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PubMed1989

Pharmacological activities of spirogermanium and other structurally related azaspiranes: effects on tumor cell and macrophage functions.

Spirogermanium is a germanium containing azaspirane which has been shown to have activity in experimental models of cancer and immune dysfunction. A series of analogs of the parent compound were synthesized and evaluated in a number of in vitro and in vivo biological assays to define the structure-activity relationships of this class of compounds relative to their potential therapeutic activities. In a colony-forming assay using HT-29 human colon carcinoma cells various analogs in which carbon replaced germanium (e.g. carbon) retained the potent cytotoxic activity in vitro seen with spirogermanium. Increased cytotoxic potency within the group of carbon containing analogs was directly related to increase in the length of the alkyl group(s) attached to the carbon atom opposite the azaspirane ring structure. DNA and protein synthesis by HT-29 cells was inhibited by these compounds. However, inhibition occurred only at supralethal concentrations or after long exposure times with the drug. None of the azaspiranes demonstrated in vivo anti-tumor activity against P388 leukemia or ADJ-PC6 plasmacytoma. The effect of these compounds on macrophage cell function was evaluated in vitro by their ability to modulate superoxide (O2-) production by macrophages. Spirogermanium inhibited the production of O2- by activated macrophages with an IC50 of 5 microM. Although macrophage viability did not appear to be decreased at the respective IC50 concentrations, the rank order potency for the analogs in the O2- production assay was directly proportional to that measured for their cytotoxic potency in the HT-29 colony formation assay. The results demonstrate that, within this class of compounds, (1) potent biological activity does not require the presence of germanium in the structure; (2) in vitro cytotoxic activity does not appear to be a direct result of the inhibition of macromolecular synthesis, and (3) macrophage function can be modulated in vitro at non-cytotoxic concentrations. These results are discussed in context with the reported anti-tumor activity of spirogermanium and the potential anti-arthritic and immunomodulatory activity of this class of compounds.

Animals↗
PubMed1986

Long-lasting deficit of functional T cell precursors in human bone marrow transplant recipients revealed by limiting dilution methods.

We have applied limiting dilution methods suitable for the estimation of mitogen-reactive helper (pHTL) and cytotoxic (pCTL) T cell frequencies to the analysis of immune function in patients 1 mo to 6 yr after allogeneic bone marrow transplantation (BMT). Although the majority of these patients have regained normal levels of Leu-3+ (helper) and Leu-2+ (killer/suppressor) cells by 6 to 12 mo after BMT as assessed by cytofluorimetry, the fraction of these cells that can function in limiting dilution cultures is substantially below normal levels in nearly all patients. Although some BMT patients eventually recover normal frequencies of pCTL and pHTL, values typically remain greatly depressed even in patients transplanted as many as 4 to 6 yr previously. In contrast, recovery of precursors able to proliferate (without expressing either helper or cytotoxic function) in response to phytohemagglutinin (PHA) and interleukin 2 occurs in many patients by 1 yr after transplant. In spite of the decreased frequency of functional precursor cells found after BMT, each precursor is capable of giving rise to the same amount of function at limiting dilutions as that produced by cells from normal controls. In many BMT patients, proliferation in conventional PHA-stimulated cultures returns to near-normal levels even though precursor frequencies remain low. The limiting dilution method is sensitive to residual immune dysfunction in BMT recipients not easily quantitated by other, more conventional techniques.

Adolescent↗
PubMed1986

Immunological abnormalities in intravenous drug abusers and relationship to the prolonged generalized lymphadenopathy syndrome in Italy.

The prolonged generalized lymphadenopathy syndrome (PGL) has been considered a prodromal condition to the Acquired immunodeficiency syndrome (AIDS), but the clinical, virological and immunological characteristics of patients who will develop AIDS are not known. We report on the immunological profile of intravenous drug abusers with or without PGL in Northeastern Italy. We found a reduction of lymphocyte-absolute numbers with reversal of the T4/T8 ratio and decreased Leu-11b+ cells. The response to mitogens and natural killer activity are compromised in PGL patients. Neutrophil function is reduced both in drug abusers with or without lymphadenopathy. The serological investigations revealed a high prevalence of antibodies against HTLV III and the Epstein-Barr viruses. The recognition of immune dysfunction in the intravenous drug abusers appears to be important since these patients develop AIDS and these abnormalities may precede AIDS.

