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PubMed1982

Studies on the effect of deoxyadenosine on deoxycoformycin-treated myeloid and lymphoid stem cells.

Adenosine deaminase (ADA) deficiency has been reported in association with severe combined immunodeficiency disease (SCID). The mechanism by which ADA deficiency causes immune dysfunction has been investigated in model systems to which the ADA inhibitor deoxycoformycin (dCf) had been added. Previously, we demonstrated that dCF did not prevent proliferation and differentiation of myeloid and lymphoid stem cells. We have now shown that addition of deoxyadenosine to dCf-containing cultures inhibited proliferation of hemopoietic stem cells. This inhibition was, however, equally effective for both normal myeloid and lymphoid stem cells. These findings suggest that other differences may exist between SCID myeloid and lymphoid stem cells to account for the relative sparing of myelopoiesis in SCID patients.

Adenosine Deaminase Inhibitors↗
PubMed1982

Treatment of severe aplastic anemia with antithymocyte globulin.

Eleven patients with acute-onset (less than 2 months), severe aplastic anemia were treated with antithymocyte globulin (ATG) at a total dose between 50 and 420 mg/kg. Median age was 27 (5-74) years. Two additional patients with chronic severe aplastic anemia received ATG but were excluded from analysis after development of bone marrow morphologic and cytogenetic abnormalities suggestive of acute leukemia. Of the 11 analyzed patients, 5 died within 6 months after initial ATG treatment. Six patients, or 54 percent, survived with a minimum follow-up of 24 months and the longest 48 months. Median survival is 42 months. All patients are transfusion-independent although none are completely normal, due to mild thrombocytopenia. The in vitro effect of ATG on pretreatment marrow CFUE was determined in 8 patients and concordance with clinical outcome was observed for only 3 patients. Three patients had no in vitro response and survived, and 2 patients had a positive in vitro response and died. Survival after ATG correlated with maximum percent decrease in absolute lymphocyte count during treatment. No significant correlation was determined for any other parameter. The mechanism of ATG action remains unknown but the clinical response suggests that immune dysfunction may play an important role in the development or prolongation of aplastic anemia, and that this abnormality may be reversible by ATG in some patients.

Acute Disease↗
PubMed1995

Death by destruction of will. Lest we forget.

This report describes an unexplained death following the collapse of will caused by resisted mechanical restraint in a 93-year-old woman with dementia. Clinical and experimental evidence is cited supporting resisted restraint as a significant noxious stimulus that can be linked to sudden death and immune dysfunction. This woman's story serves to remind us of the critical link between mind and body, and of the mortal consequences possible when we forget.

Aged↗
PubMed1993

Expression and function of CD5 and CD28 in patients with rheumatoid arthritis.

To assess the role of CD5 and CD28 in the pathogenesis of the decreased cellular immune function in patients with rheumatoid arthritis (RA) we analysed the expression and function of these T-cell surface molecules. The expression of CD5 as well as of CD28 in synovial and peripheral blood T cells was similar to that of control T cells. Monoclonal antibodies (mAb) directed at CD28 and CD5 were able to provide an accessory signal to anti-CD3 activated T cells both from the synovial fluid and from the peripheral blood. However, the proliferation induced by anti-CD3 mAb in conjunction with anti-CD5 or anti-CD28 mAb was always higher in peripheral blood (PB) T cells compared to the paired synovial fluid T cells. After simultaneous ligation of CD5 and CD28, proliferation was induced in the PB T cells. However, when compared to control PB T cells, this proliferation was significantly lower in the RA patients. Purified normal memory (CD45RO+) T cells proliferated less strongly than naive (CD45RA+) T cells, but no difference was observed between rheumatoid and normal memory T-cell proliferative responses. However, enriched PB CD45RA+ T cells from rheumatoid patients proliferated less vigorously to CD5 and CD28 ligation when compared to normal enriched CD45RA+ T cells. Synovial fluid (SF) T cells, which are mainly of the memory cell type, did not proliferate after simultaneous ligation of CD5 and CD28. This refractory state of synovial T cells could not be explained by a difference in the surface expression of CD5 or CD28. Our data suggest that the cellular immune dysfunction in the PB from rheumatoid patients may be due to a decreased responsiveness of the naive T-cell subset to accessory signals provided by CD5 and CD28. In addition, SF T cells appear hyporesponsive to stimulating signals provided through CD5 and CD28.

Antibodies, Monoclonal↗
PubMed1993

Expression cloning of multiple human cDNAs that complement the phenotypic defects of ataxia-telangiectasia group D fibroblasts.

