Suppression Of Humoral Immune Response Research Articles

Immunoprotective therapy for suppression of humoral immune response induced by hypoxia and toxemia

The possibility of using preparations limiting toxemia and hypoxia, in particular inhibitors of proteoletic enzymes and antihypoxants, as preparations having immunoprotective activity is considered. Under the conditions of the experimental model of severe mechanical injury on mice-hybrids of the first generation F1 (CBAC57BL6), the immunoprotective activity of such antihypoxants as amtisol and a derivative of 1, 2, 4-triazino-5, 6 indole, as well as a counterkal, a drug limiting toxemia and a cationoacceptor preparation of dimexide, administered to immunized erythythermal It has been shown that in the body of mice receiving antihypoxants, contrical and dimexide accumulate significantly more antibody-forming cells compared to their number in animals of the control group. Thus, amtisol, a derivative of 1, 2, 4-triazino-5, 6 indole, contrical and dimexide can be considered not only as preparations for pathogenetic therapy of trauma, but also as immunoprotectors drugs that indirectly limit the formation of post-traumatic immunodeficiency and the risk of infection in an immunocompromised host. The risk of infectious complications and the generalization of the inflammatory process in patients after severe mechanical injury is more than 50%. Prevention of infectious complications of traumatic disease should be comprehensive and aimed at correcting the function of the immune system.

Immunoprotective therapy of suppression of humoral immune response, pain induced (search for narcotic analgesics with immunoprotective activity)

Problematic issues of prevention of humoral immune response suppression induced by pain in conditions of the experimental model of severe mechanical trauma are highlighted. It has been established that one of the pathogenetic factors of trauma depressing the humoral immune response is pain. Thus, drugs inhibiting intra-central transmission of afferent impulse, and, in particular, narcotic analgesics, may be considered as drugs with immunoprotective activity. Evaluation of the immunoprotective activity of five narcotic analgesics administered immediately after trauma to immunized mice in the first 24 hours of post-traumatic period showed the presence of the estimated effect in morphine hydrochloride, fentanyl and pifurben. By 106 splenocytes of mice received these preparations and immunized on the first day after the trauma, reliably more antibodies forming cells are formed in mice in comparison with their number in animals received after the trauma as narcotic analgesics intermediol and dipidolor. Thus, morphine hydrochloride, fentanyl and pifurben, i.e. drug analgesics with immunoprotective activity, should be considered as the preferred drugs in the group of narcotic analgesics in emergency care for patients with severe trauma. The use of narcotic analgesics with immunoprotective properties should be considered as one of the measures in the complex of measures aimed at the prevention of post-traumatic immunodeficiency and infection in an immunocompromised host. Infections are difficult to diagnose and often with an unfavorable outcome.

The Effect of One Bout of Intensive Judo Exercise on Select Hematological and Immunological Parameters in Adolescent Elite Judo Athletes

Background: Exercise-related studies do not agree on changes in blood parameters regarding anemia and serum immunoglobulin concentration as adaptive immunity. Objectives: The current study aimed to investigate exercise-induced variations in hematological and immunological parameters in response to one bout of intensive judo exercise in adolescent elite judoka. Methods: Venipuncture was performed on ten adolescent male Iranian elite judoka (age: 15.60 ± 0.69 years; body mass index: 24.15 ± 2.80 kg/m2) before and immediately after one bout of intensive judo protocol. Erythrocyte variables [red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), red distribution width (RDW), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC)], platelets variables [platelet count (PLT), platelet distribution width (PDW), mean platelet volume (MPV), plateletcrit (PCT)], cellular immune variables [white blood cell (WBC), neutrophil (NEU), lymphocyte (LYM)], and humoral immune variables (IgM, IgA, IgG, IgE) were measured. Data were analyzed using Wilcoxon and paired-samples t-test, and P < 0.05 was considered significant. Results: After the plasma volume was corrected using the Dill and Costill equation, the results showed that RBC, HGB, HCT, MCHC, IgA, and IgM decreased significantly immediately after exercise. However, MCH, RDW, PLT, PDW, MPV, PCT, WBC, LYM, NEU, IgG, and IgE did not change significantly. Conclusions: According to the findings, it can be concluded that intensive judo exercise results in transient anemia and suppression of humoral immune response among adolescent elite judoka.

