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Biomedical subjects

M Ballow

Publications and source records attributed to M Ballow.

At least 37 records · Page 2Linked to original sources
PubMed1994

Cell-mediated immunity in allopurinol-induced hypersensitivity.

Allopurinol may induce severe hypersensitivity characterized by hepatitis, interstitial nephritis, and skin rash. The mechanisms for this hypersensitivity syndrome are incompletely elucidated. Immunologic studies were performed on tissue and peripheral blood lymphocytes from a patient with allopurinol hypersensitivity. Immunohistochemistry was performed on sections of the liver biopsy utilizing monoclonal antibodies for T and B lymphocytes. Peripheral blood lymphocyte immunophenotyping by flow cytometry and peripheral blood lymphocyte stimulation studies with either allopurinol or oxypurinol measured as tritiated thymidine uptake were performed in the hypersensitive patient and compared to a group of six patients treated with allopurinol without hypersensitivity and eight normal control patients. Additional single- and dual-color immunophenotyping by flow cytometry of oxypurinol-stimulated lymphocytes was performed in the hypersensitive patient and compared to normal controls. The liver biopsy demonstrated predominantly a T lymphocyte infiltrate. The number of peripheral blood lymphocytes expressing activation antigens was significantly greater in the hypersensitive patient compared to that of both control groups. Lymphocytes from the hypersensitive patient were moderately stimulated by allopurinol and markedly stimulated by oxypurinol compared to both control groups. Oxypurinol-stimulated lymphocytes from the hypersensitive patient demonstrated enhanced expression of activation antigens compared to unstimulated lymphocytes from this patient and normal controls. These studies suggest that cell-mediated immunity directed toward allopurinol and more importantly to its oxypurinol metabolite is involved in the pathogenesis of allopurinol-induced hypersensitivity.

Acute Disease↗
PubMed1993

The effects of retinoic acid on in vitro immunoglobulin synthesis by cord blood and adult peripheral blood mononuclear cells.

Retinoic acid (RA) has attracted considerable attention as an agent with a broad range of physiologic and metabolic effects. The importance of RA in the susceptibility of vitamin A-deficient animals and humans to infection is well known. Initial studies from our laboratory showed that RA augmented the IgM response of cord blood mononuclear cells (CBMC) at concentrations ranging from 10(-5) to 10(-8) M, but not adult peripheral blood mononuclear cells (PBMC), to formalinized Cowan I strain Staphylococcus aureus (SAC), a T-cell-dependent polyclonal B-cell activator. In the present study, we demonstrate that RA augments the SAC-stimulated IgG synthesis of adult PBMC at very low concentrations (10(-11) to 10(-13) M) indicating that adult PBMC is 10(4) to 10(6) times more responsive to the augmenting effects of RA than CBMC. To evaluate the differences in dose-response characteristics between CBMC and adult PBMC, co-mixture experiments between T- and B-cells of CBMC and adult PBMC were performed. The dose-response characteristics of the augmenting effects of RA for a particular Ig isotype were related to the responding B-cell population. The results of 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. When RA was added to CBMC stimulated by EBV, a T-cell-independent polyclonal activator, or to EBV-transformed B-cell clones, a small (twofold) augmentation in IgM synthesis was seen which suggested that RA may also have some direct effect on B-cells. However, if cord blood T-cells were preincubated with RA for 36 hr, washed, and added to cord blood B-cells with SAC, a 2.5- to 9-fold augmentation in IgM was obtained. These studies suggest that the principal mechanism(s) by which RA augments the Ig synthesis of SAC-stimulated cultures is mediated by the T-cell, or T-cell products, e.g., cytokines, which induces an increased proportion of B-cells to differentiate into Ig-secreting cells. RA may also have an effect, although minor, directly on B-cells. The differences in the dose-response characteristics between CBMC and adult PBMC appears to reside within the intrinsic capabilities of an Ig-producing B-cell subpopulation.

Adult↗
PubMed1993

Severe combined immunodeficiency of reduced severity due to homozygosity for an adenosine deaminase missense mutation (Arg253Pro).

