[Immunotherapy in allergic diseases. Evaluation of short-term efficacy of aluminum hydroxide-absorbed slow-release preparations]. / L'immunoterapia nelle malattie allergiche. Valutazione dell'efficacia a breve termine di preparati ritardo assorbiti su idrossido di alluminio.

Clinical and immunological changes after immunotherapy (ITS) for respiratory allergy were evaluated in 29 subjects during a one year follow up period. No adverse effects were noted with alum-absorbed allergen extracts. However, only patients receiving ITS for grass pollens demonstrated clinical improvement and blocking IgG increase as compared with those with multiple allergen sensitivity.

Basis for defective proliferation of peripheral blood T cells to anti-CD2 antibodies in primary Sjögren's syndrome.

Anti-CD2-induced T cell proliferation was analyzed in the peripheral blood samples of 31 primary and 8 secondary untreated Sjögren's syndrome patients. Anti-CD2-stimulated PBMC proliferation was very low in about one-third of primary Sjögren's syndrome samples, despite the number of CD2+ cells being similar in primary and secondary Sjögren's syndrome and normal PBMC samples. The depressed response to anti-CD2 was mainly found in anti-Ro+/La+ patients. Experiments on purified T cells demonstrated that a defect at the T cell level was responsible for the anti-CD2 unresponsiveness. Cell proliferation failure was associated with poor IL-2 and IL-2 receptor mRNA expression and, consequently, IL-2 and IL-2 receptor synthesis. Since defective anti-CD2-induced mitogenesis could be reversed by phorbol myristate acetate, but not calcium ionophore A23187, it is probably correlated with impaired protein kinase C activation. Comparison of anti-CD2-triggered PBMC proliferation in treated and untreated patients and a long-term study of nine patients showed that the defect is a stable characteristic in primary Sjögren's syndrome patients, but that it can be reversed by pharmacological immunosuppression.

Activation of cord T lymphocytes. II. Cellular and molecular analysis of the defective response induced by anti-CD3 monoclonal antibody.

Despite the fact that the percentage of circulating CD3-positive cells is similar in cord and adult blood, the proliferative response induced by anti-CD3 monoclonal antibody (mAb) was impaired in the majority of human cord peripheral blood mononuclear cell (PBMC) samples we tested. The cell proliferative defect was associated with low interleukin 2 (IL 2) gene expression and scant IL 2 production. However, interleukin 2 receptor was fully expressed at both the mRNA and protein levels. Such a finding is consistent with the observation that exogenous recombinant IL 2 is able to boost the anti-CD3-mediated response of cord PBMC. Furthermore, when anti-CD3 and phorbol myristate acetate (PMA) were added together, they exerted a very marked synergistic effect on both the proliferation of, and IL 2 production by, cord PBMC. The addition of allogeneic antigen presenting cells plus soluble anti-CD3 or Sepharose-coupled anti-CD3 mAb to the cord T cell cultures had no significant effect on proliferation, whereas both elicited good mitogenesis of adult T cells. Moreover, addition of exogenous recombinant interleukin 1 to anti-CD3-stimulated T cells failed to trigger any proliferation in either adult or cord samples. Since the combination of PMA and calcium ionophore A23187 is effective in triggering optimal proliferation of cord T cells, the defect would seem to be associated with a failure in transmembrane transduction of the activation signals provided by the anti-CD3 stimulus for the cord T cell.

Pharmacokinetics of vincristine in cancer patients treated with nifedipine.

The pharmacokinetics of vincristine (VCR) after an intravenous bolus dose of 2 mg were studied in patients with cancer with and without a concomitant treatment with the calcium-entry blocker nifedipine (NIF). VCR concentrations were determined by a sensitive radioimmunoassay. Pharmacokinetic data were analyzed by a nonlinear weighted least-square regression program (SAS-NLIN). A tri-exponential model fitted the raw data better than a bi-exponential model in five of 14 (35%) patients treated with VCR alone and in seven of 12 (58%) patients treated with VCR plus NIF (P = NS). The T1/2 alpha was shorter in NIF-treated patients, whereas the T1/2 gamma was longer in the NIF-treated group. The NIF-treated group showed an increase in the AUC O-infinity and AUC 1 to 96 hours, and a decrease in the AUC 0 to 1 hour. Total plasma clearance of VCR and 7-day urinary excretion of VCR was reduced in the NIF-treated patients. These data suggest that, when VCR is administered to NIF-treated patients with cancer, there is a decrease in VCR clearance from the body. Theoretically, a greater cytotoxicity may be anticipated.

[Bone marrow aplasia associated with ticlopidine treatment in a patient with idiopathic hypothyroidism]. / Aplasia midollare associata a trattamento con ticlopidina in soggetto con ipotiroidismo idiopatico.

A new case of severe bone-marrow aplasia due to Ticlopidine therapy is described. On the basis also of immunologic findings, the drug seems to be the cause of the hematologic syndrome. The presence of an idiopathic hypothyroidism may have favored the immune mediated reaction to the drug.

Anti-CD3 and anti-CD2-induced T-cell activation in primary Sjögren's syndrome.

