Sublingual immunotherapy alters expression of IL-4 and its soluble and membrane-bound receptors.

Seasonal allergic rhinitis (SAR) is a disease of increasing prevalence, which results from an inappropriate T helper cell, type 2 (Th2) response to pollen. Specific immunotherapy (SIT) involves repeated treatment with small doses of pollen and can result in complete and lasting reversal of SAR. Here, we assayed the key Th2 cytokine, IL-4, and its soluble and membrane-bound receptor in patients with SAR before and after SIT. Using allergen-challenge assays, we found that SIT treatment decreased IL-4 cytokine levels, as previously reported. We also observed a significant decrease in the IL-4 membrane-bound receptor (mIL4R) at the level of both mRNA and protein. SIT treatment resulted in a significant increase in the inhibitory soluble IL-4 receptor (sIL4R). Reciprocal changes in mIL4R and sIL4R were also observed in patient serum. Altered mIL4R and sIL4R is a novel explanation for the positive effects of immunotherapy with potential basic and clinical research implications.

Prospective open-label study of pharmacokinetics, efficacy and safety of a new 10% liquid intravenous immunoglobulin in patients with hypo- or agammaglobulinemia.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the pharmacokinetics, efficacy and safety of a newly developed 10% liquid immunoglobulin preparation in patients with primary immunodeficiency diseases. This new preparation for intravenous use includes three dedicated virus clearance steps in its manufacturing process to ensure a high margin of viral safety. MATERIALS AND METHODS: This was a prospective, open-label, non-controlled, multicentre study. Twenty-two subjects with primary immunodeficiency were treated initially with three infusions of a licensed intravenous immunoglobulin to standardize the immunoglobulin G (IgG) replacement therapy of all subjects to the same intravenous product. A total of nine infusions of the new 10% liquid preparation were subsequently administered. RESULTS: The median terminal half-life of total IgG following administration of the new preparation was 30.1 days. Median terminal half-lives for IgG subclasses IgG(1), IgG(2), IgG(3) and IgG(4) were 28.3, 31.3, 20.9 and 24.2 days, respectively. The median total serum IgG steady-state trough level was 8.51 g/l. No severe infection episodes started after initiation of treatment with the new preparation. The median rate of mild or moderate infection episodes was 0.48 per month. A total of 194 infusions with the new 10% liquid immunoglobulin preparation were administered. The mean dose per infusion was 0.41 g/kg body weight and the maximum infusion rates recorded were 8 ml/kg/h. Adverse experiences were mostly mild and unrelated to the study drugs. Only 4% of infusions with the new product were followed by one or more related adverse experiences. CONCLUSION: The new 10% liquid immunoglobulin preparation was well tolerated and shown to have an excellent pharmacokinetic, efficacy and safety profile. The liquid formulation provides convenience to patients and healthcare professionals.

Antibody response to the Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in healthy and infection-prone individuals with IgG3 subclass deficiency.

Searching for a possible explanation for the phenotypic heterogeneity in IgG3 deficiency, we studied the antibody response to a polysaccharide and a protein antigen in IgG3-deficient (IgG3d) adults after vaccination with Haemophilus influenzae type b capsular polysaccharide (Hib CP) conjugated to tetanus toxoid. Distribution of isotypes, idiotypes, clonotypes, and Gm allotypes were compared. All the vaccinated individuals, irrespective of the level of IgG3 and proneness to infections, developed protective levels of anti-Hib CP. Significantly lower prevaccination levels of IgG2 (p < 0.05) and IgG4 anti-Hib CP (p < 0.04 and p < 0.03) were noted among the infection-prone compared to the healthy IgG3d individuals and/or controls. Seventy percent of the IgG3d patients and none of the controls had the low responding Gm(ga-n/ga-n) genotype, while the majority of the controls had the alternative Gm(bfn/bfn) genotype. The conjugate ACT-HIB vaccine efficiently overcomes the IgG3 subclass deficiency state and the genetic predisposition for lower responsiveness, providing protection against Hib and tetanus infections. The proneness to infection in some IgG3d individuals may relate to their low prevaccination antibody levels.

