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The results are presented of the treatment of 55 patients for hyperplastic endometrial processes with the preparation norcolut combined with the immune modulators thymalinum and myelopidum. It was found that the application of the suggested schemes of the introduction of the medicines mentioned increase the treatment effectiveness and enlarges its possibilities.
This study was carried out to assess the safety and efficacy of a combination of lentinan, an immune modulator, and didanosine (ddI) in a controlled study in HIV positive patients with CD4 levels of 200-500 cells/mm3. Didanosine was administered to HIV patients at doses of 400 mg/day (po) for six weeks (bid), then 2 mg of lentinan i.v. was added per week for 24-80 weeks. A control group (20%) received ddI only. A total of 107 patients were enrolled at three sites, and 88 patients started the ddI/lentinan phase. The combination caused significant increases in CD4 levels up to 38 weeks, whereas ddI alone was significant at the 5% level at 14 weeks. Based on these data, lentinan qualifies as a participant in future multi-drug studies in HIV.
For many years, probiotic bacteria have been known to confer health benefits to the consumer. One possible mechanism for this may be the ability of probiotic bacteria to modulate immune responses. Oral administration of Lactobacillus casei strain Shirota (LcS) has been found to enhance innate immunity by stimulating the activity of splenic NK cells. Oral feeding with killed LcS was able to stimulate the production of Th1 cytokines, resulting in repressed production of IgE antibodies against Ovalbumin in experimental mice. The ability to switch mucosal immune responses towards Th1 with probiotic bacteria provides a strategy for treatment of allergic disorders. Growth of Meth A tumour cells in the lungs was also inhibited by intrapleural injection of LcS. Oral administration of other probiotic bacteria, such as Streptococcus thermophilus (St), Lactobacillus fermentum (Lf) and yeast (Y), elicited different immune responses. Mice that were prefed yeast or Lf followed by feeding with ovalbumin (OVA) responded better to vaccination with OVA than mice not given either probiotic or OVA or mice that had been prefed only OVA. However, antibody responses were significantly suppressed in response to vaccination with OVA in mice that had been prefed yeast followed by yeast and OVA as well as mice prefed Lf followed by Lf and OVA. Prefeeding St followed by OVA feeding enhanced cellular immune responses against ovalbumin. In contrast, mice prefed St followed by St + OVA were hyporesponsive against OVA. While antigen feeding alone appears to prime for an immune response, cofeeding antigen with probiotic bacteria can suppress both antibody and cellular immune responses and may provide an efficacious protocol to attenuate autoimmune diseases, such as experimental allergic encephalomyelitis, by jointly dosing with myelin basic protein and probiotic bacteria.
The effects of the anti picornaviral drug WIN 54954 (5-(5-(2.6-dichloro-4-(4.5-dihydro-2-oxazolyl)phenoxy)pentyl)-3-me thyl- isoxazole) and the immune modulator LS 2616 (Quinoline-3-carboxamide) on plasma cachectin/TNFa and g-interferon (IFN-g) responses were investigated during the clinical course of a myocarditic coxsackievirus B3 (CB3) infection in the mouse. Virus as well as inflammatory and necrotic lesions were found in the hearts on days 4 and 7 post inoculation (p.i.), respectively. This was demonstrated using in situ virus RNA hybridization and immune histological techniques with monoclonal antibodies against lymphocyte subsets. The CB3 infection increased TNFa levels during the first three days of disease. This response was suppressed by WIN 54954 and LS 2616. IFN-g was decreased in infected mice in the late phase of the disease (day 11). Therapy, however, was protective, and WIN 54954 even tended to increase the IFN-g response at day 5, corresponding to the time when viremia peaks. These results indicate that cytokines may serve as prognostic markers in the therapy of infectious diseases and also that WIN 54954 and LS 2616 are both possible candidates for treatment of coxsackievirus infections in man. It is suggested that a combined antiviral and immune stimulatory treatment could be of future value.