Genetic deficiency of adenosine deaminase (ADA) results in varying degrees of immunodeficiency, including neonatal onset severe combined immunodeficiency (ADA- SCID) and milder, later onset immunodeficiency. We have determined the molecular basis of disease in a child from a consanguineous mating with ADA- SCID of clinically and biochemically reduced severity, diagnosed at 15 months of age and characterized by retention of more immunologic function than is typical of the fulminant neonatal onset type. The course was notable for an early predominance of bacterial infections and eosinophilia. In contrast to its absence in most ADA- SCIDs, residual ADA activity (1-2% of normal) could be detected in EBV-transformed B cells. Consistent with the increased residual ADA, excretion of the substrate deoxyadenosine and accumulation of the toxic metabolite deoxyATP were less than seen in ADA- SCID patients with fulminant disease. Sequence analysis of cDNA revealed a G853C transversion, predicting a substitution of proline for arginine at codon 253 (Arg253Pro). The parents were heterozygous and the child was homozygous for the mutation, as shown by sequence analysis of amplified genomic DNA. Transient expression of mutant cDNA in Cos cells revealed an electrophoretically abnormal, more negatively charged ADA with 1-2% of normal activity. These observations are consistent with replacement of positively charged arginine by proline, the lower accumulation of toxic metabolites, and the milder phenotype. By contrast, transient expression of a Gly216Arg mutant cDNA, associated, when homozygous, with neonatal onset ADA-SCID, did not reveal ADA activity. Mutations such as Arg253Pro, which retain residual activity of monomeric ADA, should be dominant for ameliorating the phenotype in patients carrying two different allelic mutations. Identification of additional similar mutations may be significant in evaluating the goals for and efficacy of current trials of gene and gene product replacement.

Adenosine Deaminase↗
PubMed1993

The effects of retinol on in vitro immunoglobulin synthesis by cord blood and adult peripheral blood mononuclear cells.

In this study we examined the effects of retinol (ROH), a metabolic precursor of retinoic acid (RA), on Staphylococcus aureus Cowan I (SAC)-induced immunoglobulin synthesis of cord blood mononuclear cells (CBMC) and adult peripheral blood mononuclear cells (PBMC). ROH augmented SAC-induced IgM synthesis of CBMC by 5.9 +/- 1.5-fold (n = 7, mean +/- s.d.), and IgG synthesis of adult PBMC by 16.3 +/- 5.1-fold (n = 3) at optimal concentrations of 10(-6) M and 10(-11) M, respectively. No augmenting effects could be demonstrated for the other immunoglobulin isotypes. Time-course studies showed that the synthesis of IgM by CBMC was accelerated with detectable immunoglobulin in supernatant fluids starting on day 3. ROH augmented immunoglobulin synthesis of CBMC stimulated by Epstein-Barr virus (EBV), a T cell-independent polyclonal activator, and of EBV-transformed B cell clones (2.5 +/- 0.2 and 4.1 +/- 1.5-fold increase, respectively), which suggests that ROH can act directly on B cells to enhance immunoglobulin synthesis. In contrast, when ROH was preincubated with cord blood T cells, washed and added to the B cell-enriched fraction with SAC, no increase (0.9-1.8-fold) in IgM synthesis was obtained. Thus, the principal mechanism(s) by which ROH augments immunoglobulin synthesis is by acting on B cells. This is in contrast to the immunoglobulin-enhancing effects of RA which is mediated by T cells, or T cell products, e.g. cytokine. Our studies suggest that RA and ROH may have different pathways of immunoglobulin-enhancing effects, perhaps mediated by different retinoid binding proteins resulting in gene activation and immunoglobulin synthesis.

Adult↗
PubMed1993

Are thymus-derived lymphocytes (T cells) defective in the nasopharyngeal and palatine tonsils of children?

The present study was conducted to evaluate the response of adenoidal T cells and B cells in the production of immunoglobulins. There appears to be a consistent inability of adenoidal T cells to turn on B cells to mature into immunoglobulin-secreting plasma cells. This phenomenon did not appear to be due to suppressor activity of adenoidal T cells because T cells from other sources appeared to effectively result in adenoidal B cell maturation, even in the presence of adenoidal T cells. Both tonsils and adenoids appear to have defective IL-2 production, in response to both mitogens and specific antigens. It is hypothesized that a cytokine(s) may be released in adenoids that downregulate IL-2 production and result in immune suppression in the adenoids of children with recurrent otitis media and chronic sinusitis.