Aberrant IgG2 antibody response to Neisseria meningitidis polysaccharide A after vaccination in frequently infected compared to healthy IgA-deficient individuals.

In search for a possible explanation of the phenotypic heterogeneity in selective immunoglobulin (Ig)A deficiency, we studied the IgG2 antibody response to meningococcal polysaccharide A (PSA) in IgA-deficient (IgAd) individuals after vaccination with meningococcal A + C polysaccharide vaccine. Two groups of IgAd individuals, one frequently infected and one clinically apparently healthy, as well as healthy controls, were studied. In response to meningococcal A + C polysaccharide vaccine, a significant titre increase of specific IgG2 anti-PSA was found in 71% of the control individuals, in 50% of the healthy and in 42% of the infection-prone IgAd individuals. The specific IgG2 response against meningococcal PSA was significantly lower in the infection-prone IgAd individuals compared to the controls (P < 0.05). Among the IgAd individuals who responded with a significant IgG2 antibody increase, the IgG2 antibody response was significantly lower in the infection-prone than in the healthy IgAd individuals (P < 0.05). Thus, a limited capacity to mount a specific IgG2 response may suggest a more profound antibody maturation defect in infection-prone IgAd patients compared to healthy IgAd individuals.

Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: a combined Danish and Swedish study.

The extremely high risk reported for some types of cancer among patients with common variable immunodeficiency (CVID) is based on a limited number of investigations. Therefore, we examined the risks for cancer among 562 Danish and Swedish patients with CVID or IgA deficiency and 2071 relatives in 1958-96. The patients were identified through an Immunodeficiency Register and hospital records, while the relatives were traced through population registers. Cancer incidence was assessed by linkage to the Cancer Registries and compared with that in the general population. Among 386 patients with IgA deficiency, the incidence of cancer was not increased (standardized incidence ratio (SI) = 1.0); but two cases of stomach cancer were found, resulting in a non-significant increase in risk (SIR = 5.4; 95% CI = 0.7-19.5). Among 176 patients with common variable immunodeficiency (CVID), the incidence of cancer at all sites combined was increased (SIR = 1.8; 95% CI = 1.0-2.9), which was due mainly to significant excesses of malignant lymphoma (obs = 4; SIR = 12.1; 95% CI = 3.3-31.0) and of stomach cancer (obs = 3; SIR = 10.3; 95% CI = 2.1-30.2). Among the 626 relatives of patients with CVID, no increase in risk was found for these types of cancer or for cancer overall (obs = 53; SIR = 1.0; 95% CI = 0.8-1.3). Our data show that the risks for malignant lymphoma and stomach cancer among patients with CVID may be lower than reported previously. The absence of an increased risk among relatives suggests that the increased cancer morbidity in patients with CVID is related to the immunodeficiency per se rather than to specific genetic traits shared with their relatives.

The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy.

To compare the efficacy of immunoglobulin replacement therapy given intravenously versus subcutaneously to prevent infections in patients with primary antibody deficiency syndromes, an international, multicenter, open label, crossover study was designed. Forty patients were randomized to receive either subcutaneous or intravenous immunoglobulin replacement therapy for 1 year. In the second year, patients were switched to the alternative treatment, enabling patients to act as their own controls. Equivalent doses were given by both routes. Ethical approval was obtained from the review boards of the hospitals in which the patients were seen and written consent obtained from each patient. Patients with a primary antibody deficiency syndrome, either common variable immunodeficiency or IgG subclass deficiency or specific antibody deficiency, who required immunoglobulin replacement therapy were included in the study. Patients were excluded if they had significant thrombocytopenia (defined as platelets less than 50 x 10(9)/liter), had high levels of anti-IgA antibodies (defined as greater than 1:8192), or had severe adverse reactions to a blood product within the last 2 years. The primary end point was the number of infections and their severity (moderate and major) during the two treatment periods. Secondary end points were adverse reactions, length of infections, days lost from school or work due to infections, and acceptability of treatment regimens to the patients. Based on the assumption that it was difficult to prove equivalence of therapies statistically in crossover studies, an arbitrary number of 40 patients was selected on the basis that this might be achievable in 2 years. There are no significant differences in efficacy or adverse reaction rates between immunoglobulin replacement therapy given subcutaneously or intravenously.

