7(th) International Immunoglobulin Conference: Poster presentations.

Immunoglobulin (Ig) therapy is the mainstay of treatment for primary antibody deficiency disorders and has proved to be efficacious in specific autoimmune and inflammatory diseases. Additionally, due to the role of Ig in complement activation, it is being used increasingly in solid organ transplantation. Furthermore, Ig is the primary or secondary treatment in some immune-mediated neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP) or multifocal motor neuropathy (MMN). This session discusses trends of Ig use in Europe, proposed mechanisms of action, adverse effects and the potential role of Ig therapy in transplantation. Dr Sedivá reported that Ig therapy is available in all European countries, although dosing is not always optimal, due partly to reimbursement plans. Subcutaneous immunoglobulin (SCIg) has become increasingly accessible in recent years; however, the chosen route of administration still varies widely between countries. Dr Berger's presentation on optimization of Ig therapy in neuropathies, and Dr Rojavin's report on a pharmacometric model to determine the serum IgG levels achieved by different dosing regimens in primary antibody deficiency (PAD) patients, led to the challenging concept of using individualized dosing strategies. Dr Klehmet reported on the potential benefit of using antigen-specific T cell responses as a biomarker of IVIg responsiveness in CIDP patients, while Dr von Gunten provided an insight into the mechanisms of action of Ig preparations, suggesting that the immunoregulatory effects of IgG may be mediated by IgG antibodies against glycans. Dr Basta reported on the potential thrombogenic adverse effects associated with Ig therapy. Although these adverse events are rare, further studies are needed to clarify the relationship between Ig replacement and immunomodulatory therapy and these adverse reactions. In transplantation, Dr Carbone described that prophylactic IVIg treatment was found to decrease the incidence of severe infection in IgG hypogammaglobulinaemia patients undergoing heart transplantations. Furthermore, Dr Clatworthy reported that inactivating polymorphisms in the inhibitory receptor FcγRIIB do not impact upon kidney allograft survival.

7th International Immunoglobulin Conference: Poster presentations.

The pan-European survey provides useful information on the accessibility and trends of intravenous and subcutaneous immunoglobulin (IVIg/SCIg) therapy, which is used to treat primary immunodeficiency disorders (PIDs). Although immunoglobulin (Ig) therapy is the first-line treatment for PIDs, the mechanisms of action of Ig therapy may differ according to the condition it is used to treat. Moreover, intriguing presentations suggest that further investigation is required to understand more clearly both the haematological and immunoregulatory effects of therapeutic immunoglobulin. This can ultimately provide more information on optimizing Ig therapy efficacy, and establish whether individualized dosing regimens for patients will be conducive to better clinical outcomes. In addition to treating autoimmune and inflammatory conditions, there is evidence to suggest that immunoglobulins can potentially play a role in transplantation, which warrants further investigation for future use.

Efficacy and safety of a new immunoglobulin G product, Gammaplex(®), in primary immunodeficiency diseases.

This open-label multi-centre study evaluated a new intravenous immunoglobulin, Gammaplex®, in the treatment of 50 patients with primary immunodeficiency and significant hypogammglobulinaemia. Patients treated previously with other intravenous immunoglobulins received Gammaplex® on their same infusion schedule for 1 year; 22 were on a 21-day and 28 on a 28-day regimen (300-800 mg/kg/infusion). There were no serious, acute bacterial infections, whereas six subjects (12·0%) had at least one such infection in the 6 months before enrollment. Forty subjects (80·0%) had at least one non-serious infection; the median number of infective episodes per subject per year was 3·07. Antibiotics were taken by 38 subjects therapeutically and prophylactically by 16 at some time. Fewer than half (46·0%) missed any time off work or school because of infection or other illness. Trough immunoglobulin (Ig)G levels were above 6·00 g/l in all subjects at all assessments after 15 weeks with two exceptions. Overall, 21·2% of infusions were associated with an adverse event up to 72 h after infusion. The frequency of adverse events increased with infusion rate. Headache was the most common product-related adverse event (7·5% of 703 infusions). In conclusion, Gammaplex® is effective in primary immunodeficiency and is well tolerated.

Immunodeficiencies.