Ataxia-telangiectasia (A-T) is an inherited human disease of unknown etiology associated with neurologic degeneration, immune dysfunction, cancer risk, and genetic instability. A-T cells are sensitive to ionizing radiation and radiomimetic drugs, offering the possibility of cloning A-T genes by phenotypic complementation. We have used this sensitivity to isolate the first human cDNAs reported to complement A-T cells in culture. Complementation group D A-T fibroblasts were transfected with an episomal vector-based human cDNA library, approximately 610,000 resultant transformants were treated with the radiomimetic drug streptonigrin-resistant, and nine unrelated cDNAs were recovered from 29 surviving streptonigrin-resistant clones. Five cDNAs were mapped, but none localized to 11q23, the site of A-T complementation group A and C loci. Four of the mapped cDNAs conferred mutagen resistance to A-T D fibroblasts on secondary transfection. One cDNA was identified as a fragment of dek, a gene involved in acute myeloid leukemia. The dek cDNA fragment and pCAT4.5, a 4.5-kb cDNA that mapped to 17p11, independently complemented three different phenotypic abnormalities of A-T D fibroblasts (mutagen sensitivity, hyper-recombination, and radio-resistant DNA synthesis). The pCAT4.5 cDNA did not complement the mutagen sensitivity of an A-T group C fibroblast line, suggesting that it represents a candidate disease gene for group D A-T. Our results indicate that phenotypic complementation alone is insufficient evidence to prove that a candidate cDNA is an A-T disease gene. The complementing cDNAs may represent previously uncharacterized genes that function in the same pathway as does the A-T gene product(s) in the regulation of cellular responses to DNA damage.

Ataxia Telangiectasia↗
PubMed1994

Antigen receptor-mediated transmembrane signaling in Wiskott-Aldrich syndrome.

The X-linked immunodeficiency Wiskott-Aldrich syndrome (WAS) is a condition that includes a deficient anti-polysaccharide Ab response. Recently, it has been suggested that B cells from patients with WAS show a defective calcium mobilization response upon engagement of sIgM. Because primarily EBV-transformed cells were used in these studies, we tested freshly isolated blood B cells for their calcium mobilization capability upon engagement of sIg and CD19. No significant differences in the calcium mobilization capability of CD20+ B cells of four individual WAS patients compared with capability in normal controls were found. Receptor desensitization as assessed by calcium mobilization inhibition also seemed to be intact. T cells were tested for their anti-CD3-induced calcium flux and, again, no abnormalities could be observed when compared with T cells from healthy individuals. We conclude that WAS B and T cells can be stimulated into a normal calcium mobilization response when their AgRs are cross-linked. It is highly improbable that the immune dysfunction observed in WAS patients is related to a direct disorder of their B and/or T cell AgRs.

Adolescent↗
PubMed1995

Functional heterogeneity of in vitro selected variants from an IgM-secreting rat immunocytoma.

A long-term tissue culture line of highly metastatic IR202 immunocytoma of LOU rats, and five of its clones (B4, C2, C4, C5, and D3) were established and studied comparatively. All such cells were similar in terms of: (i) light microscopic morphology, (ii) growth rate, (iii) saturation density, (iv) cell cycle progression, and (v) cell surface IgM, major histocompatibility complex (MHC) class I and class II antigen expression, but (vi) showed a non-homogeneous pattern of chromosomal constitution, with both numerical and structural abnormalities detected in variable proportions of the different cell variants. Moreover, IR202 variants exhibited a marked difference in the production of soluble factors which was closely associated with the ability of their supernatants to inhibit mitogen (affinity-purified goat F(ab')2 fragments specific for rat mu-chains (anti-mu antibody), lipopoly saccharide (LPS), or concanavalin A (ConA))-induced proliferation of normal splenic B and/or T lymphocytes. These results are consistent with the concept of intratumor heterogeneity and the ability of immunoglobulin-secreting tumors to induce severe immune dysfunction in host animals and humans.

Animals↗
PubMed1995

Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes.