HYPOXIC THERAPY IN THE CORRECTION OF NEUROIMMUNOENDOCRINE DISORDERS IN AUTOIMMUNE THYROIDITIS

Efficiency of interval hypoxic training in treatment of hypothyroidism with autoimmune genesis in children and adolescents was shown. The therapeutic effect of hypoxic therapy realized not only through amplification of compensatory mechanisms for the oxygen delivery to the tissues, but also through inhibition of humoral immune responses and the stimulation of T-cell immunity in patients with autoimmune thyroiditis. Increase of function and quantity of CD8+-cells after a course of hypoxic therapy prevents the progression of the autoimmune process and helps to restore the function of the thyroid gland, which in turn leads to positive changes in the neurological status of patients: improved mental performance indicators and fine motor coordination. Complications of therapy or deterioration of the patients were not observed. Follow-up monitoring of patients conducted after 6-8 months after treatment showed that the positive effect of hypoxic therapy maintained throughout this period. Positive hormonal and immunological and neurological dynamics in children and adolescents with autoimmune thyroiditis after the interval hypoxic training suggests its inclusion in the scheme of pathogenetic treatment of patients with this pathology.

Bystander inhibition of humoral immune responses by Epstein-Barr virus LMP1.

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1), which mimics a constitutively active receptor, is required for viral transformation of primary B cells. LMP1 is expressed in EBV-infected germinal center (GC) B cells of immunocompetent individuals, suggesting that it may contribute to persistent EBV infection. In this study, we generated and analyzed mice that expressed LMP1 under the control of the CD19 or activation-induced cytidine deaminase (AID) promoter. Expression of LMP1 induced activation of B cells but severely inhibited their differentiation into antibody-secreting cells (ASCs) in vitro and GC B cells in vivo. LMP1-expressing (LMP1+) B cells not only suppressed the functions of wild-type (WT) B cells in in vitro co-culture, but also blocked differentiation of WT B cells into GC B cells and ASCs in immunized bone marrow chimeric mice. Microarray analysis revealed that the gene encoding indoleamine 2,3-dioxygenase 1 (IDO1), a major enzyme involved in the tryptophan metabolic process, was highly induced by LMP1. Either inhibition of IDO1 activity by methyl-l-tryptophan or knockout of Ido1 in LMP1+ B cells could rescue WT B cells from such suppression. IDO1-induced tryptophan consumption and production of tryptophan metabolites appeared to be responsible for inhibition of B-cell function. We conclude that LMP1 expression in antigen-committed B cells not only directly impairs GC B-cell differentiation, but also indirectly inhibits the functions of neighboring B cells, resulting in suppression of humoral immune responses. Such bystander inhibition by LMP1+ B cells may contribute to immune evasion by EBV.

Suppression of the IgM Response by Aryl Hydrocarbon Receptor Activation in Human Primary B Cells Involves Impairment of Immunoglobulin Secretory Processes.

Aryl hydrocarbon receptor (AHR) activation by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is well established at suppressing humoral immunity. Previous studies in mouse B cells revealed that decreased IgM production was due to a significant suppression in the mRNA levels of the immunoglobulin M components (IgH, IgJ, and Igκ chains) and subsequent decrease in IgM synthesis. In contrast, the current study shows that activation of AHR in human B cells also results in a significant suppression of the number of IgM-secreting cells, but this is not due to a decrease in the transcription or translation of IgH, IgJ, and Igκ chains. Instead, the reduced humoral response is due to the impairment of IgM secretion. This is further evidenced by an accumulation of intracellular IgM in human B cells, which indicates that activation of AHR alters distinct regulatory pathways in human and mouse B cells leading to the suppressed primary IgM response. Collectively, these results demonstrate that although AHR activation mediates suppression of humoral immune responses across many different animal species, the mechanism of action is not necessarily conserved across species.