Primary immunodeficiencies (PIDs) are uncommon, chronic and severe disorders of the immune system in which patients cannot mount a sufficiently protective immune response, leading to an increased susceptibility to infections. The treatment of choice for PID patients with predominant antibody deficiency is intravenous immunoglobulin (Ig) replacement therapy. Despite major advances over the last 20 years in the molecular characterization of PIDs, many patients remain undiagnosed or are diagnosed too late, with severe consequences. Various strategies to ensure timely diagnosis of PIDs are in place, and novel approaches are being developed. In recent years, several patient registries have been established. Such registries shed light on the pathology and natural history of these varied disorders. Analyses of the registry data may also reveal which patients are likely to respond well to higher Ig infusion rates and may help to determine the optimal dosing of Ig products. Faster infusion rates may lead to improved convenience for patients and thus increase patient compliance, and may reduce nursing time and the need for hospital resources. Data from two recent studies suggest that Gamunex and Privigen are well tolerated at high infusion rates. Nevertheless, careful selection of patients for high infusion rates, based on co-morbid conditions and tolerance of the current infusion rate, is advisable. Based on the available data, intravenous Ig offers broad protection against encapsulated organisms. As vaccine trends change, careful monitoring of specific antibody levels in the general population, such as those against pneumococcal and meningococcal bacteria, should be implemented.

Clinical experience with Flebogamma 5% DIF: a new generation of intravenous immunoglobulins in patients with primary immunodeficiency disease.

The development of effective, safe, liquid intravenous immunoglobulins (IVIG) preparations has represented a major therapeutic advancement in the treatment of patients with antibody deficiencies. Flebogamma 5% was the first liquid IVIG licensed in Europe that has been widely used in the treatment of immunodeficiency diseases. It has been proven to have an excellent efficacy and safety profile. Flebogamma 5% dual inactivation and filtration (DIF) is a newly developed IVIG preparation that shares formulation characteristics and identical biochemical and stability profiles with Flebogamma 5%. In addition to pasteurization, already performed in Flebogamma 5%, solvent-detergent treatment and sequential nanofiltration through filters with pore sizes of 35 nm followed by 20 nm have been added to further enhance the pathogen safety margin. The purpose of this study was to evaluate the efficacy, safety, and pharmacokinetics of Flebogamma 5% DIF for immunoglobulin replacement therapy in patients with primary immunodeficiency diseases (PID). Flebogamma 5% DIF was administered at seven clinical sites to 46 subjects with well-defined primary immunodeficiency diseases at a dose of 300-600 mg/kg every 21-28 days for 12 months. The serious bacterial infection rate was 0.021/subject/year. The incidence of adverse events considered potentially related to Flebogamma 5% DIF during or within 72 h after completing an infusion was approximately 10%. The half-life in serum of the administered IgG was around 31 days. In summary, Flebogamma 5% DIF is efficacious and safe, has good pharmacokinetic properties, is well-tolerated and maintains the profile of Flebogamma 5% for the treatment of patients with primary humoral immune deficiency diseases.

Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%).

BACKGROUND AND OBJECTIVES: A new intravenous immunoglobulin (IGIV) process has been developed that integrates efficient inactivation of enveloped virus, using caprylate, with immunoglobulin G (IgG) purification and caprylate removal by column chromatography. Two clinical studies were conducted to compare the pharmacokinetics of the new product, IGIV-C, 10% (Gamunex, 10%), formulated with glycine, with the licensed solvent-detergent (SD)-treated intravenous immunoglobulin IGIV-SD, 10% (Gamimune N, 10%), formulated with glycine, and IGIV-C, 5%, formulated with 10% maltose. MATERIALS AND METHODS: Both studies were randomized, multicentre crossover trials of 18 and 20 (respectively) adult patients with primary humoral immune deficiency in which patients received one IGIV product for three consecutive periods (3-4 weeks) before crossing over to the other product. Pharmacokinetic parameters were determined after the third infusion of each product. RESULTS: IGIV-C, 10% was bioequivalent to IGIV-SD, 10%, with half-lives (t1/2) of 35 and 34 days, respectively. IGIV-C, 5%, was bioequivalent to IGIV-C, 10%, with t1/2 of 35 and 36 days, respectively. The products had comparable safety profiles. CONCLUSIONS: The pharmacokinetic profiles observed in these trials indicate that IGIV-C, 10% may replace, and be administered in a manner similar to, IGIV-SD, 10%.

