 (Th1) cytokines (IL-2 and IFN-gamma) and enhanced production of Th2 cytokines (IL-4, IL-6, and IL-10). ISF seems to shift the Th1/Th2 pattern in favor of Th2. ISF exhibited an antiproliferative activity on mouse B lymphoma cells.     

Anti-interleukin-4 modulation of the Th2 polarized response to the parasitic nematode Brugia pahangi.

Lymphatic filariasis is a chronic disease characterized by a pronounced Th2 bias in the immune response and impaired antigen (Ag)-specific Th1 responses. We have used a mouse model of filariasis to investigate the role of the infective form (the third-stage larvae [L3]) in modulating the immune response. Subcutaneous infection of BALB/c mice with L3 of Brugia pahangi has a profound effect on Th cell function. By day 12 post-infection, spleen cells from these mice exhibited a dramatic reduction in concanavalin A-driven proliferation and interleukin-2 (IL-2) and gamma interferon (IFN-gamma) secretion in comparison with uninfected controls. However, exposure to L3 did not render the mice completely unresponsive; these animals mounted a strong Th2 response to the parasite, characterized by elevated levels of IL-4, IL-5, and IL-10 and parasite-specific serum immunoglobulin G (IgG), IgG1, and IgE. Treatment of spleen cells from L3-infected mice with neutralizing anti-IL-4 or recombinant IL-2 resulted in a dramatic increase in concanavalin A-induced proliferation and IL-2 and IFN-gamma production. Despite their defective polyclonal Th1 response, cells from L3 infected mice proliferated when stimulated with Ag, and this response was blocked by anti-IL-4. However, anti-IL-4 treatment failed to induce Ag-specific IL-2 or IFN-gamma production, indicating that B.pahangi-primed Th1 cells do not appear to be present or are still unable to respond even in the absence of IL-4.     

Central Role for Interleukin-4 in Regulating Nitric Oxide-Mediated Inhibition of T-Cell Proliferation and Gamma Interferon Production in Schistosomiasis

Schistosoma mansoni-infected wild-type (WT) mice develop a Th2 response and chronic disease. In contrast, infected interleukin-4 double-deficient (IL-4(-/-)) mice develop a Th1-like response and an acute, lethal syndrome. Disease severity in these animals correlates with excessive and prolonged production of nitric oxide (NO) associated with enhanced antigen-driven gamma interferon (IFN-gamma) production in the absence of IL-4. Strikingly, splenic lymphocytes from infected IL-4(-/-) mice failed to proliferate as well as those from infected WT mice following stimulation in vitro with antigen or anti-CD3 antibody. Contrary to antigen-driven IFN-gamma responses, anti-CD3 antibody stimulation of splenocytes resulted in significantly less IFN-gamma being produced by CD8 cells from infected IL-4(-/-) mice than by those from infected WT mice or normal mice. NO is largely responsible for the impaired T-cell functions in infected IL-4(-/-) mice, as inhibition of iNOS significantly enhanced proliferation and IFN-gamma production.     

Heterogeneity of cytokine functions in HIV infection.

Immunological responses, especially cytokines, play important roles in determining the persistence of infectious agents in chronic diseases. Th1 responses enhance cellular immunity to control infection whereas Th2 immune responses down-regulate these effector immune responses. It has been suggested that the Th1 to Th2 switch is involved in human immunodeficiency virus (HIV) disease progression. We studied the regulatory role of interleukin-4 (IL-4; Th2 response) on interferon-gamma (IFN-gamma; Th1 response) in HIV infection and its role in the generation of HIV-specific cytotoxic T lymphocytes (CTL) in an in vitro system. Forty HIV-infected, asymptomatic individuals and 20 HIV-seronegative individuals were included in this study. Peripheral blood mononuclear cells were stimulated with phytohaemagglutinin and tetanus toxoid in the presence or absence of IL-4 to determine the effect of IL-4 on IFN-gamma production and HIV-Env-specific CTL activity. IL-4 showed a dual effect on IFN-gamma production in HIV patients. IL-4 down-regulated IFN-gamma production in HIV-seronegative individuals and in 55% of HIV patients whereas it stimulated IFN-gamma production in 45% of HIV patients. IL-4 increased HIV-Env-specific CTL activity in five of seven patients of the latter group. IL-4 has multiple biological activities, e.g. IL-4 inhibits IFN-gamma production as well as stimulates CTL generation which in turn produces IFN-gamma. Understanding the biological significance of these interactions is of importance for immunotherapeutic approaches against HIV infection.     

Induction of murine T-helper-cell responses to the filarial nematode Brugia malayi.