Why Serological Responses during Cystitis are Limited.

The high frequency of urinary tract infections (UTIs), some of which appear to be endogenous relapses rather than reinfections by new isolates, point to defects in the host’s memory immune response. It has been known for many decades that, whereas kidney infections evoked an antibody response to the infecting bacteria, infections limited to the bladder failed to do so. We have identified the existence of a broadly immunosuppressive transcriptional program associated with the bladder, but not the kidneys, during infection of the urinary tract that is dependent on bladder mast cells. This involves the localized secretion of IL-10 and results in the suppression of humoral immune responses in the bladder. Mast cell-mediated immune suppression could suggest a role for these cells in critically balancing the needs to clear infections with the imperative to prevent harmful immune reactions in the host.

Influence of miR-30b regulating humoral immune response by genetic difference.

Investigation of genetic difference will be beneficial to researchers to understand the origins and nature of diseases. Previous studies have revealed that L-kynurenine (L-Kyn) level was changed significantly in patient with cancer and that miR-30b play different role in tumor cells and immune cells. Moreover, it has been also conformed that miR-30b involved in the process of L-Kyn-mediated suppression of humoral immune responses induced by lipopolysaccharide (LPS) in human normal B cells separated from volunteers' peripheral blood. Nevertheless, the miR-30b role regulating humoral immune response in B lymphoma cells has been still unclear due to the genetic difference between normal cells and tumor cells. The current study demonstrated that the selected concentration of L-Kyn (100, 1000 μM) significantly reduced the immunoglobulin M secretion induced by LPS when compared with the control group in B lymphoma, CH12.LX, and BCL-1 cells, which had, at least, incomplete dependence on Aryl hydrocarbon receptor, the receptor of L-Kyn. In addition, although L-Kyn (100 μM) significantly attenuated the expression of miR-30b in BCL-1 cells rather than in CH12.LX cells, no significant differences in the strength of L-Kyn-mediated suppression of humoral immune responses induced by LPS were detected by enzyme-linked immunosorbent assay between the LPS (10 μg/ml) + L-Kyn (100 μM) group and the LPS (10 μg/ml) + L-Kyn (100 μM) + miR-30b mimics/miR-30b inhibitor group in CH12.LX and BCL-1 cells, respectively. Further data also showed that mouse Bach2 mRNA was a novel target of miR-30b. These results suggest that genetic difference among cells has a great influence on the miR-30b role in the process of L-Kyn-mediated suppression of humoral immune responses induced by LPS.

Heterophil/lymphocyte ratios predict the magnitude of humoral immune response to a novel antigen in great tits (Parus major)

Animals display remarkable individual variation in their capacity to mount immune responses against novel antigens. According to the life-history theory, this variation is caused by the costs of immune responses to the hosts. We studied one of such potential costs, depletion of somatic resources in wintering wild-caught captive passerines, the great tits (Parus major) by immune challenging the birds with a novel antigen, killed Brucella abortus (BA) suspension. We found that despite mild temperature conditions in captivity and ad libitum availability of food, immune challenge depleted somatic resources (as indicated by a body mass loss) and elevated relative proportion of heterophils to lymphocytes (H/L ratio) in the peripheral blood of birds. However, body mass loss did not covary with an increase in H/L ratios between two sampling events, which indicates that these two markers of health state describe different aspects of individual physiological condition. Antibody titres were not associated with the extent of body mass loss during the development of immune response, which shows that the somatic cost of immune response was not proportional to the amount of antibody produced. Birds with high pre-immunisation H/L ratios mounted weaker antibody response, which is indicative of stress-induced suppression of humoral immune response and is consistent with the concept of an antagonistic cross-regulation between different components of the immune system. The latter finding suggests a novel diagnostic value of H/L ratios, which reinforces the utility of this simple haematological index for prediction of the outcomes of complicated immune processes.