Variable increases of IgG and IgM antibodies in milk of IgA deficient women.

Serum, milk and saliva from seven IgA deficient mothers were studied for the presence of IgA, IgG and IgM antibodies to Escherichia coli and poliovirus antigens. Different variable patterns were obtained. One mother had very much increased IgM and IgG antibodies in milk and saliva against both antigens; the milk IgG antibodies were 11-14 times higher than the reference milk pool. Another mother showed also striking increases of both IgM and IgG antibodies in milk, as well as in saliva where the increases were much higher for the poliovirus than the E. coli antibodies. Yet another mother showed a certain increase of IgM but not of IgG antibodies in the milk. The uneven appearance of IgG and IgM antibodies in serum and secretions suggests local production. So do the differences of antibody avidities, the variations in IgG subclass distribution of antibodies and different patterns after isoelectric focusing (IEF)/immunoblotting analysis of antibody spectrotypes in secretions and serum. The study illustrates the variable patterns of compensatory increases of IgG and IgM antibodies which may occur in IgA deficiency. It also shows that the milk from IgA deficient mothers can still be rich in antibodies, in spite of the lack of secretory IgA.

Intravenous immunoglobulin and hepatitis C virus: the Scandinavian experience.

In Sweden, 44 patients were reported to have contracted hepatitis C virus (HCV) infections from treatment with intravenous immunoglobulin. Gammagard was the product implicated in HCV transmission in 12 patients; 8 of these 12 patients were HCV ribonucleic acid (RNA)-negative during the 2 years before Gammagard was administered and 10 showed clustering by sequencing of the HCV core gene. Further studies are being conducted to correlate the sequenced HCV RNA with specific batches of Gammagard. Nine patients who received Gammonativ in 1983 and 1984 had a strong time-related possibility of HCV infection. Sequencing analyses are being performed in these patients as is being done for the patients who received Gammagard. Another 21 patients who received Gammonativ from 1982 to 1985 are probably infected with HCV, but confirmation of implicated batches is lacking. The association between Sandoglobulin and HCV is questionable in two patients, although plausible because of a time relationship. In Norway, relationships between Gammonativ and the incidence of HCV infection are similar to those in the 21 sporadic cases in Sweden. Also in Denmark and Finland, HCV infection appears to be related to the lack of additional viral inactivation steps used in the preparation of intravenous immunoglobulin. Clearly, there is a need for increased antiviral inactivation and antiviral screening in the production of intravenous immunoglobulin products.

Family and linkage study of selective IgA deficiency and common variable immunodeficiency.

Screening of close relatives of Swedish patients with selective immunoglobulin A deficiency (IgAD) and common variable immunodeficiency (CVID) for serum immunoglobulin levels has identified the positive family history of IgAD/CVID as the most significant risk factor for developing the disease. The relative risk for siblings of patients with IgAD was estimated to be approximately 50. In 12 of 34 Swedish multiplex families identified in the study, both IgAD and CVID occurred, usually CVID in the parental generation and IgAD in the subsequent generation. This proportion was much higher than expected by chance and strongly suggests that the two clinically discernible disorders represent an allelic condition, reflecting a variable expressivity of a common defect. In 27 multiplex families the disorders segregated as an autosomal dominant trait, affecting at least two generations. A high relative risk for siblings, permanent phenotype, low number of phenocopies, and common population prevalence, which makes it possible to obtain a sufficient sample size, make these immunoglobin deficiencies amenable to genetic linkage analysis. In a pilot multicenter linkage study involving 16 multiplex families with dominant transmission of IgAD/CVID, we have attempted to confirm previously reported genetic linkage of the disease susceptibility to the major histocompatibility complex (MHC) region. Using both parametric and nonparametric linkage analyses with a set of microsatellite markers at and flanking the MHC region, no evidence for linkage was found. In accordance with these results, no evidence for linkage to the MHC region was obtained by analyzing previously published segregation data at the MHC region in multiplex families with IgAD/CVID in more than one generation.(ABSTRACT TRUNCATED AT 250 WORDS)

Lifelong treatment with gammaglobulin for primary antibody deficiencies: the patients' experiences of subcutaneous self-infusions and home therapy.

