Biotherapies in inflammatory ocular disorders: Interferons, immunoglobulins, monoclonal antibodies.

Biotherapies used in clinical practice for the treatment of ophthalmologic manifestations of systemic diseases include interferons (IFN), intravenous immunoglobulins (IVIG) and monoclonal antibodies (anti-TNF, anakinra, tocilizumab and rituximab). Several open prospective studies have shown the effectiveness of IFN-α (78 to 98% complete remission) for the treatment of severe uveitis in Behcet's disease. IFN is capable of inducing prolonged remission and continued after his arrest, in 20-40% of patients. Side effects (flu-like, psychological effects) limit its use in practice. Anti-TNFα (infliximab and adalimumab) represents an attractive alternative therapeutic in severe uveitis refractory to immunosuppressants, especially in Behcet's disease. They are almost always (>90% of cases) and rapidly effective but their action is often suspensive. Anti-TNFα requires an extended prescription or takes over from another immunosuppressant once ocular inflammation has been controlled. IVIG are used for the treatment of Kawasaki disease and Birdshot disease. Several open or retrospective studies showed their effectiveness for the treatment of severe and refractory cicatricial pemphigoid. Tolerance of IVIG is good but their efficacy is transient. Rituximab showed an efficacy in few observations of various inflammatory eye diseases (uveitis, scleritis and idiopathic inflammatory pseudo-tumors or associated with granulomatosis with polyangiitis) and cicatricial pemphigoid. The risk of infection associated with this biotherapy limits its use in refractory diseases to conventional therapy. Anakinra (a soluble antagonist of IL-1R) showed interesting results in terms of efficiency in one small open study in Behcet's disease. Its safety profile is good and with a quick action that could be interesting for the treatment of severe uveitis.

Transfer of antibodies across the placenta and in breast milk from mothers on intravenous immunoglobulin.

We studied the levels of immunoglobulins in colostrum, milk and sera from two common variable immunodeficiency (CVID) mothers (M1 and M2), and in sera from their newborn infants. During pregnancy they continued intravenous immunoglobulin therapy (IVIG). Antibody levels from maternal and cord blood collected at delivery and colostrum and milk, collected on the 3rd and 7th post-partum days, respectively, were analyzed. Although cord/maternal blood ratios of total immunoglobulins and subclasses, as well as specific antibodies differed between M1 and M2, both showed good placental transfer of anti-protein and anti-polysaccharide antibodies, despite lower cord/maternal blood ratios in M2. Anti-Streptococcus pneumoniae antibody avidity indexes were similar between paired maternal and cord serum. Both mothers' colostrum and milk samples showed only traces of IgA, and IgM and IgG levels in colostrum were within normal range in M1, whereas M2 presented elevated IgG and low IgM levels, when compared with healthy mothers. The study of colostrum and milk activity showed that they strongly inhibited enteropathogenic Escherichia coli adhesion in vitro. CVID patients must be informed about the relevance of regular IVIG administration during pregnancy, not only for their own health but also for their immune immature offspring. Breast-feeding should be encouraged as colostra from these CVID patients strongly inhibited E. coli adhesion to human epithelial cells thus providing immunological protection plus nutritional and psychological benefits for the infant.

Solar urticaria treated successfully with intravenous high-dose immunoglobulin: a case report.

Solar urticaria is an idiopathic, chronic and rare photodermatosis, characterized by the sudden onset of pruritic urticarial hives and plaques on the exposed areas of the skin, after a brief period of exposure to the natural sunlight or to an artificial light source. A Caucasian 27-year-old man presented with clinical features suggestive of solar urticaria was referred to our photodermatology unit, where phototesting confirmed the diagnosis of solar urticaria induced by visible light. As he was refractory to oral antihistamines and had slight improvement under UVA plus visible phototherapy, human high-dose intravenous immunoglobulin was administered, with an excellent clinical-sustained response.

Interaction of curcumin with intravenous immunoglobulin: a fluorescence quenching and Fourier transformation infrared spectroscopy study.

The interaction of curcumin with intravenous immunoglobulin (IVIG) mainly composed of immune gamma globulin (IgG) was studied in vitro by spectroscopic methods including fluorescence spectroscopy and Fourier transformation infrared (FTIR) spectroscopy. Docking was used to calculate the interaction mode between curcumin and IVIG. The binding parameters for the reaction were calculated according to the Sips equation, which suggested that the binding of IVIG to curcumin was characterized by two binding sites with the average affinity constant K(o) at 1.170 x 10(4) M(-1) (296 K), and it was a non-specific and weak drug-protein interaction. The secondary structure compositions of free IVIG and its curcumin complexes were calculated by the FTIR difference spectra, self-deconvolution, second derivative resolution enhancement and the curve-fitting procedures of amide I band. The observed spectral changes indicate a partial unfolding of the protein structure, but the typical beta structural conformation of IVIG is still retained. The average binding distance between curcumin and the chromophore of IVIG (5.57 nm) was obtained using the theory of Förster energy transfer. IVIG can serve as transport protein (carrier) for curcumin.

Intravenous immunoglobulin products contain neutralizing antibodies to vaccinia.

BACKGROUND AND OBJECTIVES: Individuals with primary or secondary immune-deficiency diseases may be at risk for vaccinia infection if widespread smallpox-immunization programmes are implemented in the United States of America (USA) for bioterrorism preparedness. The objective of this study was to determine whether commercial immune globulin (intravenous, human) products contain biologically active antibodies to vaccinia that have the potential to protect people, with immune deficiencies, from complications of vaccinia. MATERIALS AND METHODS: Eight currently United States (US)-licensed and two European intravenous immunoglobulin (IVIG) products were tested in a vaccinia plaque-reduction neutralization assay. The in vivo activity of five of these lots was assessed in severely immune-deficient mice. RESULTS: All tested products contained neutralizing anti-vaccinia activity, in vitro and in vivo. CONCLUSIONS: The use of IVIG by individuals with inherited or acquired humoral immune deficiencies may provide some protection if they are inadvertently exposed to vaccinia.