Suppression of humoral immune responses by 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin intercalated in smectite clay

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant found in soils and sediments. Because of its exceptionally low water solubility, this compound exists predominantly in the sorbed state in natural environments. Clay minerals, especially expandable smectite clays, are one of the major component geosorbents in soils and sediments that can function as an effective adsorbent for environmental dioxins, including TCDD. In this study, TCDD was intercalated in the smectite clay saponite by an incipient wetness method. The primary goal of this study was to intercalate TCDD in natural K-saponite clay and evaluate its immunotoxic effects in vivo. The relative bioavailability of TCDD was evaluated by comparing the metabolic activity of TCDD administered in the adsorbed state as an intercalate in saponite and freely dissolved in corn oil. This comparison revealed nearly identical TCDD-induced suppression of humoral immunity, a well-established and sensitive sequela, in a mammalian (mouse) model. This result suggests that TCDD adsorbed by clays is likely to be available for biouptake and biodistribution in mammals, consistent with previous observations of TCDD in livestock exposed to dioxin-contaminated ball clays that were used as feed additives. Adsorption of TCDD by clay minerals does not appear to mitigate risk associated with TCDD exposure substantially.

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was first reported in the mid-1970s. Since this initial observation, much effort has been devoted by many laboratories toward elucidation of the cellular and molecular mechanisms responsible for the profound impairment of humoral immune responses by TCDD, which is characterized by decreased B cell to plasma cell differentiation and suppression of immunoglobulin production. These efforts have led to a significant body of research demonstrating a direct effect of TCDD on B-cell maturation and function as well as a requisite but as yet undefined role of the aryl hydrocarbon receptor (AhR) in these effects. Likewise, a number of molecular targets putatively involved in mediating B-cell dysfunction by TCDD, and other AhR ligands, have been identified. However, our current understanding has primarily relied on findings from mouse models, and the translation of this knowledge to effects on human B cells and humoral immunity in humans is less clear. Therefore, a current challenge is to determine how TCDD and the AhR affect human B cells. Efforts have been made in this direction but continued progress in developing adequate human models is needed. An in-depth discussion of these advances and limitations in elucidating the cellular and molecular mechanisms putatively involved in the suppression of B-cell function by TCDD as well as the implications on human diseases associated in epidemiological studies with exposure to TCDD and dioxin-like compounds is the primary focus of this review.

Enhanced humoral immune responses against T-independent antigens in Fcα/μR-deficient mice

IgM is an antibody class common to all vertebrates that plays a primary role in host defenses against infection. Binding of IgM with an antigen initiates the complement cascade, accelerating cellular and humoral immune responses. However, the functional role of the Fc receptor for IgM in such immune responses remains obscure. Here we show that mice deficient in Fc alpha/muR, an Fc receptor for IgM expressed on B cells and follicular dendritic cells (FDCs), have enhanced germinal center formation and affinity maturation and memory induction of IgG3(+) B cells after immunization with T-independent (TI) antigens. Moreover, Fc alpha/muR-deficient mice show prolonged antigen retention by marginal zone B (MZB) cells and FDCs. In vitro studies demonstrate that interaction of the IgM immune complex with Fc alpha/muR partly suppress TI antigen retention by MZB cells. We further show that downregulation of complement receptor (CR)1 and CR2 or complement deprivation by in vivo injection with anti-CR1/2 antibody or cobra venom factor attenuates antigen retention by MZB cells and germinal center formation after immunization with TI antigens in Fc alpha/muR(-/-) mice. Taken together, these results suggest that Fc alpha/muR negatively regulates TI antigen retention by MZB cells and FDCs, leading to suppression of humoral immune responses against T-independent antigens.