Adenoidectomy↗
PubMed1991

Mechanisms of action of intravenous immunoglobulin therapy and potential use in autoimmune connective tissue diseases.

It has been almost 10 years since the observations on the efficacy of intravenous immunoglobulin (IVIG) in patients with autoimmune thrombocytopenic purpura. Over the next decade, IVIG was used in other types of autoimmune diseases. Much work has also been done on gaining a better understanding of the mechanism(s) by which IVIG exerts its effects in these autoimmune diseases. This review examines the proposed mechanisms of action of IVIG and establishes a rationale for the use of this type of therapy in systemic lupus erythematosus (SLE) and other autoimmune connective tissue disorders. Currently, only anecdotal reports are available on the treatment of SLE with IVIG. Nevertheless, studies thus far suggest that IVIG may be useful in selected SLE patients with cytopenias and cutaneous vasculitis and may have a steroid-sparing effect in patients with SLE and juvenile rheumatoid arthritis. In SLE patients with renal disease, it should be used cautiously because some patients have worsening of their renal function with IVIG infusions. These preliminary experiences suggest that multicenter controlled trials on the therapeutic use of IVIG in SLE and other connective tissue disorders would be important.

Animals↗
PubMed1991

The effects of retinoic acid on immunoglobulin synthesis by human cord blood mononuclear cells.

Derivatives of vitamin A have attracted considerable attention as agents which have immune potentiating properties and possibly tumor-suppressive effects. Recent investigations have shown that retinoic acid (RA) can augment immunoglobulin production of B-cell hybridomas from patients with immune deficiency. In this study we examined the ability of RA to modify the mitogen-induced polyclonal immunoglobulin synthesis of cord blood mononuclear cells (CBMC). RA in concentrations ranging from 10(-5) to 10(-7) M augmented IgM synthesis of CBMC in response to formalinized Cowans I strain Staphylococcus aureus (SAC) up to 45.6-fold which was greater at suboptimal responses to SAC. There were no changes in IgG or IgA synthesis and minimal effects on SAC-induced proliferative responses. RA did not produce similar changes in IgM synthesis of SAC-stimulated adult peripheral blood mononuclear cells (PBMC), and RA had no effect on the immunoglobulin synthesis of Epstein-Barr virus (EBV)-stimulated CBMC or adult PBMC. Time course studies showed that peak enhancement occurred when RA was added between 4 and 24 hr after culture initiation and required prior activation by SAC for augmentation of IgM synthesis. Cell separation experiments showed that prior incubation (18 hr) of an enriched T-cell fraction with RA enhanced the IgM synthesis of a T-cell-depleted B-cell fraction. These experiments and the findings that RA-induced augmentation of IgM production in response to SAC, but not to EBV suggest that the immunoregulatory effects of RA may be mediated by either T cells or T-cell products. Further studies will be necessary to understand the mechanism by which RA augments IgM synthesis of CBMC.

Adult↗
PubMed1990

Absent specific viral antibodies in patients with transient hypogammaglobulinemia of infancy.

Of 247 patients referred to the Pediatric Immunology Clinic, University of Connecticut Health Center, Farmington, Conn., for recurrent infections, 13 patients were found to have an abnormal delay in the onset of IgG synthesis and prolongation of the physiologic hypogammaglobulinemia of infancy. At first observation, their mean age was 10.6 months. All patients had abnormally low serum IgG levels (less than or equal to 2 SD for their age). The mean serum IgG level for our patient population was 270 +/- 81 mg/dl; the mean serum IgG level of the control group was 749 +/- 440 mg/dl. Clinically, these patients were first observed with recurrent otitis media, respiratory infections, bronchitis and/or asthma, and formula intolerance. Despite recurrent respiratory tract infections, specific antibodies to the respiratory viruses were absent in nine of 11 patients tested who were observed before 17 months of age. On follow-up, two of the 13 patients never developed specific antibodies to viral agents, although their serum IgG levels normalized; one patient became serology positive at the same time that the serum IgG normalized. In two patients, the serum IgG levels returned to within the normal range for age before the appearance of specific viral antibodies. In eight patients, the appearance of specific viral antibodies was detected before the serum IgG levels returned to normal. Five of these eight patients were treated for short periods (9 months) with replacement immune serum globulin (intramuscular) therapy and did clinically well. These observations suggest that replacement immune serum globulin for short periods of time does not appear to suppress the production of specific, naturally occurring antibodies and the resolution of the hypogammaglobulinemia.