AIDS-Related Complex↗
PubMedDate not supplied

Sarcoidosis: current concepts and case reports.

Sarcoidosis is a systemic granulomatous disease of unknown etiology associated with various immune alterations and biochemical changes. This article reports recent advances in the conceptualization of the immune dysfunction with emphasis on helper T-cell overactivity in the lungs. Because 90 percent of patients with sarcoidosis have intrathoracic disease, the mode of presentation, radiographic findings, clinical course, and treatment of pulmonary involvement are discussed. Case reports are used to demonstrate the typical course of the disease and generally favorable outcome of the vast majority of patients seen in the non-referral setting. A rare case of neurosarcoidosis with neuroendocrine features is presented.

Adult↗
PubMed1987

Effects of a synthetic extract (thymopentin) on the immune system of lepromatous leprosy patients.

Twenty three patients with lepromatous leprosy (LL) not in reactional phase and bacteriologically negative were evaluated for their immune status (T cell frequency and interferon gamma production). In six patients with deficits of both immune parameters, a synthetic thymic extract (TP-5) was administered. At the end of the treatment, a full recovery of immune dysfunction was observed. In the light of these results, the efficacy of TP-5 as an immunomodulating agent in LL patients is discussed.

Adjuvants, Immunologic↗
PubMed1987

Serum beta 2-microglobulin and human immunodeficiency virus infection.

Serum beta 2-microglobulin (beta 2-M) was measured in two prospectively evaluated groups of homosexual men in 1983 and 1985. Serum beta 2-M was raised in 64% of patients with HIV infection, but in only 6.7% of uninfected homosexuals. Depression of the total lymphocyte count was only clinically useful when it reached less than 1.0 X 10(9)/l. In further studies all patients with AIDS and AIDS-related complex (ARC) had raised levels of serum beta 2-M. Mean levels of beta 2-M did not differ between patients with persistent generalized lymphadenopathy (PGL) and asymptomatic HIV-infected patients. Raised serum levels of beta 2-M accompanied major immune dysfunction in HIV infection. Serum beta 2-M levels of greater than 3.0 mg/l in HIV-infected homosexual men were associated with progression to AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Parenteral nutrition in the management of gastrointestinal Kaposi's sarcoma in a patient with AIDS.

A patient with acquired immunodeficiency syndrome (AIDS) who required aggressive nutritional intervention via home parenteral nutrition therapy is described, and nutritional status, etiology and therapeutic management of AIDS-associated malnutrition, role of nutrition support, and factors for consideration in using parenteral nutrition in AIDS patients are discussed. Parenteral nutrition therapy was initiated in a 30-year-old AIDS patient with Kaposi's sarcoma lesions of the gastrointestinal tract because of rapid weight loss, low serum protein levels, and malnutrition. He had previously undergone a small-bowel resection and a jejunojejunostomy, and radiation and antineoplastic-drug therapy was planned. During parenteral nutrition therapy, the patient demonstrated increased physical strength and was able to care for himself during most of the time spent at home or in a long-term-care facility. Aggressive measures, including parenteral nutrition therapy, were discontinued 11 days before the patient's death. Complications of therapy included one episode of sepsis and a tear in the external catheter tubing. Malabsorption and diarrhea mainly caused by gastrointestinal disease, reduced food intake because of oral and esophageal infections, adverse effects from medication, and depression are factors that can contribute to AIDS-associated malnutrition. Also, hypermetabolism resulting from infections and fevers may contribute to malnutrition in AIDS. The extent to which this malnutrition affects the underlying immune dysfunction occurring in the syndrome and the response to other more direct drug therapies in AIDS is not known. Available methods for nutritional intervention are based on clinical experience and anecdotal reports. Because of gastrointestinal disease, an oral diet, supplements, and enteral tube feedings may not meet nutritional goals for an AIDS patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1986

Management of iron overload in dialysis patients.