Enhanced humoral immune responses against T-independent antigens in Fcα/μR-deficient mice (39.14)

Abstract IgM is an antibody class common to all vertebrates that plays a primary role in host defences against infection. Binding of IgM with an antigen initiates the complement cascade, accelerating cellular and humoral immune responses. However, the functional role of the Fc receptor for IgM in such immune responses remains obscure. Here we show that mice deficient in Fcα/μR, an Fc receptor for IgM expressed on B cells and follicular dendritic cells (FDCs), had enhanced germinal center formation and affinity maturation and memory induction of IgG3+ B cells after immunization with T-independent (TI) antigens. Moreover, Fcα/μR-deficient mice showed prolonged antigen retention by marginal zone B (MZB) cells and FDCs. In vitro studies demonstrated that interaction of the IgM immune complex with Fcα/μR partly suppressed TI antigen retention by MZB cells. We further showed that downregulation of complement receptor (CR)1 and CR2 or complement deprivation by in vivo injection with anti-CR1/2 antibody or cobra venom factor attenuated antigen retention by MZB cells and GC formation after immunization with TI antigens in Fcα/μR-/-_mice. Taken together, these results suggest that Fcα/μR negatively regulates TI antigen retention by MZB cells and FDCs, leading to suppression of humoral immune responses against T-independent antigens.

Involvement of Blimp-1 and AP-1 dysregulation in the 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated suppression of the IgM response by B cells.

B cell differentiation and humoral immune responses are markedly suppressed by the persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The suppression of humoral immune responses by TCDD occurs by direct actions on the B cell and involves activation of the aryl hydrocarbon receptor. Transcriptional regulation of paired box gene 5 (Pax5), an important regulator of B cell differentiation, is altered by TCDD in concordance with the suppression of B cell differentiation and humoral immunoglobulin M response. We hypothesized that TCDD treatment leads to dysregulation of Pax5 transcription by interfering with the basic B cell differentiation mechanisms and aimed to determine the effects of TCDD on upstream regulators of Pax5. A critical regulator of B cell differentiation, B lymphocyte-induced maturation protein-1 (Blimp-1) acts as a transcriptional repressor of Pax5. In lipopolysaccharide (LPS)-activated murine B cell lymphoma, CH12.LX, Blimp-1 messenger RNA, and DNA-binding activity within the Pax5 promoter were suppressed by TCDD. Furthermore, LPS activation of CH12.LX cells upregulated DNA-binding activity of activator protein 1 (AP-1) at three responsive element-like motifs within the Blimp-1 promoter. TCDD treatment of LPS-activated CH12.LX cells suppressed AP-1 binding to these motifs between 24 and 72 h, in concordance with the suppression of Blimp-1 by TCDD. A more comprehensive analysis at 72 h demonstrated that the suppression of AP-1 binding within the Blimp-1 promoter by TCDD was concentration dependent. In summary, our findings link the TCDD-mediated suppression of Blimp-1 through AP-1 to the dysregulation of Pax5, which ultimately leads to the suppression of B cell differentiation and humoral immune responses.

Blunted Humoral Response to Influenza Vaccination in Patients Exposed to Zidovudine plus Trimethoprim‐Sulfamethoxazole