Patients with end-stage renal disease present an immunodeficiency that paradoxically coexists with activation of most immunocompetent cells, and the roles of chronic uremia and maintenance dialysis are poorly understood. We determined circulating levels of IL-1 beta and IL-1Ra, TNF-alpha and its soluble receptors (TNF-sR55 and TNF-sR75), and activation markers of T cells (soluble CD25), B cells (soluble CD23), and monocytes (neopterin) in a large cohort of undialyzed patients at various stages of chronic renal failure and in dialyzed patients on maintenance hemodialysis or chronic peritoneal dialysis. The progression of uremia was associated with a gradual increase in soluble CD25, CD23, and especially neopterin levels. Although IL-1 beta could not be detected, IL-1Ra levels were significantly increased from the earliest stage of renal failure. Plasma levels of TNF-alpha, TNF-sR55, and TNF-sR75 progressed with the severity of renal failure and correlated with soluble CD25, CD23, and neopterin levels, whereas IL-1Ra levels correlated exclusively with TNF-sR55 levels. Compared with undialyzed patients, levels of IL-1 beta were higher in patients on maintenance hemodialysis, whereas those of IL-1Ra were lower and decreased further at the end of dialysis sessions. In contrast, both TNF-sR55 and TNF-sR75 levels were significantly higher than in undialyzed patients and increased further at the end of dialysis sessions in the absence of an increase of TNF-alpha. Such an imbalance between cytokines and their inhibitors may play a pivotal role in the multifaceted process of immune dysfunction.

B-Lymphocytes↗
PubMed1994

Relationship of HIV-1 provirus load, CD8+ CD11+ T cells and HIV-1 envelope-specific cytotoxic T lymphocytes in HIV-infected asymptomatic offients.

The course of human immunodeficiency virus (HIV) infection progresses from an acute infection, through a prolonged asymptomatic phase, to an immunocompromised state. Some of the possible mechanisms underlying immune dysfunction include decreased HIV-specific cytotoxic T lymphocyte (CTL) activity, increased suppressor T cells, and/or increased HIV load. However, no study has been carried out to correlate all these factors. In this study, 26 patients showed > 3 log DNA copy number/10(6) CD4+ T cells, and seven patients had < 3 log DNA copy/10(6) CD4+ T cells. Patients with higher virus load had greater than 15% (19-45%) CD8+ CD11+ T cells. HIV-1 envelope-specific, HLA-restricted CTL activity (> 10%) was observed in 11 of 25 asymptomatic patients, and the remaining 14 patients lacked CTL activity (< 10%) in bulk assay. Although CTL activity was undetectable in these individuals, there was no significant difference in the frequency of activated CTL and their precursors in limiting dilution analysis. The patients with undetectable CTL activity had a higher percentage of CD8+ CD11+ T cells and a higher HIV-1 DNA copy number/million CD4+ T cells. Each of these parameters were significantly correlated with CD4+ T-cell numbers. The inverse relationship of CD8+ CD11+ T cells and virus load with HIV-specific CTL activity observed in this study may be one of the underlying factors which determines the course of HIV infection.

CD11 Antigens↗
PubMed1994

[A case of severe measles encephalitis in a pregnant woman].

A 23-year-old woman in her 23rd week of gestation became febrile and then developed cutaneous eruption typical of measles on July 16, 1993. Two weeks prior to this, her 8-month-old daughter has developed measles. The woman became comatose in a few days and was admitted to our hospital where coma, flaccid paralysis of all four limbs and midbrain corectopia were apparent. High titers of anti-measles antibodies were found in the serum and cerebrospinal fluid. She received a 3-day course of pulse-dose intravenous methylprednisolone, however, without effect. Her consciousness gradually improved and after 1 month, subtle volitional movements were observed. However, fetal death was found and the fetus was removed by cesarean section. In MRI T2-weighted images, earlier in her illness, high signal intensity areas were scattered deeply in the cerebral white matter and the posterior limbs of the internal capsule. However, T1-weighted image was unremarkable. Marked, diffuse cerebral atrophy was noticed 3 months later by both CT and MRI, which was accompanied by wide spread high signal intensity areas around the lateral and fourth ventricles. Regarding the pathogenesis, there are two possibilities, i.e., her encephalitis was due to direct measles viral invasion into the CNS, or due to the autoimmune processes triggered by measles infection. Immune dysfunction known to occur during pregnancy might be responsible for the severity of encephalitis the patient suffered from. A recent increase in the number of adult measles infection might be an admonition that pregnant women are not exceptional to measles infection and that the infection could give rise to a severe form of measles encephalitis.

Adult↗
PubMed1994

Tumor necrosis factor alpha regulation of immunoglobulin secretion in trauma patients.