Agammaglobulinemia↗
PubMed1989

Establishment and characterization of adenosine deaminase-deficient human T cell lines.

We have established long term cell lines from a patient with adenosine deaminase (ADA)-deficient severe combined immunodeficiency by stimulation of blood and bone marrow cells with PHA and IL-2 followed by transformation of the activated cells with the human retrovirus HTLV-I. Despite the absence of detectable T cells in the patients blood, cell lines grew that carried the phenotype of mature activated T cells. TJF-2, the line established from blood, was characterized in detail. The concentration of ADA in TJF-2 cells was less than 1% of normal (3.2 U vs 413.0 U). Studies with pharmacologic inhibitors of ADA suggest that the residual adenosine deaminating activity of TJF-2 is from an enzyme distinct from true ADA, a nonspecific aminohydrolyase. Growth of TJF-2 cells was hypersensitive to inhibition by 2'-deoxyadenosine compared to normal T cells (ID50, 55 microM vs greater than 1000 microM). Analysis of 2'-deoxyadenosine-challenged cells showed that TJF-2 cells accumulated significant levels of deoxyadenosine triphosphate, whereas normal T cells did not unless they were also incubated with the ADA inhibitor deoxycoformycin. Southern and Northern blot analysis of these cells revealed a grossly intact ADA gene that produced a normal size ADA mRNA. Yet, despite ADA deficiency, cells of the TJF-2 line were otherwise indistinguishable from HTLV-I-transformed T cells derived from normal donors with respect to dependence on exogenous IL-2 for growth, clonal rearrangement patterns of TCR beta-chain genes, response to PHA, and rapid restoration of cellular volume after hypotonic challenge. The TJF-2 line thus represents a unique HTLV-I-transformed human T cell line exhibiting ADA deficiency and its expected metabolic consequences.

Adenosine Deaminase↗
PubMed1989

Modulation of in vitro synthesis of immunoglobulin and the induction of suppressor activity by therapy with intravenous immune globulin.

Intravenous immune globulin has become an important modality of replacement therapy for children and adults with hypogammaglobulinemia or agammaglobulinemia. It is also evident that intravenous immune globulin is effective in patients with a variety of automimmune disorders. The present study was undertaken to evaluate the effects of intravenous immune globulin replacement therapy in patients with common variable hypogammaglobulinemia. We measured pokeweed mitogen-induced immunoglobulin synthesis of patients' peripheral blood mononuclear cells cocultured in equal numbers with normal subjects' lymphocytes to assess suppressor cell activity. The mean suppressor cell activity in coculture experiments at baseline of nine patients in the study was -16%. Suppressor activity was demonstrated in two of nine patients at baseline who received intravenous immune globulin therapy before initiation of the study. After intravenous immune globulin therapy at a low dose (100 to 200 mg/kg/mo), suppressor cell activity was demonstrated in all nine patients, which ranged from -63% to -100%. In five patients intravenous immune globulin therapy was discontinued for 4 months. There was a return to baseline levels, with suppressor activity ranging from -20% to -50%. On reinstitution of high-dose intravenous immune globulin therapy (300 to 400 mg/kg/mo), all patients except one again demonstrated increased suppressor cell activity. Cell separation and recombination cell culture experiments were performed. All patients had an intrinsic B cell defect before the initiation of therapy so that the effects of intravenous immune globulin therapy on B cell function could not be assessed. Combining normal B cells with the patient's T cell-enriched fraction showed marked suppression of pokeweed mitogen-induced immune globulin synthesis. This suppression was reversible by irradiation of the T cell fraction. Removal of CD8-positive T cells by cell sorting resulted in normal immunoglobulin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Agammaglobulinemia↗
PubMed1989

The uses of intravenous immune globulin in collagen vascular disorders.