To determine as proof of principle the effect of combination exposure to zidovudine plus trimethoprim-sulfamethoxazole (TMP-SMX) on humoral immune responses to influenza vaccination in patients with human immunodeficiency virus (HIV). Prospective, open-label trial. University-affiliated infectious diseases outpatient clinic. Twenty-three HIV-infected adults receiving antiretroviral therapy, with CD4+ cell counts greater than 350 cells/mm3 and undetectable viral loads. Patients were assigned to one of four treatment groups: zidovudine (6 patients), TMP-SMX (7), zidovudine plus TMP-SMX (5), or neither drug (5); TMP-SMX was given as a 28-day course. Patients were subsequently immunized with the yearly influenza vaccine, and humoral responses were compared among groups 20-24 days after vaccination. Antibody responses to influenza A and B were measured, and total and activated T and B cell percentages in the peripheral blood were determined. Mean influenza B-specific serum immunoglobulin (Ig)G titers were significantly lower in patients receiving TMP-SMX alone (0.98 +/- 0.60 reference value, p=0.010) or the combination of zidovudine plus TMP-SMX (0.73 +/- 0.29 reference value, p=0.003) compared with those receiving neither drug (1.95 +/- 0.38 reference value). This corresponded to a significantly lower percentage of patients in the combination group that achieved immunoprotective titers to influenza B compared with the group who received neither drug (control group; 20% vs 100%, p=0.048). In addition, the relationship between serum IgG titer and CD4+ cell count was statistically significantly different for patients exposed to zidovudine plus TMP-SMX versus control patients for both influenza A and B (F statistics 8.72 and 11.70, respectively, compared with critical F value 7.26 for p<0.025). Likewise, the relationship between influenza B serum IgG and CD4+ cell count was different among patients who received TMP-SMX versus those who did not receive TMP-SMX (F statistic 5.95 compared with critical F value 4.56 for p<0.025). No significant differences were observed among T and B cell percentages in the blood. Combination exposure to zidovudine plus TMP-SMX causes a clinically significant suppression of humoral immune responses to influenza vaccination in HIV-infected patients.

High‐dose cyclophosphamide inhibition of humoral immune response to murine monoclonal antibody 3F8 in neuroblastoma patients: Broad implications for immunotherapy

The murine monoclonal antibody 3F8 mediates lysis of neuroblastoma (NB) by complement and leukocytes (including neutrophils) but is neutralized if human anti-mouse antibody (HAMA) forms. We assessed the impact on rapid HAMA formation of prior chemotherapy in NB patients. For the 153 patients treated with 3F8 after conventional therapy (Group 1), the analysis included time from chemotherapy to the start of 3F8. For the 103 patients treated with 3F8 after myeloablative alkylator-based therapy (MAT) (Group 2), the analysis included both chemotherapy administered before stem-cell collection and time from MAT to the start of 3F8. In Group 1, the incidence of HAMA-positivity was significantly lower if patients received high-dose cyclophosphamide (HD-Cy, > or = 4,000 mg/m2) before 3F8 treatment (P < 0.001). In addition, HAMA-positivity was least likely if 3F8 treatment was initiated <90 days post-HD-Cy (2/76 compared to 3/19 first treated at 90-120 days, and 17/27 first treated at >120 days, P < 0.001). In Group 2 patients who were transplanted with stem cells collected after HD-Cy, HAMA-positivity occurred in 1/60 patients treated <90 days post-MAT versus 13/23 treated >90 days post-MAT (P < 0.001). Among Group 2 patients transplanted with stem cells collected after no prior HD-Cy, the incidence of HAMA-positivity was significantly higher (15/19, P < 0.001), including 5/7 whose 3F8 treatment began <90 days post-MAT. HD-Cy reliably blocks humoral responses to a murine antibody. This capacity to prevent host rejection of foreign or not fully humanized proteins raises the possibility of a broad role for HD-Cy in immunotherapeutic strategies.

Noninfectious X4 but not R5 human immunodeficiency virus type 1 virions inhibit humoral immune responses in human lymphoid tissue ex vivo.

