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C Cunningham-Rundles

Publications and source records attributed to C Cunningham-Rundles.

At least 55 records · Page 3Linked to original sources
PubMed1993

Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients.

To determine whether warm-antibody autoimmune hemolytic anemia (AIHA) responds to treatment with intravenous gammaglobulin (IVGG), we conducted separate pilot studies at three institutions enrolling a total of 37 patients. We combined these results with a review of 36 cases of AIHA treated with IVGG reported in the literature. Sixteen clinical variables were examined to determine associations with response to IVGG. Overall, 29 of 73 patients (39.7%) responded to IVGG therapy. Two variables were strongly related to a good response to IVIG: the presence of hepatomegaly (with and without splenomegaly) and a low pre-treatment hemoglobin. A trend towards a better response was observed in the 11 children. Overall, IVGG provided acute benefit in only 1/3 of patients and therefore cannot be recommended as standard therapy for AIHA. It may, however, be useful as adjunctive treatment in selected cases, such as in those with a pre-treatment hemoglobin < 6-7 gm/dl or those with hepatomegaly, and in clinical settings where the toxicity of other treatments may be an important consideration.

Adult↗
PubMed1993

Long-term use of IgA-depleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies.

The use of intravenous immunoglobulin is standard practice for antibody replacement in the humoral immunodeficiency diseases. Most infusions proceed uneventfully, but a proportion of infusions (5-8%) produces some degree of an infusion reaction. While the cause of most of these infusion reactions is unknown, an established, but rare cause of reactions is IgA antibodies in the serum of the patient, which apparently forms an immune complex with the traces of IgA in the infused immunoglobulin. This article describes our studies of five immunodeficient patients who had high-titered anti-IgA antibodies and a history of severe infusion reactions to intravenous immunoglobulin products not depleted of IgA (IgA content, 270-720 micrograms/ml). Over a 6-year period we gave these patients IgA-depleted intravenous immunoglobulin for a total of 170 infusions. These infusions were generally well tolerated; however, mild to moderate infusion reactions did occur in 9 of the 170 infusions (5.3%). These reactions were not related to the IgA content of the immunoglobulin solutions used--ascertained to vary between 0.4 and 2.9 micrograms/ml of IgA. Levels of plasma C3a and C4a increased after immunoglobulin infusions but the appearance of these components was not accompanied by any infusion reaction. We conclude that the long-term infusions of IgA-depleted intravenous immunoglobulin, within the range of IgA concentrations investigated, into patients with even very high-titered antibodies to IgA, is a safe practice.

Adolescent↗
PubMed1992

Biological activities of polyethylene-glycol immunoglobulin conjugates. Resistance to enzymatic degradation.

Serum IgG has been covalently bonded to polyethylene glycols of either 2000 or 8000 molecular weight to produce immunoglobulin conjugates with 4.4-27.2% of primary amines bonded to polyethylene glycol. Polyethylene glycol immunoglobulin conjugates retain the ability, comparable to native IgG, to bind to a range of protein and microbial antigens, but have a reduced ability to bind to Fc receptors or to fix complement C3. When 6.8% or more of available primary amines are conjugated, IgG-PEG conjugates are impervious to trypsin, and at 14% or more conjugation, more resistant than native IgG to pepsin and chymotrypsin. We suggest that PEG-Ig conjugates may be useful for the oral treatment of various gastrointestinal diseases in which secretory humoral immunity is insufficient.

Antigens, Protozoan↗
PubMed1992

Restoration of immunoglobulin secretion in vitro in common variable immunodeficiency by in vivo treatment with polyethylene glycol-conjugated human recombinant interleukin-2.

Patients with common variable immunodeficiency (CVI) have decreased immunoglobulin levels resulting in frequent infections. Although previous studies have suggested that the B cell is intrinsically defective, numerous T cell deficiencies, including reduced interleukin-2 (IL-2) production, have been described. Since the addition of T cell cytokines to CVI B cells can increase Ig secretion in vitro, hypogammaglobulinemia in CVI may be due to defective T cell functions. To assess this possibility directly, we treated five CVI patients intravenously with a new biologic, human recombinant IL-2 conjugated to polyethylene glycol. Doses were 250,000 IU/m2 weekly for Weeks 1-4, 500,000 IU/m2 for Weeks 5-8, and 10(6) IU/m2 for Weeks 9-12. During and after treatment, B cells of all patients secreted 10- to 1000-fold more Ig in vitro. There was also a striking improvement in T cell helper activity since T cells of treated patients could induce 10- to 10,000-fold increases in Ig secretion by B cells from normal donors. No increase was seen in serum Igs during the study, but the anti-tetanus antibody of the IgG isotype could be detected in cell culture supernatants. Whether the effects of infused polyethylene glycol IL-2 are mediated through T or B cells, or both, is still unknown. However, these data reinforce the concept that CVI B cells may be competent, but, lacking essential T cell growth factors, in vivo maturation to Ig production does not occur.