Acquired hemosiderosis resulting from massive iron deposits in various organs, including heart, liver, and pancreas, may lead to architectural and functional disturbances of these organs. Even though iron overload can occur in nonuremic as well as in uremic individuals, the dialysis patient is at particular risk for developing hemosiderosis. Many dialysis patients receive exogenous iron from either oral iron therapy or blood transfusions. In addition, these patients seem to be at high risk for retaining iron. A diagnosis of excess iron deposition should be considered if the patient has unexplained cardiomyopathy, hepatic cirrhosis, proximal myopathy, diabetes mellitus, arthropathy, or immune dysfunction such as listeriosis. Several techniques are available for determining iron overload. Diagnostic tests include measuring serum ferritin levels, staining bone marrow preparations for excess iron, measuring tissue hemosiderin concentrations, magnetic resonance imaging, and the deferoxamine (DFO; Desferal) "challenge test." The simplest treatment for iron overload in nonuremic patients is removal of iron by venesection. However, in patients in whom venesection is not feasible, the chelating agent DFO can effectively remove excess iron. In the dialysis patient, DFO therapy can be combined with either dialysis or hemoperfusion to remove the iron-DFO complex that would otherwise be removed by the kidney. DFO therapy in the nondialyzed individual has proven to be successful, but before treatment, the benefits of the treatment must be weighed against possible adverse side effects such as cataracts, changes in color vision, and anaphylaxis. In the dialysis patient, indications for iron removal are less clearly defined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Humoral immunity in aged mice exposed to cadmium.

Twelve month old female BDF1 mice were exposed to cadmium chloride in the drinking water at concentrations ranging from 0 to 50 micrograms/mL cadmium for 26 days. The humoral immune response against sheep red blood cells, a T-lymphocyte dependent response, was evaluated during the last five days of the exposure period. The antibody response was not suppressed by cadmium exposure (P = 0.661). Weight gains (P = 0.205) and water consumption (P = 0.378) during the exposure period were also unaffected. These results indicate that the immunosuppressive effects of cadmium which have been documented in younger, more immunologically competent mice were masked by the natural age-related immunosuppression that was observed in this study. Immunotoxicological investigations in aged animal models appear to be a poor indicator of immune dysfunction in the general population.

Aging↗
PubMed1987

Immune responses in newly developed short-lived SAM mice. I. Age-associated early decline in immune activities of cultured spleen cells.

Using a cell culture system, age-associated changes in immune activities were investigated in newly developed, short-lived mouse strains. These SAM-P strains of mice (H-2k), which have a remarkably short life span (around 9 months) under conventional breeding conditions, showed an age-associated early decline in several immune functions, as compared to ordinary strains of AKR/J (H-2k) and C3H/He (H-2k) mice. Their antibody-forming capacity to T-independent antigen, DNP-Ficoll, and natural killer (NK) cell activity showed a markedly early onset of regression and a sharp decline from the level of control mice at 2 months of age. SAM-P strains of mice have a profound defect in antibody response to a T-dependent (TD) antigen, such as sheep red blood cells (SRBC), thus there was only a feeble antibody response to SRBC as early as the age of 2 months, and a negligible response at a later age. In contrast, the allo-specific cytotoxic T lymphocyte (CTL) response of the mice was as high as that of control mouse strains at 2 months of age and declined little until at least 6 months of age. The early age-related functional decline in the immune system of SAM-P mice suggests that these new inbred strains are appropriate models for investigating the age-related appearance of immune dysfunctions.

Aging↗
PubMed1985

Eczema in primary immune-deficiencies. Clues to the pathogenesis of atopic dermatitis with special reference to the Wiskott-Aldrich syndrome.

Eczema is one of the cutaneous manifestations of primary immune deficiencies. It may therefore serve as a model for the understanding of atopic dermatitis (AD) provided the eczema in the immune deficiency under consideration is a constant feature and is similar to AD. In the Wiskott-Aldrich syndrome the eczematous eruption is (i) a constant feature of the syndrome, (ii) indistinguishable from AD when diagnostic criteria for AD are used, and (iii) clears dramatically after a successful bone marrow graft, which suggests that immune dysfunction is directly involved in the pathogenesis of the eczema.