Primary antibody deficiencies are chronic conditions and the patients usually need lifelong replacement therapy with gammaglobulin to prevent or reduce infections. It has been shown that the gammaglobulin can be given safely as subcutaneous infusions, instead of intramuscular injections or intravenous infusions. The major aim of this multi-centre study was to investigate the perceptions of the subcutaneous method among patients using it, both in hospital settings and as self-infusions at home. The study included 152 patients: 89 women, 63 men, mean age 44 years (range 18-76). Data were collected by using questionnaires. The patients were found to have a strongly positive attitude towards receiving the replacement therapy as subcutaneous infusions, perceived the method as effective in preventing infections and wished to retain the treatment. However, the younger patients found the subcutaneous infusions more uncomfortable and were less determined to continue with the therapy as compared with the older individuals. The responsibility for self-infusions at home was accepted by the patients, leading to an increased independence from the health care personnel and to a feeling of flexibility and freedom. As these patients have a chronic disease and are in need of lifelong treatment, it is important to discuss the development of structured education and training programmes in which special emphasis is placed on the support of the younger patients. It is suggested that Orem's nursing model of self-care may serve as a conceptual framework for nurses working in this specific area of nursing care.

Linkage of IgA deficiency to Gm allotypes; the influence of Gm allotypes on IgA-IgG subclass deficiency.

IgA deficiency (IgAD) is the most common immunodeficiency, characterized by an arrest in B cell differentiation. It has a sporadic occurrence or variable inheritance pattern, and is also linked to the HLA genes. IgA deficiency is sometimes associated with IgG subclass deficiency. In this study the Gm allotypes, as genetic characteristics of the IgG1, IgG2 and IgG3, were analysed in 83 Caucasian IgAD individuals. Half of the patients presented with IgG4 < 0.01 g/l compared with 5% (P < 0.001) in a healthy population. Three of the 83 had significantly low IgG2 and four had significantly low IgG3 levels. Gm allotype frequencies in IgAD deviated compared with a normal population. Of the 83 patients, 44 (53%) showed homozygous G2 m(",") expression on the IgG2 locus (33% in controls, P < 0.01). In IgAD the Gm(a,",g) haplotype was more frequent (43%) compared with controls (31%, P < 0.01). The Gm homozygous phenotype Gm(a,",g/a,",g) was most common, found in 20 of 83 patients (24%, P < 0.05) compared with controls (14%). On the other hand the Gm(f,n,b) haplotype of IgAD was rare (28%) compared with controls (45%, P < 0.001). The low IgG4, < 0.01 g/l, found in 50% of the patients, was even more frequent (56-69%) among the G2 m(",") phenotypes. IgG subclass levels were given for different Gm phenotypes of the IgAD group and compared with controls. Significantly low IgG4 was revealed in the Gm(a,",g/a,",g) phenotype (P < 0.01) and significantly low IgG2 in the Gm(a,",g/f,",b) phenotype (P < 0.01). The Gm(a,",g/f,",b) phenotype contained the three patients found with IgG2 levels < -2 s.d., and the four patients with IgG3 levels < -2 s.d. were present among those with the homozygous Gm(a,",g/a,",g) phenotype; both phenotypes with G2 m(",") on the IgG2 locus. The 'compensatory' increase of IgG was significant for both IgG1 and IgG3 in all Gm phenotypes, but in the Gm(a,",g/f,",b). Thus, the susceptibility of IgAD with the additional IgG antibody deficiencies, down-regulated IgG4 and IgG2/IgG3, is associated with Gm allotypes, especially the homozygous G2 m(",") expression on the IgG2 locus.

Subcutaneous immunoglobulin replacement in patients with primary antibody deficiencies: safety and costs.