In vitro antiviral and antibacterial activity of commercial intravenous immunoglobulin preparations--a potential role for adjuvant intravenous immunoglobulin therapy in infectious diseases.

The identification of specific antimicrobial activity of intravenous immunoglobulin (IVIG) preparations against particular microbial pathogens can assist in determining their therapeutic potential for specific infectious diseases. We analysed five different commercial IVIG preparations for the presence of antibodies directed against a large panel of viral, bacterial, fungal and parasitic pathogens. All IVIG batches contained high activity against herpesviruses types 1, 2, 6 and 7, as well as against varicella zoster virus, Epstein-Barr virus (EBV), measles, mumps, rubella and parvovirus B19. Some IVIG batches also had a significant activity against adenovirus and Saint Louis encephalitis virus. The IVIGs held high activity against several bacterial pathogens, including Mycoplasma pneumonia, Chlamydia pneumonia, Helicobacter pylori and tetanus. No activity was found against various parasitic and fungal pathogens. Our findings may provide further support for the use of IVIG for the prevention and treatment of infections caused by specific viral and bacterial pathogens.

Human polyspecific immunoglobulin for therapeutic use induces p21/WAF-1 and Bcl-2, which may be responsible for G1 arrest and long-term survival.

High-dose intravenous immunoglobulin (IVIg) is used as therapy in an increasing number of immune mediated disorders including infections and autoimmune conditions. IVIg exerts profound effects both in vivo as well as in vitro on humoral and cell-mediated immunity. In this study we investigated whether IVIg could alter the pattern of apoptosis and apoptosis related proteins including Bcl-2, Bax, p53, CD95, and p21/WAF-1, a protein well known to arrest cells in G1 phase of the cell cycle and finally proliferation marker Ki-67 on peripheral blood mononuclear cells (PBMC). The cells were cultured either unstimulated or with mitogen in the presence or absence of different IVIg preparations. A dual effect by IVIg was found. The incidence of apoptosis was elevated in activated Ki-67 and CD95 positive PBMC, whereas it was lower in small, nonactivated cells. The cells that survived were associated with a striking increase in the expression of p21/WAF-1 suggesting G1 arrest. A concomitant upregulation of Bcl-2 was also obtained by IVIg exposition resulting in long-term survival. We suggest that these abilities of IVIg to alter cell cycle progression and apoptosis could explain some of the beneficial effects obtained in vivo with IVIg therapy.

Advances in the treatment of lupus nephritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease that leads to the formation and deposition of immune complexes throughout the body, which are pathogenic for the disease. Different forms of glomerulonephritis can occur in patients with SLE and can contribute significantly to the associated morbidity and, ultimately, mortality from the disease. Over the past two decades, there have been significant strides in our understanding of the disease and in treatments that attempt to control the formation and deposition of anti-DNA auto-antibodies and immune complexes, as well as the subsequent inflammatory cascade mediated through various cellular and humoral pathways leading to progressive renal damage and end-stage renal disease. In this chapter, we review the current understanding of the pathogenesis and treatment of lupus nephritis in its various stages and discuss the experimental and human data regarding some of the potential newer forms of therapy. We discuss data regarding the use of steroids, azathioprine, cyclophosphamide, cyclosporine A, mycophenolate mofetil, gammaglobulin, plasmapheresis, LJP 394, flaxseed oil, bindarit, anti-CD40 ligand, and CTLA4Ig.

[The preventive properties and therapeutic efficacy of an antitetanus immunoglobulin for experimental intravenous administration]. / Preventivnye svoistva i lechebnaia éffektivnost' protikvostolbniachnogo immunoglobulina dlia vnutrivennogo vvedeniia v éksperimente.

The new preparation of antitetanus immunoglobulin for intravenous injection has been developed at the Kirov Research Institute of Hematology and Blood Transfusion. The technology for obtaining this preparation is based on the method of acidic fermentative hydrolysis. The preparation has high specific potency: one dose contains at least 1,500 I.U. of tetanus antitoxin. As demonstrated in the experimental study of the preparation on mice, its intravenous injection 0.5 hours after challenge completely neutralizes the action of tetanus toxin, its use 24 hours after challenge protects all animals from death, while eliminating the clinical signs of the disease in 50% of them. The intramuscular injection of the preparation has proved to be considerably less effective.

Leukotriene B4 and Kawasaki disease.

The role of LTB4 in Kawasaki disease as a chemo-attractant and immunomodulator is reviewed through our own experience and reports by other investigators. In our experiment using 19 patients, we measured calcium ionophore-stimulated LTB4 synthesis in PMNs obtained in three different stages of the illness (acute, convalescent and recovered phases). LTB4 synthesis was significantly increased in the convalescent phase of the illness. Other investigators showed increased serum-LTB4 concentration in acute as well as convalescent phases, suggesting that LTB4 participated in the inflammatory process of Kawasaki disease as an inflammatory mediator and immunomodulator. However, no difference was found in LTB4 synthetic activity in PMNs in any phases of the illness between the patients with and without coronary lesions, which indicated that LTB4 was not a parameter of coronary aneurysm formation. Therapeutic use of high-dose gamma-globulin showed a tendency to decreased LTB4 synthesis in PMNs, although it is not conclusive.