Ex vivo human immunodeficiency virus type 1 (HIV-1) infection of human lymphoid tissue recapitulates some aspects of in vivo HIV-1 infection, including a severe depletion of CD4(+) T cells and suppression of humoral immune responses to recall antigens or to polyclonal stimuli. These effects are induced by infection with X4 HIV-1 variants, whereas infection with R5 variants results in only mild depletion of CD4(+) T cells and no suppression of immune responses. To study the mechanisms of suppression of immune responses in this ex vivo system, we used aldrithiol-2 (AT-2)-inactivated virions that have functional envelope glycoproteins but are not infectious and do not deplete CD4(+) T cells in human lymphoid tissues ex vivo. Nevertheless, AT-2-inactivated X4 (but not R5) HIV-1 virions, even with only a brief exposure, inhibit antibody responses in human lymphoid tissue ex vivo, similarly to infectious virus. This phenomenon is mediated by soluble immunosuppressive factor(s) secreted by tissue exposed to virus.

Effect of l-arginine on restraint stress induced modulation of immune responses in rats and mice

The present study investigates the role of nitric oxide (NO) on restraint stress (RS)-induced modulation of humoral and cell-mediated immune responses in rats and mice. RS produced suppression of humoral immune response, i.e., anti-SRBC antibody titre (7.38±0.32 versus 4.13±0.30; mean±S.E.M., P<0.001). In case of cell-mediated immunity, in delayed type hypersensitivity (DTH) response the change in paw volume decreased from 0.069±0.003 mm (mean±S.E.M.) in control non-stressed group to 0.038±0.002 mm in the stressed group ( P<0.001) while percentage leucocyte migration inhibition (% LMI) decreased from 39.7±1.95 in control non-stressed animals to 15.2±1.07 in animals subjected to stress ( P<0.01). Pretreating the animals with an NO precursor, l-arginine (1000 mg kg −1, i.p.) antagonized the effect of RS on humoral (anti-SRBC antibody titre 6.50±0.27 versus 4.13±0.30, P<0.001) and cell-mediated (DTH response 0.066±0.002 mm versus 0.038±0.002 mm, P<0.001; % LMI 41.5±1.46 versus 15.2±1.07, P<0.01) immune responses. Administration of 7-nitroindazole (7-NI, 50 mg kg −1, i.p.), an inhibitor of neuronal NO synthase, alone further enhanced the immunosuppressive effect of RS (anti-SRBC antibody titre 2.75±0.25 versus 4.13±0.30, P<0.001; DTH response 0.019±0.002 mm versus 0.038±0.002 mm, P<0.001; % LMI 5.0±1.08 versus 15.2±1.07, P<0.01). However, when given before l-arginine treatment, 7-NI reversed the effect of the latter drug on stress-induced immunomodulation (anti-SRBC antibody titre 3.00±0.27 versus 6.5±0.27, P<0.001; DTH response 0.043±0.003 mm versus 0.066±0.002 mm, P<0.001; % LMI 12.0±0.93 versus 41.5±1.46, P<0.01). Unlike its effect on RS-induced immune responsiveness, l-arginine (250, 500, 1000 mg kg −1) when given for 5–7 days to naive non-stressed animals produced dose dependent suppression of both humoral (anti-SRBC antibody titre 6.4±0.32 versus 5.4±0.32, 4.0±0.27, 3.1±0.30, respectively) and cell-mediated (DTH 0.065±0.003 mm versus 0.064±0.004 mm, 0.039±0.003 mm, 0.020±0.002 mm, respectively and % LMI 37.52±1.58 versus 30.48±1.07, 28.18±1.22, 19.76±0.83, respectively) immune responses. 7-NI significantly blocked these immunosuppressive effects of l-arginine (anti-SRBC antibody titre 6.0±0.38 versus 3.1±0.030, P<0.001; DTH response 0.056±0.004 mm versus 0.020±0.002 mm, P<0.001; % LMI 34.76±1.31 versus 19.76±0.83, P<0.01). However, 7-NI when given to non-stressed animals failed to modulate immune responsiveness. Thus, NO appears to play an important role in RS-induced immunomodulation and these effects are different from its effect on immune responsiveness in non-stressed animals.

