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C Cunningham-Rundles

Publications and source records attributed to C Cunningham-Rundles.

At least 37 records · Page 2Linked to original sources
PubMed1998

Analysis of cytokine signaling in patients with extrinsic asthma and hyperimmunoglobulin E.

BACKGROUND: Recent data suggest that the regulation of class switching to IgE by cytokines is mediated by STAT transcription factors. The induction of IgE by IL-4 and IL-13 occurs through the activation of the intracellular signal-transducing protein Stat6, whereas the inhibition of IgE class switching by interferon-y (IFN-gamma) occurs through the activation of Statl. OBJECTIVE: We hypothesized that in extrinsic asthma or in cases of markedly elevated IgE (ie, hyperimmunoglobulin E [HIE]) increased levels of IgE may be associated with alterations in the cytokine levels or the activation of Stat6. METHODS: PBMCs and sera from 8 patients with extrinsic asthma (mean IgE, 285+/-100 IU/mL), 3 patients with HIE (mean IgE, 7050+/-1122 IU/mL), and 14 nonatopic control subjects (mean IgE, 112+/-28 IU/mL) were analyzed. RESULTS: The mean IL-4 level detected by ELISA was much greater in patients with HIE than control subjects (88.6+/-11.5 pg/mL vs 11.5+/-7.1 pg/mL, P = .005), and increased IL-4 levels among patients with both asthma and HIE correlated with the increased IgE levels. In contrast, IL-13 levels were not elevated. Levels of Stat6 protein present in PBMCs did not differ in the patients and control subjects. Examination of Stat6 DNA-binding activity demonstrated no activation of IL-4 signaling in patients with either HIE or acute asthma. Interestingly, evidence for the presence of B cells that have already switched to IgE was seen in PBMCs of several patients with asthma or HIE. CONCLUSION: These results indicate that (1) IgE production in asthma and HIE usually is associated with elevated levels of IL-4, but not IL-13, in the peripheral blood; (2) the increased sera IL-4 levels in asthma and HIE are not sufficient to induce Stat6 activation in PBMCs; and (3) evidence of switch recombination to epsilon may be detected in isolated cases of elevated IgE. This implies that high levels of IgE in these patients either results from B cells that have already undergone class switching, from Ig class switching that is localized to target tissues, or both.

Adult↗
PubMed1997

Outcome analysis and cost assessment in immunologic disorders.

A number of novel biologic agents are being introduced to replace, enhance, or modulate immune responses in medical illnesses. The use of these therapies has become crucial in treating some of these diseases, yet there is relatively little available information about their cost-effectiveness. Two examples are presented. Interferon gamma, used in chronic granulomatous disease, costs about $140 for a 100-microg vial; yearly costs average $21840 per patient. Study data estimated a 69% to 76% reduction in serious illness with interferon gamma treatment; a reduced incidence of infections could cover drug costs. Intravenous immunoglobulin is used lifelong in antibody deficiency and clearly reduces the number of serious illnesses. Projected savings derive from fewer hospital admissions and reduced organ damage, but infusion costs vary widely because of the prices charged for the drug and infusion services.

Adjuvants, Immunologic↗
PubMed1997

Granulomatous disease in common variable immunodeficiency.

BACKGROUND: Granulomatous lesions are occasionally found in the lymphoid or solid organs of patients with common variable immunodeficiency. OBJECTIVE: To examine the clinical and immunologic conditions in patients with common variable immunodeficiency who have granulomas. DESIGN: Case series. SETTING: Large tertiary care medical center. PATIENTS: 17 hypogammaglobulinemic patients with common variable immunodeficiency whose organ or tissue biopsy samples contained noncaseating granulomas. MEASUREMENTS: Results of lymphocyte function tests. RESULTS: Eight of 17 patients had granulomas at some point before hypogammaglobulinemia was diagnosed. Sixteen of the 17 had deficient T-cell proliferation to mitogens. Although 14 patients received standard treatment with intravenous immunoglobulin, they have had substantial illness, including frequent autoimmune disease. CONCLUSIONS: Dysregulated T-cell function or macrophage activation may have been involved in formation of granulomas and increased illness in hypogammaglobulinemic patients with common variable immunodeficiency. Delay in recognition of antibody deficiency may have contributed to the severity of illness in these patients.

Adolescent↗
PubMed1996

B-cell proliferation and differentiation in common variable immunodeficiency patients produced by an antisense oligomer to the rev gene of HIV-1.

The immunostimulatory activity of a phosphorothioate oligodeoxynucleotide (27 mer) that is antisense to the rev gene of HIV-1 was studied on normal human lymphocytes and on cells from patients with common variable immunodeficiency (CVI). For peripheral blood mononuclear cells from nine normal individuals, the proliferation index (16.8 +/- 12.5) after anti-rev oligomer exposure was proportional to the percentage of peripheral B-cells (r = 0.76, P = 0.02). In five experiments, enriched B- or T-cell populations had proliferation indices of 47.2 +/- 32.9 and 2.4 +/- 1.9, respectively. The addition of T-cells to anti-rev oligomer treated B-cells had no effect (proliferation index = 47.5 +/- 38.1). After anti-rev oligomer stimulation, autoradiography, and counterstaining for B- and T-cell markers, all detectable [3H]thymidine uptake was by CD19-positive cells. Eight of the 14 CVI patients had a proliferation index and secreted levels of IgM and IgG comparable to cells from normal individuals. In contrast to normal cells, the direct correlation between proliferation of peripheral blood mononuclear cells and the percentage of peripheral B-cells was weak in samples from 13 CVI patients (r = 0.4, P = 0.2). These findings indicate that peripheral blood B-cells from about half of CVI patients proliferate and produce immunoglobulin after exposure to anti-rev oligomer. These data demonstrate that under the appropriate circumstances, B-cells of some CVI patients can proliferate and differentiate normally.