The purpose of this study was to examine the murine T-helper-cell (Th) cytokine response to the human filarial parasite Brugia malayi. In the first 14 days following intraperitoneal inoculation of live microfilariae into BALB/c mice, filarial antigen-driven splenic lymphoid cells produced gamma interferon (IFN-gamma) and little or no interleukin-5 (IL-5). After this time, IL-5 production increased (to 10 to 12 ng per 5 x 10(6) cells) coincident with a marked diminution in IFN-gamma generation. A single subcutaneous immunization with soluble microfilarial antigens also induced an IFN-gamma but no IL-5 response, whereas immunization three times elicited a predominant Th2-like reaction characterized by IL-4 and IL-5 production by CD4+ lymph node lymphocytes and a 10-fold increase in serum immunoglobulin E. The importance of IL-10 in establishing the balance between parasite-specific Th1 and Th2 responses was demonstrated by the ability of neutralizing monoclonal antibody to this cytokine to increase IFN-gamma production by splenic and lymph node cells from mice chronically exposed to live microfilariae or immunized multiple times with soluble filarial antigens.     

Cellular immune responses to the murine nematode parasite Trichuris muris. II. Differential induction of TH-cell subsets in resistant versus susceptible mice.

We have analysed the production of a wide variety of cytokines by in vitro concanavalin A (Con A) stimulated mesenteric lymph node cells (MLNC) from strains of mice experiencing chronic (B10.BR, AKR) versus acute (BALB/K) infection with the nematode parasite Trichuris muris. MLNC from infected BALB/K mice produced elevated levels of the Th2-specific cytokines interleukin-5 (IL-5) and IL-9. IL-3 and IL-4 remained at or just above normal. Interferon-gamma (IFN-gamma) (a Th1-type cytokine) was secreted only in small amounts. MLNC from infected susceptible B10.BR and AKR mice produced large amounts of IFN-gamma in the relative absence of IL-4 and IL-9. IL-5 levels failed to rise significantly above normal in B10.BR mice whilst in AKR mice high levels of IL-5 were detected early post-infection (p.i.) but levels decreased dramatically as the infection proceeded to reach normal levels by Day 34. IL-3 levels were depressed below normal. Our results are consistent with the polarization of the Th-cell response during T. muris infection to give predominantly IFN-gamma-secreting Th1 cells in strains of mice unable to expel the parasite and mainly IL-4, IL-5 and IL-9 producing Th2-type cells in resistant strains.     

ICAM-1 costimulation induces IL-2 but inhibits IL-10 production in superantigen-activated human CD4+ T cells.

We have previously reported that costimulatory pathways including B7-CD28 and lymphocyte function-associated antigen-3 (LFA-3)-CD2 shape distinct activation profiles in human CD4+ T cells. We now show that superantigen (SAg), in combination with intracellular adhesion molecule-1 (ICAM-1) costimulation drives a proliferative response accompanied by high levels of interleukin-2 (IL-2) and moderate levels of interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF). This response profile differs from that observed in B7 or LFA-3 costimulated T cells because our previous results showed that B7-CD28 costimulation was accompanied by high levels of IL-2, IFN-gamma and TNF, whereas LFA-3 was a potent inducer of IFN-gamma and TNF, but had little influence on IL-2 production. The ICAM-1-induced IL-2 production could efficiently be abrogated with monoclonal antibody (mAb) against ICAM-1 or LFA-1, showing that the activation is dependent of a functional ICAM-1-LFA-1 pathway. SAg-induced IL-2, IFN-gamma and TNF were detected in both CD4+ and CD8+ T cells, whereas production of IL-10 was restricted to CD4+ T cells. A major finding in the present study was that ICAM-1 costimulation strongly inhibits IL-10 production in CD4+ T cells. Our data demonstrate that ICAM-1 costimulation is sufficient to induce large amounts of IL-2. The presence of ICAM-1 results in suppression of IL-10 production in T helper (Th) cells, which may favour the development of Th1 and not Th2 T cells.     