Major trauma-related immune dysfunction is observed at the time of augmented release of immunopathologic mediators. In the present study, T cell-dependent immunoglobulin (Ig) synthesis in peripheral blood mononuclear cell (PBMC) cultures from blunt trauma patients (N = 12, injury severity score (ISS) 27-50), was reduced by 30- > 90%. This coincided with significantly (P < 0.001-0.01) elevated secretion of the biologically active tumor necrosis factor alpha (TNF alpha). Modulation of the TNF alpha activity by anti-TNF alpha antibody (anti-TNF alpha Ab) led to dose-dependent alterations in IgG synthesis. IgG production increased (up to 300%) in cultures treated with 0.5-2 micrograms/ml of the antibody, where low levels of TNF alpha activity often persisted. However, immunoglobulin synthesis was eradicated in preparations exposed to higher concentrations (10 micrograms/ml) of anti-TNF alpha Ab and devoid of TNF alpha biological activity. The treatment with anti-TNF alpha Ab had no effect on mitogen- or alloantigen-induced PBMC proliferation. Thus, in severely traumatized patients, biological activities of endogenous TNF alpha may include modulation of T cell-dependent B lymphocyte function. Immunoregulatory potential of TNF alpha should, therefore, be considered in therapeutic strategies to abrogate its activity.

Adult↗
PubMed1994

[Pre- or neonatal corticotherapy: what are the long-term consequences?].

This paper is a literature overview on the potential long-term side effects of steroid therapy in the prenatal and neonatal period. Incomplete and transient suppression of adrenal function without growth impairment has been reported in prolonged treatment with steroids for bronchopulmonary dysplasia. There seems to be no secondary chronic immune dysfunction. There is evidence for deleterious effects on lung and brain development in experimental animals. In human preterm neonates, no pulmonary and cerebral secondary effects were observed after short prenatal steroid courses, but it is as yet uncertain whether this applies also to prolonged steroid therapy which requires further long-term investigations, including school performance.

Adrenal Cortex Hormones↗
PubMedDate not supplied

[The immune reactions of the cerebrospinal fluid in victims of gunshot wounds of the skull and brain in relation to the treatment procedure and outcome].

The paper shows the formation of immunopathological syndromes in the cerebrospinal fluid in the victims with gunshot wounds in relation to the policy and outcome of treatment. Suturing the dura mater during a primary surgical treatment should be regarded as a protective process to limit antigen release, the development of immunological paralysis and autoimmunization. Deaths are caused by the neurogenic immune dysfunction induced by the inadequate functioning of the psychoneuroimmunoendocrine connections of the whole body.

Afghanistan↗
PubMed1994

Alterations in Ca2+ signal transduction in critically ill surgical patients.

BACKGROUND: Despite improvements in supportive care and pharmacologic therapies, sepsis and related disorders such as systemic inflammatory response syndrome (SIRS) continue to be a leading cause of death in the intensive care unit. We hypothesized that immune dysfunction in this setting may in part be mediated at the level of early signal transduction in monocytes and neutrophils as manifested by changes in intracellular free Ca2+. METHODS: Monocytes and neutrophils were isolated from patients in the intensive care unit who met the criteria for SIRS and from normal volunteers. Cells were loaded with the Ca(2+)-sensitive fluorescent dye Indo-1 and stimulated with the chemotactic peptide f-Met-Leu-Phe (fMLP). Changes in intracellular calcium ion concentration were measured by flow cytometry. RESULTS: Patient monocytes exhibited a decreased Ca2+ flux (43% +/- 3.1%) as compared with normal monocytes (63% +/- 2.5%) (p < 0.05). Patient neutrophils also exhibited a decreased Ca2+ flux in response to fMLP of 58% +/- 3.7% versus 69.3% +/- 3.1% for normal neutrophils (p < 0.05). Incubation of patient cells in normal plasma reversed this dysfunction and showed an improved Ca2+ flux to 60% +/- 2.7% for monocytes and 71% +/- 3.7% for neutrophils (p < 0.05). Conversely, calcium flux was decreased in both normal monocytes (42.3% +/- 3.1%) and normal neutrophils (55.4% +/- 3.8%) after incubation in SIRS patient plasma (p < 0.05). Incubation of normal monocytes and neutrophils in interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor, or lipopolysaccharide did not show a statistically significant alteration in calcium flux in response to fMLP. CONCLUSIONS: Patients with SIRS exhibit alterations in early signal transduction after stimulation with fMLP in monocytes and neutrophils. This effect appears to be mediated by a soluble factor because the defect in SIRS patient cells can be reversed by incubation in normal plasma and normal cells appear to acquire this defect after incubation in patient plasma. Further studies are underway to identify the factor or factors responsible for this functional defect.