Detection of intracytoplasmic cytokines by flow cytometry in adenoids and peripheral blood lymphocytes of children.

Cytokine flow cytometry at the single-cell level has never been utilized in the study of adenoidal lymphocytes. We describe the multiparameter capability of flow cytometry to simultaneously detect an antigen on the surface of the adenoidal and peripheral blood lymphocytes and detect Th1 and Th2 cytokines within the cytoplasm of these lymphocytes. The data suggest that the percentage of cells producing interferon (IFN)-gamma are decreased in adenoidal as compared to peripheral blood lymphocytes, confirming our previous studies. The new findings show that the CD8 subset of adenoidal lymphocytes produces lower amounts of IFN-gamma as compared to peripheral blood CD8 cells. The intracytoplasmic synthesis of interleukin (IL)-2, however, appears to be similar in both adenoidal and peripheral blood lymphocytes. The CD4 subset of lymphocytes in the adenoid produces more IL-2, whereas the CD8 subset produces more IFN-gamma. Finally, as shown in our previous studies, the Th2 cytokines appear to be produced in similar quantities in both adenoidal and peripheral blood lymphocytes.

Office evaluation of children with recurrent infection.

This discussion provides an overview of the diagnostic approach to children with recurrent infections for the evaluation of a possible immunodeficiency. This article sets the stage for more detailed discussions of specific immunodeficiencies and therapeutic approaches used to reconstitute immune function in patients with these disorders.

Th1/Th2 cytokine profiles in the nasopharyngeal lymphoid tissues of children with recurrent otitis media.

The cytokine profile in adenoidal lymphoid tissue was studied in 22 patients. Lymphocytes from adenoid tissues and peripheral blood were submitted for cytokine assays using an enzyme-linked immunosorbent assay kit for interferon-gamma, interleukin (IL)-2, IL-4, IL-5, IL-6, and IL-10. Adenoidal lymphocytes appear to produce significantly less Th1 cytokines (IL-2, interferon gamma) compared to the patient's peripheral blood lymphocytes, whereas IL-4 and IL-5 (Th2 cytokines) appear to be synthesized to the same extent as, if not slightly more than, in the homologous peripheral blood lymphocytes. Because the relationship between Th1 and Th2 cytokines is extremely important in modulating the immune response, it is advisable to determine the role of the cytokine profiles of T-lymphocytes in the nasopharynx and its relationship to the development of inflammation of the eustachian tube and middle ear.

Immunopharmacology: immunomodulation and immunotherapy.

Immunopharmacology has changed dramatically over the past 25 years. Although a variety of traditional nonspecific immunosuppressive drug therapies are available for the treatment of autoimmune disease and organ transplantation rejection, with advances in cell biology and monoclonal antibody technology, a highly specific antibody can be engineered to cell surface determinants on immune cells or tumors or to neutralize inflammatory and immune mediators from an immune response. Many of these modalities are still in early phases of study for the treatment of autoimmune disease. In addition to therapies that suppress immune responses, advances in molecular biology have led to new agents and methods to enhance immune responses and correct immune deficits, such as growth factor replacement and cytokine therapies. Finally, gene therapy is a method for the long-term treatment of disorders in which a defective gene leads to disease.

Open trial of intravenous immune serum globulin for chronic sinusitis in children.

BACKGROUND: Chronic sinusitis in children is a complex clinical problem. Some patients do not improve with medical therapy and some fail surgery as well. OBJECTIVE: A therapeutic trial of intravenous immune serum globulin (IVIG) was given to children whose sinus disease was recalcitrant to the usual therapeutic modalities. The objective of IVIG administration was to modulate the inflammatory process contributing to the chronicity of the sinusitis. METHODS: Six patients were given a 12-month trial of monthly (400 mg/kg) IVIG infusions. Entry criteria included persistence of sinusitis after 3 months of full course antibiotics, or two episodes of sinusitis within a 3-month period while on prophylactic antibiotics. All patients had abnormal sinus CT (computerized tomography) scans at entry. Three of the six patients remained symptomatic despite prior sinus surgery. Patients with primary immune deficiencies were excluded. Each patient served as his own control based on their previous 12-month history and clinical course. Four of the 6 patients were atopic as demonstrated by prick skin testing; however, all patients had nasal eosinophilia. RESULTS: Full course antibiotic use decreased in five of the six patients (183 to 84 days); correspondingly, the episodes of sinusitis decreased (average 9 to 4 per year). In addition, sinus CT scans showed significant improvement. CONCLUSION: This preliminary open-trial of IVIG suggests its usefulness as adjunct therapy to medical management in selected patients with chronic sinus disease. The mechanism(s) by which IVIG may be helpful is probably not based on the concept of replacement therapy, but more likely as an immune or inflammatory modulating agent.

Mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory diseases.

Intravenous immune serum globulin (IVIG) is primarily used as replacement therapy in patients with hypogammaglobulinemia. It has been over 15 years since IVIG was first shown to be effective in the treatment of patients with autoimmune thrombocytopenic purpura. Over the past decade, IVIG has been used in the treatment of a number of autoimmune and systemic inflammatory disorders. Although the use of IVIG in many of these immune-mediated disorders was purely speculative initially, we now have a much better understanding of the mechanisms by which IVIG exerts its effects in these autoimmune diseases. IVIG exhibits a number of immune modulatory activities that are mediated by the Fc portion of IgG through the Fc gamma receptor on a variety of cell types. Although the major component in IVIG is IgG, other minor components such as solubilized lymphocyte surface membrane determinants and specific antibodies to lymphocyte surface molecules may have important immunoregulatory effects on T- and B-cell immune responses. This review discusses the proposed mechanisms of action of IVIG in autoimmune and inflammatory disorders.

Retinoic acid-induced modulation of IL-2 mRNA production and IL-2 receptor expression on T cells.

BACKGROUND: Retinoic acid (RA) has important immune-modulating effects on both T and B cell function. Our laboratory has shown that RA can enhance in vitro polyclonal B cell immunoglobulin (Ig) response. Investigating cytokines known to affect B cell differentiation, we have recently shown that IL-6 production is augmented by RA. In the present study we have examined the immune modulating effects of RA on IL-2 mRNA, another important cytokine for B cell immunoglobulin production, the expression of IL-2 receptors on T cells, and the RA nuclear receptors. METHODS: Purified T cells were obtained from adenoidal tissues, and incubated with RA (10(-7) M) or DMSO solvent/media control for 0, 6-8, and 24 h. Total mRNA was extracted from T cells, and using RT-PCR, changes in the production of IL-2 and RA receptors (RAR)-alpha,beta,gamma mRNA were determined. The effects of RA on IL-2-alpha receptor expression was determined by flow cytometry on T cells. CONCLUSION: These studies suggest that RA can augment IL-2 mRNA production by T cells with a possible paracrine effect on IL-2R-alpha expression. These changes appear to be mediated by RAR-alpha. Thus, IL-2 may be another important cytokine modulated by RA in the immune response.

Hot dog vapor-induced status asthmaticus.

BACKGROUND: Asthma induced by the inhalation of food vapors is unusual and indicative of extreme allergy. Identification of the specific cause and subsequent avoidance is essential. METHODS: We report a patient with asthma who had status asthmaticus following inhalation of boiling hot dog vapors. Prick skin tests were performed to various ingredients of the offending hot dog including chicken, pork, potato, and the aeroallergens. RESULTS: Prick skin tests reacted strongly to chicken and mildly to pork and potato. There was no reaction to aeroallergens. Our patient has not had any acute asthma after avoiding eating and exposure to chicken and hot dog vapors. CONCLUSIONS: Exquisite allergy to chicken was responsible for acute asthma.

Successful formation of a chimeric human thymus allograft following transplantation of cultured postnatal human thymus.

Transplantation of cultured postnatal human thymus was performed in a patient with complete DiGeorge syndrome. Biopsy of the graft 3 mo after implantation revealed normal CD1+ thymocytes in thymic cortical epithelial regions and CD1- thymocytes in thymic medullary epithelial regions, respectively. HLA analysis of graft thymocyte and thymic microenvironment components demonstrated that developing thymocytes and thymic macrophages were recipient derived, while thymic epithelial components were of donor origin. The patient, who initially had no T cells and had profoundly defective T cell function, developed normal T cell responses to mitogens and Ags, tolerance to donor in a mixed lymphocyte reaction, and normal Ab titers after tetanus toxoid and pneumovax immunization. Thus, transplantation of cultured postnatal human thymic tissue in humans can form functional chimeric thymic tissue, and may provide a strategy to reconstitute the peripheral T cell pool in select congenital and acquired immune deficiency syndromes.