Transforming growth factor (TGF)-beta exerts a counter-regulatory effect on interleukin (IL)-12-mediated immune modulation. The underlying mechanism is not fully understood. Here we demonstrate that the expression of IL-12Rbeta1 and IL-12Rbeta2 in MBP peptide Ac1-11-primed splenocytes is upregulated upon antigen stimulation. TGF-beta induces an unresponsiveness of these primed splenocytes to IL-12 signaling through a mechanism involved in inhibition of both IL-12Rbeta1 and beta2. The modulation of IL-12Rbeta1 and beta2 expression by Ac1-11 stimulation and TGF-beta is mainly involved in CD4+ population. These data indicate that both IL-12Rbeta1 and IL-12Rbeta2 expression are crucial during T cell activation. TGF-beta-induced inhibition of IL-12R expression will reduce cellular immune responses during IL-12-mediated autoimmune disease.
Lewis lung carcinoma (LLC-LN7) tumors stimulate myelopoiesis and increase the presence of granulocyte/macrophage (GM) progenitor cells having natural suppressor activity. Treatment of these tumor-bearing mice with interleukin-12 (IL-12) resulted in minimal immune modulation. The objective of this study was to determine whether eliminating natural suppressor activity would allow for immune stimulation by IL-12. Treatment of LLC-LN7 tumor-bearing mice with vitamin D3 eliminated natural suppressor activity. In mice that were first treated with vitamin D3 and then also with IL-12, there was stimulation of splenic T cell proliferation in response to immobilized anti-CD3 plus IL-2. In addition, spleen and lymph node cells from vitamin-D3/IL-12-treated tumor-bearing mice became stimulated in response to autologous tumor to produce interferon gamma (IFN gamma), although IL-2 production was not stimulated. A prominent effect of the combined vitamin-D3/IL-12 treatment regimen was the synergistic augmentation of autologous tumor-specific cytolytic activity within the regional lymph nodes. The generation of these tumor-specific effector cells required the presence of the tumor mass since such activity was not elicited in the lymph nodes of mice from which the tumors had been surgically excised. The results of this study show that, after treatment of tumor bearers with vitamin D3 to eliminate GM-suppressor cells, IL-12 can induce select regional antitumor immune responses, particularly IFN gamma production and cytolysis by regional lymph node cells of autologous tumor.
AIM: Liver sinusoidal endothelial cells (LSECs) have been implicated to play a role in the induction of liver allograft rejections. Here, we studied the clinical consequences of preformed LSEC-reactive antibodies and their functional capacity in modulating T-cell responses. METHODS: Pre- and posttransplant sera and T lymphocytes from 95 liver transplant patients were used in this study. LSECs were isolated from a normal healthy liver. Binding of antibodies to LSECs was detected using flow cytometric analysis. To study whether LSEC antibodies facilitated cell-mediated immunity, a mixed cell culture (MCC) assay was used. Cytokines in the supernatant of MCC were also measured by enzyme-linked immunosorbent assay. Immunohistochemical staining on liver biopsy sections was performed to detect deposition of immunoglobulins in LSEC during rejections. RESULTS: Significantly higher numbers of patients with rejections had LSEC antibodies (35/50, 70%) compared with 8/45 (18%) without rejections (P < .0001). Purified fractions of LSEC antibodies induced the expression of the costimulatory marker CD86 on LSECs. Significantly higher numbers of patients with LSEC antibodies and rejections had an increased proliferation of T cells and markedly decreased levels of transforming growth factor (TGF)-beta in the MCC as compared with those without antibodies and rejections (P < .0001, P < .0001, respectively). Deposition of antibodies in LSECs during rejection episodes was observed in the biopsies of patients with LSEC antibodies but not in those without LSEC antibodies. CONCLUSION: Our data suggest that antibodies to LSEC may facilitate acute liver allograft rejections by down-regulating the immune modulating cytokine TGF-beta and thus up-regulating alloreactive T-cell proliferation.
Variant antigens, encoded by multigene families, and expressed at the surface of erythrocytes infected with the human malaria parasite Plasmodium falciparum and the simian parasite Plasmodium knowlesi, are important in evasion of host immunity. The vir multigene family, encoding a very large number of variant antigens, has been identified in the human parasite Plasmodium vivax and homologues (yir) of this family exist in the rodent parasite Plasmodium yoelii. These genes are part of a superfamily (pir) which are found in Plasmodium species infecting rodents, monkeys and humans (P. yoelii, P. berghei, P. chabaudi, P. knowlesi and P. vivax). Here, we show that YIR proteins are expressed on the surface of erythrocytes infected with late-stage asexual parasites, and that host immunity modulates transcription of yir genes. The surface location and expression pattern of YIR is consistent with a role in antigenic variation. This provides a unique opportunity to study the regulation and expression of the pir superfamily, and its role in both protective immunity and antigenic variation, in an easily accessible animal model system.