Immunoglobulins (IgG) as replacement therapy in primary antibody deficiencies can be given as intramuscular injections, or as intravenous or subcutaneous infusions. Our aims were to obtain information on the frequency of adverse systemic reactions during subcutaneous therapy, the occurrence and intensity of tissue reactions at the infusion sites, and serum IgG changes. Furthermore, we compared costs between the different replacement regimes. Our study included 165 patients (69 women, 96 men, aged 13-76 years) with primary hypogammaglobulinaemia or IgG-subclass deficiencies. Data were compiled from questionnaires filled in by the patients and from their medical records. 33,168 subcutaneous infusions (27,030 in home therapy) had been given. 106 (of which 16 were at home) adverse systemic reactions (100 mild, 6 moderate) were recorded in 28 patients (17%). No severe or anaphylactoid reactions occurred. Despite large immunoglobulin volumes given during 434 patient years (28,480 infusions), no signs have been found that indicate the transmission of hepatitis virus. Transient tissue reactions occurred at the infusion sites but were not troublesome to most patients and we found significant increases in mean serum IgG. The use of subcutaneous instead of intravenous infusions at home would reduce the yearly cost per patient for the health-care sector by US $10,100 in Sweden alone. We conclude that subcutaneous administration of IgG is a safe and convenient method of providing immunoglobulins. We were able to reach serum IgG concentrations similar to those by the intravenous therapy and we found that the method could also be used successfully in patients with previous severe or anaphylactoid reactions to intramuscular injections.

Hepatitis C virus transmission by intravenous immunoglobulin.

The polymerase chain reaction was used to detect hepatitis C virus infection in patients who had previously been reported to have developed non-A, non-B hepatitis after intravenous immunoglobulin infusion. Of the 33 patients with intravenous immunoglobulin associated non-A, non-B hepatitis studied, HCV RNA could be detected in 15 out of 17 patients (88%) who were HCV RNA negative prior to the development of non-A, non-B hepatitis after implicated intravenous immunoglobulin batches. Similarly, eight out of nine patients (89%) in whom no sample was available for polymerase chain reaction testing prior to intravenous immunoglobulin therapy, had detectable HCV RNA after intravenous immunoglobulin therapy with intravenous immunoglobulin batches implicated in non-A, non-B hepatitis transmission. Two of the three intravenous immunoglobulin preparations implicated in non-A, non-B hepatitis transmissions that were available for polymerase chain reaction testing also had detectable HCV RNA, confirming that hepatitis C virus is the implicated virus in intravenous immunoglobulin-associated non-A, non-B hepatitis.

Qualitative and quantitative analyses of the antibody response elicited by Haemophilus influenzae type b capsular polysaccharide-tetanus toxoid conjugates in adults with IgG subclass deficiencies and frequent infections.

Twenty-one IgG subclass-deficient adult patients with repeated infections of the respiratory tract, were immunized with Haemophilus influenzae type b capsular polysaccharide (HibCP) covalently bound to tetanus toxoid (TT). Specific immunoglobulin and IgG subclasses to HibCP and TT were quantified; the biological activities of HibCP antibodies were also investigated. Most patients showed an antibody response similar to that observed in healthy adults, and the bactericidal activity related to the post-immunization levels of HibCP antibodies. No relation was found between immunoglobulin isotype deficiency, the clinical symptoms and the IgG subclass responsiveness, and no relation was observed between HibCP and TT antibody responses. Our data indicate that some, but not all, patients with recurrent infections and IgG subclass deficiency have an abnormal serum antibody response to polysaccharide and protein epitopes of Hib-TT conjugate vaccine. Analysis of the antibody response after vaccination with HibCP-TT conjugate vaccine did not seem to predict the clinical course of such patients.

Intestinal and circulating antibody-forming cells in IgA-deficient individuals after oral cholera vaccination.