Secretion of cytokines,histamine and leukotrienes in chronic urticaria

BACKGROUND: Approximately 35-40% of patients with chronic urticaria have an IgG autoantibody to the IgE receptor which can activate basophils and mast cells so that they release histamine. In this study we assessed the cytokine profile present in chronic urticaria sera, and then measured cytokine and leukotriene release from basophils and mast cells upon incubation with chronic urticaria sera. Finally we assessed cytokine expression at the single-cell level and characterized the T cell subpopulations involved in their production. We chose IL-4 as representative of Th2 lymphocytes and IFN-gamma for Th1 lymphocytes. METHODS: We analyzed IL-4, IL-5 and IFN-gamma in 60 chronic urticaria sera versus 51 controls. Sera were incubated with purified human basophils and cutaneous mast cells and the release of histamine, IL-4 and leukotrienes (C(4), D(4), E(4)) was quantitated. Immunoblotting was performed to identify IgG antibody to FcepsilonRIalpha, alpha subunit. We measured intracellular cytokine production in peripheral blood mononuclear cells of 17 chronic urticaria patients compared to 50 healthy controls. RESULTS: We found higher IL-4 levels (p = 0.028) in the sera of chronic urticaria patients (1.03 pg/ml) versus healthy donors (0.20 pg/ml) but no difference between urticaria sera and atopic control sera (0.52 pg/ml). We did not detect IFN-gamma or IL-5 in any serum. However, sera that activated basophils so that they released histamine also produced leukotriene and IL-4, and leukotriene production by cutaneous mast cells and basophils was closely correlated. However, there was no correlation between immunoblotting and the functional ability to induce either histamine or IL-4. After stimulating with PMA-ionomycin we found significant differences in CD4+ lymphocyte production of IL-4 and IFN-gamma with no differences in CD8+ lymphocyte production of either cytokine. CONCLUSION: Our data support the presence of basophil and mast cell activators in the sera of patients with chronic urticaria which can lead to the production of leukotrienes and IL-4 in addition to the histamine. IL-4 levels are similar to those seen in atopic subjects. We found that CD4+ T cells from patients with chronic urticaria are activated and tend to produce higher cytokine levels than CD4+ T cells from healthy controls. There were no differences when cytokine production by CD8+ lymphocytes was similarly assessed. These results are consistent with the histology found in biopsies of chronic urticaria lesions, where a CD4+-predominant infiltrate is found with cytokine production suggesting either a Th0 response or a mixture of Th1 and Th2 lymphocytes.     

IL-15 in human visceral leishmaniasis caused by Leishmania infantum

Interleukin (IL)-15 is a recently discovered cytokine with the ability to stimulate the proliferation activity of Th1 and/or Th2 lymphocytes. Here, we investigated the involvement of IL-15 in the immune response to Leishmania infantum infection by studying patients with visceral leishmaniasis (VL). We found that IL-15 is produced by leishmanial antigen (LAg)-stimulated peripheral blood mononuclear cells (PBMC) from active VL patients at a significantly higher level than those produced by cells from healed VL subjects or healthy controls. A significant increase in IL-15 serum blood levels was also observed in acute VL patients compared with healed ones. Furthermore, recombinant IL-15 had an appreciable effect in vitro in reducing IL-4 and increasing the production of IL-12 in response to LAg, but it was ineffective in altering the production of interferon-gamma (IFN-gamma). The production of endogenous IL-15 in acute VL patients appeared to be insufficient to activate both IFN-gamma and IL-12, as attested by the absence of modification of these two cytokines by neutralization experiments in the presence of anti-IL-15 monoclonal antibodies (MoAB). On the contrary, the neutralization of IL-15 increased IL-4 production. Together, these results indicate that endogenous IL-15 plays a role in the suppression of Th2-type cytokines, even though it does not enhance the production of Th1 cytokines in acute VL patients. Since IL-15, in the presence of anti-IL-4 MoAb, caused a further increase in IL-12 production and led to a significant production of IFN-gamma, one of its indirect effects on Th1 cell activation could be due to the latter's effect on Th2 cytokines such as IL-4. Therefore, our observations indicate that there is a potential for IL-15 to augment the T-cell response to human intracellular pathogens.     

Concentrations of cytokines,soluble interleukin-2 receptor,and soluble CD30 in sera of patients with hepatitis B virus infection during acute and convalescent phases

The immunoregulatory roles of interleukin-2 (IL-2), IL-4, IL-10, gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), the soluble form of the IL-2 receptor (sIL-2R), and the soluble form of CD30 (sCD30) were evaluated in patients with hepatitis B virus (HBV) infection. Two groups of subjects were studied: 15 healthy individuals without hepatitis antecedents and 15 patients with HBV infection. Blood samples were taken during the acute and convalescent phases. The analysis of the samples was done by the enzyme-linked immunosorbent assay technique. IFN-gamma and TNF-alpha levels decreased in the convalescent phase. IL-10, IL-2, and sIL-2R levels increased in the acute and convalescent phases, while sCD30 levels increased during the acute phase. The IL-4 concentrations decreased in both phases. During the acute phase, IFN-gamma and TNF-alpha induced increases in IL-2, sIL-2R, IL-10, and sCD30 levels in serum, which allowed the development of immunity characterized by the nonreactivity of the HBV surface antigen, the onset of antibodies to the HBV surface antigen (anti-HBs), and normal alanine aminotransferase levels during the convalescent phase. Increased IL-2 levels during the acute phase would stimulate the activities of NK cells and CD8(+) lymphocytes, which are responsible for viral clearing. The raised sIL-2R levels reveal activation of T lymphocytes and control of the IL-2-dependent immune response. The sCD30 increment during the acute phase reflects the greater activation of the Th2 cellular phenotype. Its decrease in the convalescent phase points out the decrease in the level of HBV replication. The increase in IL-10 levels could result in a decrease in IL-4 levels and modulate IFN-gamma and TNF-alpha levels during both phases of disease, allowing the maintenance of anti-HBs concentrations.