5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a novel antitumour agent currently undergoing clinical evaluation, appears to mediate its antitumour effects through immune modulation and the production of cytokines. We used mice with a targeted disruption of the interferon-gamma (IFN-gamma) receptor gene as a model to evaluate the role of the host response to IFN-gamma in the antitumour action of DMXAA on colon 38 tumours. A feature of the results was that while DMXAA treatment induced both IFN-gamma and tumour necrosis factor (TNF) in serum, the increase was > 20-fold higher in IFN-gamma R0/0 mice than in wild-type mice. In contrast, mRNA levels for IFN-gamma and TNF were similar in the two mouse strains, suggesting that the concentrations of these cytokines were controlled by a post-transcriptional mechanism. Serum nitrate levels, used as a measure of nitric oxide production, were increased by DMXAA, but to a similar extent in both strains of mice. Complete regressions of colon 38 tumours were obtained in response to DMXAA in the knockout mice, although the dose required for 100% cure was higher and the reduction in tumour volume occurred more slowly than in the wild-type counterparts. The results demonstrate that the host response to IFN-gamma is not essential for an anti-tumour response. Similar results were obtained in mice that were immunosuppressed by treatment with cyclosporin A before treatment with DMXAA. The results are consistent with the concept that the antitumour activity of DMXAA involves complex immunomodulation, probably with significant redundancy in contributing cytokines.
Toxic epidermal necrolysis (TEN) is a rare but serious condition with a high mortality rate, whose clinical features resemble major thermal injury. Nutritional substrates which can affect the immune response have been shown to benefit burned and critically ill patients but there is a lack of data in the TEN literature. A case study is presented of a 63-year-old female admitted to our burn unit with extensive skin and mucosal involvement. Immune modulating artificial nutrition support was given initially via the parenteral route and then the nasogastric route. Maintenance of the patient's nutritional status and clinical outcome suggest that there may be a role for this type of intervention in TEN.
Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.
Vernal keratoconjunctivitis (VKC), a severe form of ocular allergic disease, is characterized by the formation of giant papillae at the upper tarsal conjunctiva and corneal lesions that threaten vision. Recent evidence indicates that resident fibroblasts function as immune modulators in the pathogenesis of the chronic allergic inflammation associated with VKC. The T helper 2 (Th2) cell-derived cytokines interleukin (IL)-4 and IL-13 stimulate the migration and proliferation of conjunctival fibroblasts as well as protecting these cells from apoptotic cell death, effects that likely underlie the hyperplasia of fibroblasts that contributes to the formation of giant papillae. Conjunctival fibroblasts also synthesize extracellular matrix proteins and tissue inhibitors of metalloproteinases as well as down-regulate the expression of matrix metalloproteinases in response to these cytokines, effects that likely contribute to the excessive deposition of extracellular matrix that is characteristic of giant papillae. Stimulation of fibroblasts in the corneal stroma with the combination of a proinflammatory cytokine and either IL-4 or IL-13 results in up-regulation of the expression of the chemokine eotaxin and thymus- and activation-regulated chemokine as well as of vascular cell adhesion molecule-1, which together mediate the infiltration and activation of eosinophils and Th2 cells. Fibroblasts therefore appear to play a central role in the induction and amplification of ocular allergic inflammation and the consequent development of giant papillae and corneal disorders in individuals with VKC. Fibroblasts and fibroblast-derived factors thus represent new and potentially important therapeutic targets for treatment of the giant papillae and corneal disorders associated with VKC.
Recent advances in HIV-1 pathogenesis, and in defining virological and immunological responses to highly active antiretroviral therapy (HAART), along with the identification of the numerous drawbacks of HAART, have clearly demonstrated that the eradication of the virus is not a feasible therapeutic goal, and that there is an urgent need to develop other approaches to fight HIV-1 infection. Novel therapeutic approaches of immune modulation have recently been evaluated in pilot clinical trials. First, treating primary HIV-1 infection with cyclosporin A (CsA) coupled with HAART to target massive immune activation extends the benefits achieved with HAART during primary HIV-1 infection and might contribute to the establishment of a more favourable immunological set-point affecting the ultimate pattern and rate of disease progression. Second, treating chronic HIV-1 infection in patients with long-term suppression of virus replication induced by HAART, with the addition of mycophenolate mofetil (MMF) reduces the pool of activated CD4+ T lymphocytes able to support productive HIV-1 infection, and might have an indirect impact on the pool of resting, latently infected CD4+ T cells, contributing to its depletion in vivo. The important question is clearly whether these results will have an impact on the clinical management of patients with HIV-1 infection, determining the precise therapeutic function of drugs like CsA and MMF, thus investigating the effects of these drugs on residual viral replication and the decay of the latent reservoir, on long-term immunological benefit, and, ultimately, on clinical benefit.