Studies in our laboratory demonstrated that the long-term administration of intravenous immune serum globulin in patients with common variable hypogammaglobulinemia produced increased suppressor activity, which resulted in diminished in vitro B cell immunoglobulin synthesis. These studies suggested that intravenous immune globulin therapy might be a useful modality in altering immunoregulation in patients with collagen vascular autoimmune disease. In the present preliminary study, two groups of patients with collagen vascular disease were chosen: systemic lupus erythematosus and primary Sjögren's syndrome. Patients with systemic lupus erythematosus with mild clinical disease were chosen to minimize the risk of adverse effects on the disease process, particularly specific organ involvement (e.g., lupus nephritis). Each patient was used as his or her own clinical and laboratory control. Patients received 300 mg/kg of intravenous immune globulin every 4 weeks. As a whole the patient group did not experience any adverse effects from the intravenous immune globulin therapy. No clinical or laboratory changes were observed in one patient with systemic lupus erythematosus and one patient with Sjögren's syndrome. In the other patient with Sjögren's syndrome, there were subjective changes of improved well-being and increased energy levels without any objective changes in the sicca syndrome. There was a slight steroid-sparing effect (10 to 3 mg/day) but no effects on the sedimentation rate, the antinuclear antibody, or rheumatoid factor serologic studies. In a patient with steroid-dependent systemic lupus erythematosus, there was marked clinical improvement of the cutaneous vasculitis after the third infusion, with reduction in her oral steroid requirements from 25 to 7.5 mg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Isolation of monocyte-depleted and monocyte-rich fractions from human mononuclear cells.

Utilizing a recently reported characteristic of monocytes to aggregate in cold, a new procedure for obtaining monocyte-rich and monocyte-depleted mononuclear fractions from human blood is described. After aggregation in cold and adherence to plastic, a fraction containing 88% monocyte (LeuM3 CD14+) is obtained. After treating the supernatant, which separates from the aggregates, with a monocyte lysosomotropic agent (L-Leucine Methyl Ester), a fraction containing 0% monocyte (LeuM3 CD14+) and 88% lymphocytes (Leu4 CD3+ and Leu 12 CD19+) is obtained. In round-bottom culture wells, this monocyte-depleted fraction produced immunoglobulins in response to pokeweed mitogen (5,826 +/- 2,356 IgM micrograms/ml), to a degree not significantly different that that produced in the presence of monocytes (7,426 +/- 3,347 IgM micrograms/ml). This suggests the presence of cells in the lymphocyte fraction, that are not monocytes but are capable of antigen presenting.

Adult↗
PubMed1988

Malignant osteoporosis and defective immunoregulation.

The linkage between immune cells and the osteoclast has become partially understood in the laboratory, but the full spectrum of clinical disorders of this relationship remain to be elucidated. We report a 29-month-old girl with recurrent infections and multiple fractures. Immune evaluation showed normal quantitative serum immunoglobulins but absent antibodies to the respiratory viruses and tetanus toxoid and decreased in vitro polyclonal-induced immunoglobulin production. Further analysis in vitro with separated lymphocyte populations showed normal B cell function but markedly increased suppressor T cell activity. The bone evaluation showed diffuse osteopenia on x-ray. Serum calcium, phosphorus, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal for age. Urinary calcium excretion (24 h) was, however, two times normal. An iliac crest biopsy confirmed the presence of extreme osteopenia with normal mineralization and numerous small atypical osteoclasts resorbing the bone. No circulating plasma resorptive activity was demonstrated. Calcitonin therapy markedly diminished the patient's hypercalciuria. We speculate that this patient's increased bone resorption, decreased bone formation, and suppressor activity may be linked by a common pathway involving the abnormal function of immune cells. Since no similar constellation of findings has been previously reported, this case may represent a new congenital disorder: severe osteopenia associated with increased osteoclast activity in association with a defect in T cell immunoregulation.

Biopsy↗