Adult↗
PubMed1992

Established and new uses of intravenous immunoglobulin.

We know much about the biologic activities of the immunoglobulin molecule. We know its structure, and much about its function. However, I think that surprises are still ahead of us. As we become more familiar with what the immunomodulation doses of IVGG can do, I think we will find other uses of IVGG relying on antiidiotypic antibodies and possibly other cell-mediated functions.

Autoimmune Diseases↗
PubMed1991

Non-Hodgkin lymphoma in common variable immunodeficiency.

The association between cancer and immunodeficiency is well established. In common variable immunodeficiency (CVI), a primary immunodeficiency disease characterized by low serum immunoglobulins and poor antibody production, we previously reported a total of 13 cancers in 11 individuals arising in continuously observed group of patients. Of the 13, 7 were NHL and 1 was a myeloma which progressed to lymphoma. We report here the histologic, immunologic, cytogenetic, and clinical features of these 8 NHL along with 3 new lymphomas which have appeared in this group (now 117 patients). From our studies, the lymphomas which have arisen in CVI share certain features with the lymphomas which appear in the childhood immunodeficient syndromes. Wiskott Aldrich Syndrome, Ataxia Telangiectasia, or severe combined immunodeficiency: they are similar in overall frequency (13%), are often B-cell in origin, and extranodal in location. However, unlike the lymphomas of the immunodeficient child, lymphomas in CVI may be more differentiated and secrete immunoglobulin. For CVI patients with stage I or II disease, as for non-Hodgkin lymphomas in general, the prognosis is good. In our group, NHL in CVI have appeared most often in females of the 5th to 7th decade and not in childhood. Cytogenetic studies in lymphomas show that cytogenic abnormalities, including chromosomal translocation, can be found in this group, but more studies will be needed to assess the frequency of these events.

Cytogenetics↗
PubMed1991

Relationship between naturally occurring human antibodies to casein and autologous antiidiotypic antibodies: implications for the network theory.

Previous studies on human autologous antiidiotypes have been based largely upon analyses of autoimmune disease. We have previously described polyclonal, naturally occurring human autoantibodies directed against antibodies with specificity toward bovine casein in the sera of IgA-deficient humans. In order to define this system more exactly we have not produced two murine monoclonal antibodies directed against bovine milk kappa-casein to use as clonal tools to identify specific antiidiotypes in these human sera. Kappa-casein is an important part of the casein micelle in milk and cheese; in addition to being an important immunogen for man, kappa-casein is known to have conserved amino acid sequence and two antigenic epitopes. Data presented here show that the serum of up to 74% of IgA-deficient and 10% of normal humans have specific autologous antiidiotypes in their serum which bind to monoclonal antibodies directed to bovine kappa-casein. These human antibodies [intact or F(ab)'2] can be blocked from binding to the monoclonal anti-kappa-caseins by pure bovine kappa-casein or the kappa-casein peptide fragment. In contrast to previous studies in autoimmune disease, serum levels of the autoantiidiotypes were directly proportional to the level of IgG antibody to bovine kappa-casein. These observations suggest that continual exposure to a ubiquitous dietary antigen may produce an antigen driven system in which stimulation of both Ab1 and Ab2 occurs in concert.

Adolescent↗
PubMed1991

Selective IgA deficiency, IgG subclass deficiency, and the major histocompatibility complex.

Here we have examined the connection between IgA deficiency, IgG subclass deficiency, and the absence of alleles of complement C4, and show that IgA deficient subjects who have IgG subclass deficiencies may also have an increased frequency of C4 null alleles. In our group, we found an increased incidence of HLA B38 which might reflect the ethnic composition of the patients tested. While family studies are of primary importance to assess the relationships between histocompatibility antigens and immune deficiency, these studies are complicated by the observation that C4 null alleles are not always inherited with the humoral defect.

Adult↗
PubMed1991

Dietary antigens and immunologic disease in humans.

Absorption of small amounts of various dietary antigens in an intact state is a normal phenomenon in humans. This article discusses the normal mechanisms of excess antigen exclusion, examples of the states in which absorption can occur, and some of the immunologic consequences that have been documented.

Absorption↗
PubMed1990

Genetic aspects of immunoglobulin A deficiency.