Bone Marrow Transplantation↗
PubMed1985

Cutaneous histiocytic proliferations.

The classification of histiocytic proliferations in the skin is confusing, largely due to faulty use of terms such as reticulum-cell sarcoma and reticulosis. Immunohistochemical staining procedures and ultrastructural studies have made it possible to differentiate the different cells of the mononuclear phagocyte system. The proliferations discussed here were those of the mononuclear phagocyte system that are associated with characteristic skin manifestations. They include proliferations of monocytes (acute monocytic leukemia), proliferations of tissue macrophages or histiocytes (histiocytic sarcoma and its disseminated form, malignant histiocytosis; familial histiocytoses; and multicentric reticulohistiocytosis), proliferations of Langerhans' cells (histiocytosis X), and proliferations of as yet undefined cells of the mononuclear phagocyte system (sinus histiocytosis with massive lymphadenopathy). Clinical features were presented, and special emphasis was placed on incidence, form, localization, histopathology, and marker profile of the proliferating cells in the skin lesions. The close relationship of the different entities was discussed, as was the importance of immune dysfunction.

Cell Division↗
PubMed1985

Mothers of infants with the acquired immunodeficiency syndrome. Evidence for both symptomatic and asymptomatic carriers.

Sixteen mothers of 22 infants with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex were followed up for evidence of clinical and immunologic abnormalities. With one exception, all mothers were clinically well at delivery but had evidence of immune dysfunction, with T-cell abnormalities and inverted T4/T8 ratios and/or elevation of serum immunoglobulin levels, particularly of IgG. During a follow-up period that averaged 30 months, AIDS developed in five of the mothers and AIDS-related complex in seven. Twelve subsequent pregnancies in 11 mothers produced four affected infants, suggesting that mothers can be persistently infected. Six mothers were delivered of subsequent infants who remain unaffected. These results suggest that the mothers are the likely source of infection in non-transfusion-associated cases of AIDS or AIDS-related complex in infants, that mothers have persistent immunologic abnormalities, and that they are at increased risk of developing AIDS or AIDS-related complex.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Immunoelectron microscopic application of monoclonal antibodies for identification of lymphocyte subsets bearing tubuloreticular inclusions or parallel tubular arrays.

Reactions of mouse monoclonal antibodies with T-cell, B-cell, or NK cell antigens were localized for electron microscopy by the formation of avidin-biotin-peroxidase complexes using direct or indirect labeling techniques. The techniques proved advantageous for identification of lymphocyte subsets bearing two different types of cytoplasmic structures: tubuloreticular inclusions (TRI) which have been related to interferon treatment or to diseases involving systemic immune dysfunctions, and parallel tubular arrays (PTA) which may be normal structures. Mononuclear cell samples were isolated from the peripheral blood of patients with systematic lupus erythematosus (SLE), acquired immunodeficiency syndrome (AIDS), or chronic hepatitis B (CHB). Results depended upon the fixation, the type of specific antibody, and the concentrations employed. Brief fixation in 1% glutaraldehyde/1% paraformaldehyde proved useful for stable preservation of both the inclusion fine structure and surface antigen activity, even after prolonged storage in buffer. The T-cell subset antigens (Leu-2a and Leu-3a) were more labile than the pan-T-cell antigen (Leu-1), the B-cell surface antigen (Leu-10), or the NK cell antigen (Leu-7). Localization of the former was improved by a two-step labeling procedure with primary and secondary antibodies. Both TRI and PTA were identified in T cells. Either type of inclusion could be found in the suppressor/cytotoxic or helper/inducer T-cell subsets. TRI also were found in a few anti-Leu-10 reactive cells. A crystalline form of PTA was identified in anti-Leu-1 and anti-Leu-7 reactive cells.

Acquired Immunodeficiency Syndrome↗
PubMed1980

Alterations in cyclic nucleotides and cyclase-specific activities in T lymphocytes of aging normal humans and patients with Down's syndrome.