Adult↗
PubMed1994

Adult onset immunodeficiency caused by inherited adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency is identified here as a cause of adult onset immunodeficiency. Two sisters who noted recurrent, predominantly chest infections in their twenties were found in their thirties to have CD4+ lymphopenia and lymphocyte ADA activity of approximately 5% of the lower limit of normal. Immune function, measured by proliferation of PBMCs in vitro to mitogens and specific Ags, was impaired. Inheritance of a polymorphic marker showed that both patients were heterozygous at the ADA locus. In the paternal allele there was a deletion resulting from homologous recombination between two alu elements that normally flank the first exon and the polymorphic marker. The recombination site was distinct from that in similar deletions described in two infants having severe combined immunodeficiency. This allele is predicted to result in a null phenotype. In the mutant allele inherited from the mother, a C to T transition in a CpG dinucleotide changed the codon for arginine 211, which lies in a conserved sequence close to the active site, to that for cysteine. This mutation has been observed previously in a child in whom the other allele was also a null mutation, but who was diagnosed as having partial ADA deficiency because immune function was apparently normal. The late onset of immunodeficiency in our patients suggests that immune function in children with partial ADA deficiency may deteriorate with time and that ADA deficiency should be regarded as a possible cause of adult onset immune dysfunction of unknown etiology.

Adenosine Deaminase↗
PubMed1994

HIV infection in the parturient.

As the incidence of AIDS continues to increase in the female population, there will be more cases of HIV-positive women in the obstetric suite requiring anesthesia services. Many may be asymptomatic, but there will be patients with active opportunistic infections and malignancies who may or may not have been treated. The impact of both the disease AIDS and the drugs used to treat it on anesthetic technique can be significant. Hematological, neurological, respiratory, and immune dysfunction can be expected in a significant proportion of these women. Universal precautions should be utilized for all deliveries regardless of known HIV status. The ubiquitous presence of blood and amniotic fluid during labor and delivery mandate the use of gloves, gowns, and eye protection in the obstetric suite to avoid transmission of HIV to health care workers. Transmission to the newborn during delivery can be minimized by avoidance of skin and mucous membrane trauma and careful removal of secretions and blood. Infected parturients should be carefully assessed for neurological and hematological dysfunction prior to the use of regional anesthesia, and anesthesiologists must be aware of the potential toxicities of therapeutic drug treatment and their impact on anesthesia.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Interactions of human immunodeficiency virus infection and pregnancy.

OBJECTIVE: To assess the influence of human immunodeficiency virus (HIV) infection on pregnancy outcome and the effect of pregnancy on the short-term course of HIV infection. METHODS: Pregnant women with identified risk factors for HIV infection but without AIDS were tested serologically for HIV antibodies. Seropositive women were compared to seronegative patients with similar risk factors and demographic characteristics at enrollment, at delivery, and 6-8 weeks postpartum. One hundred one seropositive and 97 seronegative subjects were evaluated for symptoms or physical manifestations of HIV infection; evidence of immune dysfunction; historical, physical, or laboratory evidence of related infections; and maternal and neonatal outcome. Both groups were compared to the entire obstetric population delivering at the University of Maryland Hospital during 1 year. RESULTS: There was a significant reduction in reported risk behaviors in both groups during pregnancy as compared to the period before pregnancy (P < .001). The majority of women in both groups were asymptomatic, but seropositive women were more likely to have a history or physical evidence of condylomata (13 versus 4%; P < .05) and higher temperatures on admission to the labor suite (98.6 +/- 1.0 versus 98.3 +/- 0.8F; P = .02). Seropositive women were not at greater risk for antepartum medical complications. Only one woman developed an AIDS-defining opportunistic infection. Although hematologic indices in seropositive women were abnormal, these did not progress over the course of pregnancy. At delivery, seropositive women were more likely to receive antibiotics (25 versus 10%; P = .006) and less likely to have an episiotomy (25 versus 40%; P = .03), but obstetric outcome was unaffected. Neonatal status was independent of antibody status. CONCLUSION: Our findings support a growing body of evidence that pregnancy has no discernible effect on the early progression of HIV disease in asymptomatic women, and infection does not influence perinatal outcome.

Adult↗
PubMed1993

Enteric parasites and antibodies to human immunodeficiency virus in homosexual men with diarrhea.

A total of 260 homosexual men with gastrointestinal illness, 77 of them with AIDS, were selected for a study of the prevalence of enteric parasites and its association with antibodies against human immuno-deficiency virus (HIV). HIV antibodies were demonstrated in the sera of all the AIDS patients and in 111 (60.7%) of the non-AIDS patients. In the AIDS patients, 39 (50.6%) of them had enteric parasites and 33 had a single parasite recorded. By contrast, 49 (26.8%) of the non-AIDS patients had enteric protozoa detected and 25 of them had a single parasite. The protozoa most frequently recovered from the non-AIDS and the AIDS patients were Endolimax nana and Cryptosporidium, respectively. These findings indicate that immune dysfunction in AIDS patients can enhance the colonization of parasites and alter the spectrum of the intestinal flora.

Acquired Immunodeficiency Syndrome↗