IgA deficiency is one of the most common of all immune defects. While it is often not associated with clinical illness, presumably due to compensation from other sectors of the immune system, IgA-deficient individuals are distinctly more likely to become ill and have one or more of specific groups of diseases. While the unifying immunologic perturbation in IgA deficiency is a lack of mature IgA-secreting B cells, a host of other, usually minor, immunologic abnormalities have been reported in such patients. IgA deficiency can be inherited in an autosomal dominant or autosomal recessive fashion, but most individuals who are IgA deficient have no other affected family members. From a genetic point of view, IgA deficiency has been associated with three chromosomes, 18, 14, and 6. Many IgA-deficient individuals who have cytogenically detectable abnormalities of chromosome 18 have been reported, but all the individuals with these defects have severe congenital defects of other kinds. Obscuring the relationship between chromosome 18 and IgA deficiency is the fact that both short- and long-arm deletions have been reported in IgA deficiency. The chromosome deletions in the individuals who are IgA deficient thus appear to have no common pattern. While a rare individual can be IgA1 deficient on the basis of heavy-chain deletions of alpha 1 genes in concert with other heavy-chain genes on chromosome 14, such individuals are quite rare, and from a clinical point of view, those reported have usually been healthy. Absence of both IgA1 and IgA2 genes (presumably in concert with other heavy-chain genes) has never been reported. For chromosome 6, a more complex puzzle emerges. IgA-deficient individuals have been reported to have one of a few specific HLA haplotypes. While many individuals with these supratypes are not IgA deficient, these findings encourage the notion that the secretion of IgA could be at least partly controlled by genes residing in the major histocompatibility locus.

Amino Acid Sequence↗
PubMed1990

Regulation of immunoglobulin (Ig)E synthesis in the hyper-IgE syndrome.

The hyper-IgE (HIE) syndrome is characterized by high IgE serum levels, chronic dermatitis, and recurrent infections. The mechanisms responsible for hyperproduction of IgE in HIE patients are presently unknown. We investigated whether spontaneous in vitro IgE synthesis by PBMC from seven HIE patients was sensitive to signals (cell adhesion, T/B cell cognate interaction and lymphokines: IL-4, IL-6, and IFN-gamma) known to regulate IgE induction in normals. Our results show that, unlike IL-4 dependent IgE synthesis induced in normals, spontaneous IgE production by PBMC from HIE patients was not blocked by monoclonal antibodies to CD2, CD4, CD3, and MHC class II antigens. Furthermore, antibodies to IL-4 and IL-6 did not significantly suppress IgE production. IFN-gamma had no significant effects on spontaneous in vitro IgE synthesis. To test whether an imbalance in lymphokine production might underlie hyperproduction of IgE in HIE patients, mitogen-induced secretion of IL-4 and IFN-gamma by PBMC was assessed. No significant difference was detected between HIE patients and normal controls. Thus, ongoing IgE synthesis in the HIE syndrome is largely independent of cell-cell interactions and endogenous lymphokines, and is due to a terminally differentiated B cell population, no longer sensitive to regulatory signals.

Adult↗
PubMed1989

Clinical and immunologic analyses of 103 patients with common variable immunodeficiency.

Common variable immunodeficiency (CVI) or hypogammaglobulinemia is a heterogeneous primary immunodeficiency disease in which B cells produce little or no antibody. Since the disease is relatively rare and the spectrum of associated illnesses is broad, patients are given care by a variety of specialists. Thus it has been difficult to determine the incidence of specific complications. In these studies we analyzed 103 consecutively referred CVI patients of age range 3-71 years (average, 29 years) who were followed for a period of 1-13 years (total of 750 patient years). The average serum IgG was 174.4 mg/dl for untreated patients and 301 mg/dl for patients treated with intramuscular immunoglobulin at the time of the first visit. The average IgA was 14.5, and the average IgM was 80.7, with no difference between or after immunoglobulin treatment. About one-half of the patients had T-cell dysfunction, but lymphocyte stimulation responses were inversely related to age, which implies worsened T-cell immunity with age. Serum IgG and IgA levels were found to be statistically associated (P = 0.008), and serum IgG was related to lymphocyte stimulation with concanavalin A (P = 0.01). By 1986, 79 patients were alive, 23 had died, and 1 could not be located. Recurrent bacterial illnesses were common to all patients, and 22% had developed chronic lung disease, 22% autoimmune disease, 15% cancer, 13% hepatitis, and 9% malabsorption. Autoimmune disease was more common in females, and cancer was more likely to develop in the fifth and sixth decades. In 11% of the group, other family members were found to be immunodeficient (hypogammaglobulinemic or IgA deficient). Nine patients died of respiratory insufficiency (with or without other complications), and seven patients died of cancer. These data provide valuable information about the immunologic abnormalities and the spectrum and frequency of illnesses associated with hypogammaglobulinemia.