Systemic injection of lipopolysaccharide (LPS) blocks the expression of long-term potentiation in the hippocampus of the rat. This is coupled with increased IL-1beta concentration and c-Jun NH(2)-terminal kinase activity, as well as an increase in the number of cells displaying apoptotic characteristics in the hippocampus. Vasogen's Immune Modulation Therapy (IMT) is a procedure involving intramuscular administration of syngeneic blood which has been exposed ex vivo to elevated temperature, oxidation and ultraviolet light. We report that Vasogen's IMT significantly abrogates these LPS-induced effects with a concomitant increase in the concentration of the anti-inflammatory cytokine IL-10. These data suggest that Vasogen's IMT may play a protective role against the deleterious effects of immune insults in the brain.
The ability of conjugated isomers of linoleic acid (CLA) to prevent reduced growth rate following endotoxin (lipopolysaccharide, LPS) injection was studied in two chick trials and one rat trial. Chicks (10 per treatment) were fed a corn and soybean meal-based diet with or without .5% CLA. At 21 days of age, chicks were weighed and injected i.p. with 1 mg/kg BW Escherichia coli LPS and sterile PBS. Body weights were again determined 24 h later. Antibody responses to SRBC were also determined. Rats fed .5% stearic acid or CLA for 4 wk (seven per treatment) were also injected with LPS, and BW change over a 24-h postinjection period was determined. Antibody responses to BSA, phytohemagglutinin foot pad swelling, and phagocytosis of elicited peritoneal macrophages were also determined. The CLA had no adverse effects on any immune variables measured in the chicks and rats. The CLA enhanced the phytohemagglutinin response and macrophage phagocytosis in rats. Chicks fed CLA and injected with LPS continued to grow, whereas those not fed CLA either failed to grow or lost weight following LPS injection. Both control and CLA-fed rats lost weight over the 24-h period after LPS injection; however, the loss of weight in rats fed CLA was only half of the weight loss of the control rats. Thus, CLA is effective in preventing the catabolic effects of immune stimulation.
We present the results of a small uncontrolled pilot trial which suggest that contact sensitization to dinitrochlorobenzene and repeated weekly applications significantly improve the clinical status of severe atopic dermatitis in adults. Although no changes were noted in circulating levels of either lymphocyte subset populations or the serum cytokines assayed in this trial, our observations may be due to topical immune modulation by dinitrochlorobenzene. Larger controlled studies of dinitrochlorobenzene treatment in atopic dermatitis are warranted.
Mesenchymal stem cells (MSCs) represent a good choice for cell transplantation due to their multilineage differentiation ability and low immunogenicity. Our previous in vitro studies indicated that undifferentiated swine MSCs show low immunogenicity suppressing the proliferative responses of human peripheral blood lymphocyte to several antigens. In this study, we investigated the immunogenicity and immune modulation ability of osteogenic differentiated MSCs. SLA class I (P1, P14) was detectable by reverse-transcriptase polymerase chain reaction on both differentiated and undifferentiated MSCs. SLA class II (SLA-DRA, SLA-DQA) was only detectable on differentiated MSCs mixed lymphocyte reaction assays demonstrated that both differentiated and undifferentiated MSCs failed to stimulate proliferative responses by human peripheral blood lymphocytes (hPBLs). Furthermore, as undifferentiated MSCs, osteogenic differentiated MSCs also suppressed hPBL proliferation to phytohemaglutinin.
This article continues a series of reports on research developments of particular interest to those involved in the management of patients with heart failure. Summaries of the following trials, reported at the 75th Scientific Sessions of the American Heart Association held in Chicago, Illinois between 17th and 20th November 2002 are included: PROSPER; DIAL; home care monitoring trials; immune modulation therapy; COMPANION; and anaemia in heart failure.