Guben Tongluo Formula Protects LPS-induced Damage in Lamina Propria B Lymphocytes Through TLR4/MyD88/NF-κB Pathway.

OBJECTIVE: The main pathological feature of immunoglobulin A nephropathy (IgAN), an autoimmune kidney disease, is the deposition of IgA immune complexes, accompanied by mesangial cell proliferation and elevated urine protein. The Guben Tongluo formula (GTF) is a traditional Chinese medicine prescription, which has predominant protective effects on IgAN. However, the therapeutic mechanism of the GTF in IgAN remains elusive. The present study aimed to determine the effects of GTF in treating IgAN via regulating the TLR4/MyD88/NF-κB pathway. METHODS: In the present study, lamina propria B lymphocytes were treated with different concentrations of lipopolysaccharide (LPS) (0, 1, 5, 10 and 20 ng/mL). Flow cytometry was used to define positive CD86+CD19+ cells. CCK-8 assay was used to examine cell proliferation. RNAi was used to induce TLR4 silencing. qRT-PCR and Western blotting were used to determine gene expression. RESULTS: It was found that the LPS dose-dependently increased the content of IgA and galactose-deficient IgA1 (Gd-IgA), the levels of TLR4, Cosmc, MyD88 and phosphorylated (p)-NF-κB, and the ratio of CD86+CD19+ and IgA-producing B cells. However, the TLR4 knockdown reversed the role of LPS. This suggests that TLR4 mediates the effects of LPS on lamina propria B lymphocytes. Furthermore, the GTF could dose-dependently counteract the effects of LPS and TLR4 overexpression on lamina propria B lymphocytes through the TLR4/MyD88/NF-κB pathway. CONCLUSION: Collectively, these results demonstrate that the GTF can regulate the TLR4/MyD88/NF-κB pathway to treat IgAN model lamina propria B lymphocytes stimulated by LPS.

Agents that increase AAM differentiation blunt RSV-mediated lung pathology.

RSV is the most significant cause of serious lower respiratory tract infection in infants and young children worldwide. There is currently no vaccine for the virus, and antiviral therapy (e.g., ribavirin) has shown no efficacy against the disease. We reported that alternatively activated macrophages (AAMs) mediate resolution of RSV-induced pathology. AAM differentiation requires macrophage-derived IL-4 and -13, autocrine/paracrine signaling through the type I IL-4 receptor, and STAT6 activation. Based on these findings, we reasoned that it would be possible to intervene therapeutically in RSV disease by increasing AAM differentiation, thereby decreasing lung pathology. Mice treated with the IL-4/anti-IL-4 immune complexes, shown previously to sustain levels of circulating IL-4, increased the RSV-induced AAM markers arginase-1 and mannose receptor and decreased the lung pathology. Induction of PPARγ, shown to play a role in AAM development, by the PPARγ agonist rosiglitazone or treatment of mice with the macrolide antibiotic AZM, also reported to skew macrophage differentiation to an AAM phenotype, increased the AAM markers and mitigated RSV-induced lung pathology. Collectively, our data suggest that therapeutic manipulation of macrophage differentiation to enhance the AAM phenotype is a viable approach for ameliorating RSV-induced disease.

Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia.

Intravenous immunoglobulin (IVIG) is currently used to treat a multitude of autoimmune disorders including immune thrombocytopenic purpura (ITP), yet the mechanism of action of IVIG remains unresolved. Using a murine model of ITP in which IVIG functions therapeutically, our laboratory has addressed such theories as blockade/inhibition of the mononuclear phagocytic system, cytokine regulation, and neutralization of pathogenic autoantibodies mediated by anti-idiotypic antibodies, and these findings will be discussed herein. We have also demonstrated that soluble immune complexes can completely recapitulate the therapeutic effects of IVIG in ITP, and recent work from us has identified activating Fcgamma receptors on CD11c+ dendritic cells as the relevant molecular target of IVIG in the acute resolution of murine immune thrombocytopenia. This and other work to devise antibody-based IVIG alternative therapies will also be addressed.

Allergen-antibody complexes can efficiently prevent seasonal rhinitis and asthma in grass pollen hypersensitive patients. Allergen-antibody complex immunotherapy.

We have prepared antigen-antibody complexes from grass pollen allergens and autologous specific antibodies isolated by immunoadsorption from the serum of allergic patients. These complexes were inoculated into patients in a double-blind trial to evaluate their effect on grass pollen-related rhinitis and bronchial asthma. Thirty-eight grass pollen-hypersensitive patients were allocated to three groups; patients in the first two groups were treated with antigen-antibody complexes at different ratios and dosages and were compared with the third group who received the placebo carrier buffer alone. In addition, we treated a fourth group who had already received antigen-antibody complex inoculation during the previous pollen season. Injections were given every 2 weeks during the pollen season, starting 5 weeks prior to it. Tolerance was excellent with no signs of local or systemic side effects. The treatment prevented nasal symptoms while enabling the patients to reduce antihistamine intake. Bronchial asthma was virtually absent in the treated groups even though no bronchodilators or corticosteroids had to be taken. Specific IgE antibodies did not increase during the pollen season nor did IgG "blocking" antibodies. Inoculation of allergen-antibody complexes could provide a valuable alternative for the treatment of immediate hypersensitivity to airborne allergens as it appears to be safe and rapidly efficacious. This treatment offers several advantages compared to conventional hyposensitization and is characterized by the absence of an increase in specific IgG antibodies.

A comparative study of an aqueous grass pollen extract and glutaraldehyde-treated grass pollen-tyrosine adsorbate in the treatment of pollenosis.

Hyposensitization therapy gave a subjective improvement in 84% of grass pollen-sensitive patients receiving an eighteen dose course of aqueous pollen extract (SDV) and in 69% of patients receiving a three dose course of glutaraldehyde-treated pollentyrosine adsorbate (Pollinex). Systemic reactions to treatment were considerably more frequent with the aqueous course, but virtually absent with the short adsorbate course, which seems therefore more convenient for the patient. The SDV treatment induced a more pronounced IgG antibody response both in patients and in guinea-pigs receiving the clinical dosage schedule. The Pollinex treatment showed a tendency to enhance the IgE antibody response in new patients.

A multi-centre trial of pollen-tyrosine adsorbate.

We report the results of a multi-centre trial involving 433 hay fever patients treated in 1975 with a 3-injection tyrosine-adsorbed vaccine containing glutaraldehyde-modified grass pollens and cultivated rye. Despite the high pollen counts recorded in Germany in 1975, treatment was considered to be effective in 73 per cent of the patients, irrespective of their age, sex or past history. Side effects were normally mild although the incidence of local reactions was relatively high. Only six patients discontinued treatment due to untoward reactions and there were no cases of anaphylactic shock. This paper adds further evidence to support the view that this vaccine offers a safe, effective and convenient method of treatment for grass pollen allergy.

A trial of hyposensitization in 1974/5 in the treatment of hay fever using glutaraldehyde-pollen-tyrosine adsorbate.

One hundred patients with hay fever were treated in 1974/5 with a glutaraldehyde-pollen-tyrosine adsorbate, the response to treatment being assessed at the end of the hay fever season by direct questioning of the patient and examination of a daily record card. Successful results of treatment were recorded in 73% of all patients, results for both years being similar both for patients who had been previously hyposensitized and for those who had not previously received this form of treatment. Side reactions to treatment were generally infrequent or mild, and in only one patient was it necessary to discontinue treatment due to side reactions.