The levels of cyclic adenosine 3'5'-monophosphate (cAMP) in unstimulated (resting) peripheral blood thymus-derived lymphocytes (T cells) from normal old humans and young-adult Down's syndrome (DS) patients were markedly decreased when compared with those of young normal humans. By contrast, the cyclic guanosine 3'5'-monophosphate (cGMP) in resting T cells from normal old and young-adult DS patients were greatly increased. The cAMP/cGMP ratios for unstimulated T cells therefore declined in normal aged and DS subjects. The specific activity of adenylate cyclase (ATP pyrophosphate-lyase[cycling]E.C.4.6.1.1) was elevated in T cells from the aged and DS groups, whereas that of guanylate cyclase (GTP pyrophosphate-lyase[cycling]E.C.4.6.1.2) decreased with age and in DS. These results denote the existence of substantial age-related biochemical changes in peripheral T cells. An imbalance in resting cyclic nucleotide levels and their generating enzymes in T cells of normal aging and DS subjects might contribute to the immune dysfunction occurring both with aging and in DS.

Adenylyl Cyclases↗
PubMed1981

The potential importance of soluble deoxynucleotidase activity in mediating deoxyadenosine toxicity in human lymphoblasts.

Deoxyadenosine and its nucleotides have been implicated in the pathogenesis of the immune dysfunction associated with a genetic deficiency of adenosine deaminase (ADA). We have previously shown that when ADA is blocked with a synthetic inhibitor, human T lymphoblastoid cell lines are more sensitive to deoxyadenosine toxicity, dephosphorylate deoxyadenosine nucleotides at a slower rate, and have much lower levels of ecto-5'-nucleotidase than most B cell lines. It seemed unlikely, however, that an enzyme on the outer surface of the lymphocyte plasma membrane could regulate intracellular deoxynucleotide catabolism. We now report that human lymphoblasts also contain a soluble deoxynucleotidase activity that is distinguishable from the plasma membrane enzyme by several criteria. In multiple human lymphoblastoid cell lines of varying origin and phenotype. soluble deoxynucleotidase correlated significantly (rs = 0.80, p < 0.001) with sensitivity to deoxyadenosine toxicity.

Adenosine Deaminase↗
PubMed1983

The effect of thymic humoral factor on intracellular lymphocyte cyclic AMP in alcoholic liver disease.

Intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) in resting peripheral blood mononuclear cells (PBM) were determined in patients with alcoholic hepatitis (AH), with compensated alcoholic cirrhosis, in alcoholic subjects without liver disease and in healthy controls. The effect of thymic humoral factor (THF), a polypeptide extract of the thymus, on T lymphocyte cAMP levels was also evaluated. Only PBM from patients with AH had significantly lower resting levels of cAMP when compared to the controls. The net increase in cAMP levels induced with THF were comparable for all patient and control groups. These findings indicate the presence of an immune dysfunction in patients with AH.

Cyclic AMP↗
PubMed1984

[Sinus histiocytosis with massive lymphadenopathy or the Destombes-Rosai-Dorfman disease in the Ivory Coast].

Sinusal histiocytosis with massive lymphadenopathy is a rare pathological entity since, as of 1983, only 200 cases have been published. Following the seminal description in 1965 by Destombes in Blacks, histological features of this disease were specified by Rosai and Dorfman in 1969 and 1972. We report three cases in young Ivorian subjects. The presenting finding is always chronically enlarged lymph nodes, but extranodal lesions are possible, most commonly involving the eye, salivary glands, upper respiratory tract, skin, bone, testis, and nervous system. Diagnosis can be ascertained only upon histologic examination of lymph node biopsy specimens which shows the three cardinal criteria, i.e. massive sinusal histiocytosis, lymphophagocytosis, and mature plasmocytosis. Although a few fatal cases have been reported, the disease usually runs a benign course, with exacerbations of variable duration. Great caution should therefore be taken in deciding upon management, particularly as regards corticosteroid therapy, radiotherapy or anticancer chemotherapy. Etiopathogeny of the disease is unsettled; there is general agreement as to the existence of a cellular immune dysfunction resulting in the lympho-histiocytic proliferation.

Adolescent↗