In search for a possible explanation for the different susceptibility to mucosal infections in IgA-deficient (IgAd) individuals, the frequency of total immunoglobulin-secreting cells (ISC) and vaccine-specific antibody-secreting cells (ASC) in intestinal mucosa and peripheral blood was determined by the enzyme-linked immunospot (ELISPOT) assay before and after peroral vaccination with a B subunit-whole cell cholera vaccine. Two groups of IgAd individuals, frequently infected and non-infected respectively, and normal controls were studied. Before cholera vaccination there were significantly higher frequencies of total IgM and IgG ISC in the gut, but not in the blood, in the IgAd individuals than in the controls. However, there were no significant differences between healthy and infection-prone IgAd individuals in this respect. In response to oral cholera vaccination, intestinal cholera toxin (CT)-specific IgG and IgM ASC were significantly more abundant among the IgAd individuals with a history of frequent infections than among the healthy IgAd individuals and controls. A similar difference in IgG and IgM ASC, although not significant, was also noted in blood. In IgAd individuals with frequent infections the vaccine induced variable anti-CT IgM ASC responses in the gut, ranging from no increase to a few strikingly high responses. In the controls, the CT-specific responses were dominated by IgA ASC. The data show that oral cholera vaccination evoked strong CT-specific IgG ASC responses, and in some cases also strong IgM ASC responses in the intestinal mucosa of IgAd patients with a history of frequent infections. The healthy IgAd individuals unexpectedly responded with lower numbers of CT-specific IgG ASC and did not show any increase of CT-specific IgM ASC in the intestinal mucosa. Thus, inability to mount a mucosal immune response to an oral antigen cannot in itself explain recurrent infections among many IgAd individuals.

Inclusion body myositis: clinical, morphological, physiological and laboratory findings in 18 cases.

Eighteen consecutive patients with inclusion body myositis (IBM) were studied. The mean age of onset of symptoms was 60 years. A typical clinical pattern with insidious onset of muscle weakness in knee extensors and finger flexors combined with dysphagia was observed. Serial measurements of the maximal voluntary muscle strength revealed a mean loss of muscle strength of 1.4% per month. Two of the cases had common variable immunodeficiency, and three cases had reduced levels of the IgG3 subclass. Treatment with prednisone resulted in a temporary improvement of muscle function in three patients. No positive effect of azathioprine or cyclosporine A could be documented. The results show that IBM may be associated with immunodeficiency, and that prednisone treatment may temporarily improve the clinical signs. The results from our studies on the progression of the muscle weakness may provide basis for future studies on treatment of IBM.

B-cell activation in duodenal mucosa after oral cholera vaccination in IgA deficient subjects with or without IgG subclass deficiency.

Alterations in duodenal Ig-producing cells induced by two oral cholera vaccinations were studied by two-colour immunofluorescence in mucosal tissue sections from adults with selective IgA deficiency (IgAD), either with (n = 7) or without (n = 9) frequent infections, infection-prone patients with combined IgAD and IgG subclass deficiency (IgGSD) (n = 7), and normal control subjects (n = 11). The proportion of IgG-producing cells prior to immunization tended to be lower in the symptomatic IgAD subjects than in the clinically healthy ones. In the first subgroup the absolute number of IgG cells per intestinal length unit was significantly increased after immunization (P < 0.04), and this tendency was also observed in the healthy IgAD subjects (6/9) and in those with combined deficiency (5/7). Very few IgAD subjects responded with an increase of IgM-producing cells. The normal controls responded variably in all major immunocyte classes, in the order IgA > IgG > IgM. Compared with these controls, the patients with combined IgAD and IgGSD showed significantly increased IgG1 (P < 0.01) and reduced IgG2 (P < 0.006) proportions, which was in accordance with their serum subclass levels. Our study showed that oral cholera vaccination preferentially activates intestinal IgG-producing cells in IgAD subjects. This result agreed with data recently obtained by ELISPOT in the same patients with regard to antibody-forming cells specific for cholera toxin. Both methods suggested that IgG rather than IgM antibodies are elicited as compensation for a lacking IgA response. However, our overall results showed that intestinal B-cell activation is quite variable after oral cholera vaccination. Although such vaccination might be of importance for enhancing mucosal immunity also in IgAD patients, a concurrent gut disease could possibly be aggravated by IgG-mediated mucosal immunopathology in the absence of anti-inflammatory IgA antibodies.