Low‐level hepatitis C viremia and humoral immune response to NS4 in chronic hepatitis B virus‐hepatitis C virus coinfection

Background: There is a limited amount of published data on the interference of hepatitis B virus (HBV) on hepatitis C virus (HCV). The aim of this study was to investigate the effect of concurrent HBV infection on serum titers of HCV RNA and HCV antibody profiles in chronic HCV infection. Methods: The clinical and virological profiles (serum titers of HCV RNA, HCV genotypes and antibody profiles) of 25 patients with chronic HBV‐HCV coinfection were compared with those of 25 age‐ and sex‐matched patients with HCV infection alone. Results: Among the 25 patients with HBV‐HCV coinfection, only 3 were found hepatitis Be antigen (HBeAg) and HBV DNA positive by hybridization assays, and the other 11 were found HBV DNA positive by polymerase chain reaction. Genotype 1b was dominant in both HBV‐HCV coinfection and HCV infection alone (64% versus 84%, P > 0.1). Patients with HBV‐HCV coinfection had significantly lower alanine aminotransferase (ALAT) levels and inflammatory scores but higher fibrosis scores than those with HCV infection alone. Serum titers of HCV RNA were significantly lower in HBV‐HCV coinfection than in HCV infection alone. The frequency and relative intensity of antibody response to core, E2/NS1, NS3, and NS5 showed no significant difference between the two groups, but antibody response to NS4 was diminished significantly in HBV‐HCV coinfection. Conclusions: In HBV‐HCV coinfection, serum levels of HBV DNA are usually low or undetectable. Concurrent HBV infection, however, could interfere with HCV replication and suppress antibody response to NS4. The biological significance of selective inhibition of humoral immune response to NS4 in HBV‐HCV coinfection should be further studied.

Antagonism of aryl hydrocarbon receptor-dependent induction of CYP1A1 and inhibition of IgM expression by di- ortho-substituted polychlorinated biphenyls

Halogenated aromatic hydrocarbons (HAHs) are ubiquitous environment contaminants that produce many of their toxic effects by binding to the aryl hydrocarbon receptor (AhR). However, several investigations have demonstrated that certain polychlorinated biphenyl (PCB) congeners, principally di- ortho-chlorinated PCB congeners, or mixtures containing multiple di- ortho-chlorinated PCBs, inhibit AhR-mediated responses induced by other toxic HAHs. Most relevant to the present study are past reports demonstrating antagonism by these uniquely acting PCB congeners on AhR agonist-mediated inhibition of humoral immune responses. The mechanism responsible for antagonism of AhR agonists by certain PCBs is presently unknown. The present study evaluated the antagonist activity of several di- ortho-substituted PCB congeners [PCB47 (2,2′,4,4′), PCB52 (2,2′,5,5′), PCB128 (2,2′,3,3′,4,4′), and PCB153 (2,2′,4,4′,5,5′)] when present in combination with AhR agonists [TCDD (2,3,7,8,-tetrachlorodibenzo- p-dioxin), PCB126 (3,3′,4,4′,5), and PCB77 (3,3′,4,4′)] on CYP1A1 induction and inhibition of lipopolysaccharide (LPS)-induced immunoglobulin production in the CH12.LX B cell line. In contrast to non- ortho-substituted PCB (PCB77), which showed additive effects on CYP1A1 induction in combination with TCDD, all of the di- ortho-substituted PCBs examined produced antagonism. Di- ortho-substituted PCB (PCB52) also antagonized TCDD- or PCB126- mediated inhibition of IgM secretion and immunoglobulin heavy chain mRNA expression in the LPS-activated B cells. In addition, PCB52 inhibited TCDD-induced AhR DNA binding to a dioxin-responsive element. Collectively, these results suggest that the mechanism responsible for antagonism by di- ortho-substituted PCB congeners of AhR agonist-mediated CYP1A1 induction and inhibition of antibody responses in B cells occurs through interference with agonist activation of the cytosolic AhR complex.