Adolescent↗
PubMed1989

Production of a monoclonal antibody to bovine kappa-casein.

Caseins (including alpha s1, alpha s2, beta, kappa and gamma casein), a family of phosphoproteins which binds to calcium, are the major proteins in mammalian milk. Kappa-casein, in addition to its calcium binding capacities has an important role in the stabilization of the micelle structure of milk. In the course of studies to investigate the immunologic effects of ingested bovine kappa-casein in IgA deficiency, a hybridoma has been produced that secretes a monoclonal antibody, (IgG1 kappa isotype), which is specific for bovine kappa -casein. The antibody has been characterized by ELISA and it has been shown to bind specifically to bovine kappa -casein. In a sandwich radioimmunoassay, as little as 0.3 x 10(-4) nM/ml of kappa-casein. could be detected. This antibody does not bind to other bovine milk proteins, nor to human casein.

Animals↗
PubMed1989

Feedback inhibition of B cell differentiation by monomeric immunoglobulin.

Polyspecific monomeric immunoglobulin (Ig) isolated from either a commercial source (pooled, > 2000 donors), or an autologous donor was capable of inhibiting both B cell proliferation, induced by T dependent mitogens or T cell factors and B cell differentiation, induced by similar stimuli. These effects appear to be directed at the B cell itself since inhibition of differentiation is detectable when monomeric Ig is added to cultures of B cell lines in the presence of B cell differentiation factor (BCDF). The inhibition of B cell differentiation does not appear to relate to inhibition of B cell proliferation, as no detectable change is seen in thymidine incorporation or cell number in these cultures. Furthermore, the effect of monomeric lg appears to relate to an early event in B cell differentiation, as there is no effect of IgSRK on spontaneously secreting B cell lines and maturation to cytoplasmic Ig containing cells is markedly impaired. Therefore, monomeric Ig secreted by B cells may serve as an immunoregulator of further Ig secretion.

Antibody Formation↗
PubMed1988

Analysis of a common inheritable idiotype in IgA-deficient sera using monoclonal antibodies.

In these studies we describe the production of three mAb raised to an idiotype on an IgG anticasein antibody isolated from the serum of one IgA-deficient blood donor. These are IgM kappa and block the binding of casein Ag to anticasein antibody. Sera of unrelated IgA-deficient donors were tested for the presence of the idiotype; 15 of 56 IgA-deficient sera (25%) contain the anticasein idiotype, whereas 1 of 45 normal sera was positive. Anticasein antibodies as a whole were predominantly of the IgG1 and IgG3 subclass; idiotype-positive anticaseins are predominantly of the IgG1 subclass. For IgA-deficient donors, the relative amount of idiotype-positive anticasein antibody was correlated with the level of anticasein present in the serum. Studies were done to investigate the potential inheritance of the idiotype in families; in three of four families the idiotype was inherited in an apparent autosomal dominant pattern. Our data show that a common cross-reactive idiotype can be detected in the sera of IgA-deficient individuals and their family members. This suggests that V region markers may be conserved in this humoral immunodeficiency disease.

Antibodies, Monoclonal↗
PubMed1988

Intravenous immunoglobulin prophylaxis causing liver damage in 16 of 77 patients with hypogammaglobulinemia or IgG subclass deficiency.

Sixteen of 77 patients (21 percent) with common variable immunodeficiency or IgG subclass deficiency contracted non-A, non-B hepatitis in association with intravenous infusions of immunoglobulin. The hepatitis seemed to run a more severe course in these patients than in non-immunodeficient patients. Twelve patients had clinical symptoms, and five died with hepatitis being the cause of death in two and a contributing factor in three. Liver biopsy specimens showed early chronic active hepatitis and cirrhosis. In addition to increases in liver enzymes, 13 patients had increases in alkaline phosphatase levels. All but two patients who contracted hepatitis had been given 50 mg/kg per week or more of intravenous immunoglobulin. Lymphocyte counts, T/B cell ratios, and T-lymphocyte function did not differ between those in whom hepatitis developed and those in whom it did not develop. The hepatitis was associated with more than one batch of a Swedish intravenous immunoglobulin, the immunoglobulin being derived from United States sources as well as from European plasma. Three previous brief reports in the literature have also associated non-A, non-B hepatitis with the intravenous infusion of various immunoglobulins. Biologic materials given to patients, including immunoglobulin, should, whenever possible, be prepared so as to ensure absence of viruses.

Adult↗