B-Lymphocytes↗
PubMed1996

Hodgkin's disease associated with IgA and IgG subclass deficiency.

Cases of cancer have been reported in patients with primary humoral immunodeficiency syndromes, mainly non-Hodgkin's lymphoma and gastric adenocarcinoma. Two cases of Hodgkin's disease complicating IgA and IgG subclass deficiency are reported. This association is probably more than mere coincidence. A review of the literature is presented.

Adult↗
PubMed1996

Encephalomyelitis in primary hypogammaglobulinaemia.

The neurological features of 13 patients with primary hypogammaglobulinaemia are described. Seven patients had X-linked agammaglobulinaemia (XLA) and six had common variable immunodeficiency (CVID). Three clinical pictures emerged: (i) a progressive myelopathy (one case); (ii) a myelopathy progressing to an encephalopathy (four cases); (iii) a pure encephalopathy (eight cases). In four patients the encephalopathy was temporarily reversible; the relationship of this to immunoglobulin therapy is unclear. Additional features occurred in some patients. Three had retinopathy interpreted as retinitis pigmentosa, in one of whom the retinopathy resolved. Two patients had a sensori-neural hearing loss and three had features of dermatomyositis; a variable pleocytosis was found in the CSF of nine patients. Imaging revealed atrophic changes in the cerebral hemispheres in eight cases. Ten patients have died, 1-11 years after the onset of the CNS manifestations, and in four autopsies were obtained. Two patients had encephalopathy, one with XLA had evidence of end-stage encephalitis and the other with CVID had a multi-focal leucoencephalopathy. The other two with XLA had leptomeningitis without evidence of encephalitis. Enteroviral infection is probably an important cause of neurological disease in these patients as CSF from seven patients was either positive by polymerase chain reaction (PCR) or by culture for enteroviruses. Other possible mechanisms are discussed.

Adolescent↗
PubMed1995

Allergy and immunology.

The actual role of cytokines in the pathogenesis of disease remains unknown but intensely investigated. Oral tolerance therapy has recently been applied to several human autoimmune diseases.

Allergy and Immunology↗
PubMed1995

Immunologic effects of low-dose polyethylene glycol-conjugated recombinant human interleukin-2 in common variable immunodeficiency.

Children or adults with the primary immunodeficiency disease, common variable immunodeficiency (CVI), have abnormally low levels of at least two of the three serum Ig isotypes. Although there appear to be intrinsic B cell defects, many have poor T cell proliferation and deficient secretion of IL-2, IL-4, IL-5 interferon-gamma, and B cell differentiation factor. Because the addition of various T cell factors can enhance Ig secretion in vitro in CVI, we have hypothesized that the B cells in this disease may be defective because they lack appropriate investigating the in vivo effects of recombinant IL-2 using a new biologic, polyethylene glycol-conjugated recombinant IL-2 (PEG-IL-2). In these studies, CVI patients were treated with weekly subcutaneous injections of PEG-IL-2. After 12 weeks, each patient had enhanced T cell proliferation, normal IL-2 production, boosted BCDF secretion, and B cells responsive to differentiation signals. During PEG-IL-2 treatment, four of five patients produced detectable serum antibody to keyhole limpet hemocyanin. These data suggest that CVI, which has the phenotype of B cell deficiency, may be caused by a lack of appropriate T cell signals for B cell maturation.

Adolescent↗
PubMed1994

Clinical and immunologic studies of common variable immunodeficiency.

Common variable immunodeficiency is a complex primary immuno-deficiency disease that has as its hallmark subnormal amounts of at least two of the three main serum immunoglobulin isotypes. About 45% of cases are diagnosed before the patients reach 21 years of age, but the time of diagnosis may be delayed until even the sixth or seventh decade of life. The main clinical manifestations include sinopulmonary or gastrointestinal infections, autoimmunity, and neoplasia. The molecular defects of this disease are unknown and may involve intrinsic B-cell or T-cell defects, or both. At present, the mainstay of treatment is intravenous immunoglobulin, but experimental methods have shown that other in vivo methods might ultimately be found to ameliorate this immune deficiency disease.

Child↗
PubMed1993

NIH conference. New insights into common variable immunodeficiency.

Common variable immunodeficiency (CVI) is a heterogenous immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, and various immunologic abnormalities. In addition to recurrent infections, patients with this syndrome also have an increased incidence of autoimmune disease and malignancy. Because the spectrum of associated diseases is broad, patients with CVI are seen by various medical specialists. This review discusses the pathogenesis, clinical manifestations, diagnosis, and treatment of CVI.

B-Lymphocytes↗
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↗