The microbial ecology and immunology of the adenoid: implications for otitis media.

The nasopharyngeal tonsil, or adenoid, is a major inductive site for the synthesis of J-chain-positive B cells that may migrate to other areas of the upper respiratory tract, such as the nasal mucosa, the parotid gland, the lacrimal gland, and the middle ear during inflammation. The production of secretory IgA by both the nasopharyngeal tonsil and the nasal mucosa plays a major role in local immune protection against bacteria and viruses. The release of cytokines from Th1 and Th2 lymphocytes must be appropriate for B cells to produce IgA. The factors or mechanisms responsible for this are not, at present, known, but it appears that there is a difference in the profiles of cytokine secretion by Th1 and Th2 lymphocytes in the adenoids in both otitis-prone, as well as nonotitis-prone children. We have suggested that if this specific immune system does not protect the host from invasion by potential pathogens, there are other modalities of therapy to protect the nasopharynx from colonization with pathogenic bacteria or viruses. These include the production of specific antibodies against bacterial surface proteins that have been identified as mucin-binding proteins. Alteration of the microbial flora with commensal organisms such as viridans streptococci can be utilized. These alpha-hemolytic streptococci probably function by producing an acid environment that prevents colonization of organisms such as nontypeable H. influenzae. Finally, the induction of specific SIgA by conserved outer membrane protein antigens of potential pathogens may be another strategy in the prevention of colonization of potential bacterial pathogens in the nasopharynx.

Modulation of B-cell immunoglobulin synthesis by retinoic acid.

Retinoic acid (RA) and its parent compound retinol (ROH, vitamin A) have been recognized as important immunopotentiating agents since the early 1900s. We have focused our studies on the effects of retinoids on B-cell immune function in the newborn infant. The response of cord blood mononuclear cells (CBMC) to formalinized Cowan I strain Staphylococcus aureus (SAC), a T-cell-dependent factor for inducing the differentiation of B cells into immunoglobulin (Ig)-secreting cells, was used as a model system for studying whether RA could alter the immunoglobulin synthesis of newborn B lymphocytes. The addition of RA to SAC-stimulated CBMC cultures produced a 2- to 47-fold increase in IgM synthesis. An ELISA-spot assay showed that the RA-induced enhancement in Ig synthesis was due to the recruitment of more B cells to differentiate into Ig-secreting cells. Whereas RA enhanced IgM production of CBMC stimulated with SAC, RA augmented only IgG production of SAC-stimulated adult peripheral blood mononuclear cells (PBMC). To determine if the differences in dose-response characteristics between CBMC and adult PBMC resided within the target cell, i.e., the B cell, T-cell-enriched and T-cell-depleted (B-cell) fractions from CBMC and adult PBMC were cocultured in various combinations. The isotype, i.e., IgM vs IgG, and the dose-response curve characteristics were intrinsic to the responding B-cell source, i.e., newborn vs adult. Highly purified T cells from CBMC, when preincubated for 36 hr with RA, enhanced IgM synthesis of cord blood B cells. Supernatants from purified T cells generated a factor which could enhance B-cell synthesis. Although interleukin (IL)-2, IL-4, and IL-6 could not be detected by ELISA in the T-cell-derived supernatants, RA probably generates a cytokine/interleukin from T cells which modulates B-cell Ig secretion. RA can also act directly on B cells as evidenced by the augmentation in Ig synthesis of Epstein-Barr virus (EBV)-transformed B-cell lines. These data suggest that RA can have a direct effect on B cells. Since increased proliferation (numbers) of lymphoblastoid B cells was not responsible for the increased amounts of Ig in the supernatant fluids, we examined whether cytokines secreted by EBV-transformed B cells could be acting as an autocrine factor in increasing Ig synthesis. EBV-transformed B-cell clones incubated with RA for 6 days produced a 20- to 45-fold increase in IL-6. An understanding of the mechanisms by which RA enhances B-cell immune function may lead to the use of RA or its derivatives in patients with immune deficiencies and in preterm infants with immature immune systems.