Because T-cell dysfunctions have been reported in patients with primary Sjögren's syndrome (SS), peripheral blood mononuclear cell (PBMC) proliferation obtained with anti-CD3 and anti-CD2 monoclonal antibodies was evaluated in these patients. Anti-CD3-induced mitogenesis, which varied widely among the patients, was lower in subjects with evidence of anti-SSA and anti-SSB antibodies than in controls. Moreover, the anti-CD2-induced response was depressed in about half the patients and the nonresponders were mainly those with anti-SSA and anti-SSB antibodies. Phorbol myristate acetate, a protein kinase C activator, used alone or added to anti-CD3, induced greater proliferation in patients than in control PBMC. In contrast, exogenous recombinant interleukin 2 (rIL-2) did not significantly enhance the anti-CD2-induced response of patients' PBMC, as it did in normal PBMC. Peripheral blood and parotid T cells from a patient with well-defined primary SS and parotid enlargement also responded poorly to anti-CD2 stimulation. Exogenous rIL-2 restored T-cell proliferation only in the salivary gland cultures of this patient. The present findings suggest that there is a T-cell activation defect in subjects with primary SS, particularly in those with circulating anti-SSA and anti-SSB antibodies. In addition, the difference in the response to IL-2 of peripheral blood and parotid-infiltrating T cells would seem to indicate that T-cell subsets are differently distributed in the blood and inflammation site.

Defective natural killer cell activity in puerperal hyperprolactinemia.

Prolactin (PRL) influences immune reactivity in animals and in humans and both T-cell abnormalities and reduced natural killer (NK) cell activity have been reported in women with pathological hyperprolactinemia. To investigate further the possible interactions between PRL and the immune system in humans, we analysed T-cell phenotypes and NK cell activity in 15 women with physiological hyperprolactinemia of the puerperium and in 45 age-matched healthy normal cycling women. Puerperal women displayed a normal T-cell phenotype but a significant reduction in the number of Leu-7+ and Leu-11+ cells, associated with a decreased NK cell activity, as measured against K-562 target cells. There was a significant inverse correlation between the raised serum PRL levels and both the number of Leu-7+ cells and NK cell activity. These data confirm an important immunoregulatory role for PRL in humans and suggest a direct inhibitory effect of the chronically raised PRL concentrations on the maturation of NK cells.

Helper inducer T cells in the lungs of sarcoidosis patients. Analysis of their pathogenic and clinical significance.

Phenotypic analysis of helper CD4+TQ1- cell population, the major helper T-cell subset for B-cell responses, was carried out in BAL fluid of sarcoidosis patients. Most of the BAL CD4+ cells lacked TQ1 membrane antigen. A correlation between the number of helper CD4+TQ1- cells and IgM and IgA levels was observed in 27 sarcoidosis patients' BAL. A role of CD4+TQ1- cells in modulating lung B-cell immunoglobulin secretion in sarcoidosis was confirmed by the fact that BAL IgG level and helper T-cell number correlated well in patients with low-intensity alveolitis. Results showed an inverse correlation between symptom duration and BAL IgM levels and CD4+TQ1- cell number. The number of helper cells was above normal in patients who had symptoms for less than 12 months and within normal range in those who had symptoms for more than that. The pathogenic and clinical relevance of these data is discussed.

Activation of cord T lymphocytes. I. Evidence for a defective T cell mitogenesis induced through the CD2 molecule.

A study was carried out on cord blood T cell activation via the CD2-mediated pathway. Despite similar percentages of circulating CD3+ and CD2+ cells in adult and cord blood, the proliferation of cord PBMC to the anti-CD3 mAb and cord T cells to anti-CD2 mAb were defective. The T cell CD3-surface structure was normally able to control CD2-mediated activation, as its modulation by a non-mitogenic anti-CD3 mAb blocked cord PBMC proliferation induced by anti-CD2 mAb. CD2-stimulated cord T cells did not proliferate and did not produce a significant amount of IL-2 in culture, although they expressed the IL-2R. This observation was confirmed by the optimal proliferation of CD2-induced cord T cells when rIL-2 was added. Despite the alternative T cell activation pathway is monocyte-independent in adults, the defective cord T cell activation via the CD2 molecule could also be bypassed by the addition of PMA, small amounts of either autologous or allogeneic adult and cord AC or simply rIL-1 alone. Our findings provide evidence for an intrinsic functional defect in cord CD2-mediated T cell activation, which is linked to an impaired increase of free cytoplasmic calcium, as confirmed by the effectiveness of calcium ionophore A23187 in restoring a good CD2-induced cord T cell proliferation and by measurement of cellular calcium uptake after activation via the CD2 molecule. The characteristics of cord T cells revealed by this study recall the thymocyte functional pattern and may represent functional expression of the previously described phenotypic immaturity of cord T cells.

X-ring Turner's syndrome with combined immunodeficiency and selective gonadotropin defect.

A rare association of chromosomal, immunological and endocrine defects is described in a young woman with short stature, recurrent pulmonary infections and primary amenorrhea. Cytogenetic studies showed a 45, X karyotype in 65% of peripheral blood lymphocytes and 46,Xr(X) (p22q27) karyotype in the remaining 35%. Severe immunodeficiency was revealed by phenotypical and functional studies and a selective gonadotropin defect was disclosed by endocrinological investigations. An attempt is made to explain the coexistence of the three abnormal pictures.

5-Fluorouracil and isoprinosine in the treatment of advanced colorectal cancer. A limited phase I, II evaluation.

We studied the effects of 5-fluorouracil (5-FU) and isoprinosine (ISO) on 15 patients with previously untreated metastatic colorectal carcinoma. The patients were treated in a limited Phase I, II protocol. All patients received a fixed ISO dose of 4 g orally on days 1 through 5 of each cycle. Each cycle was repeated every 35 days. The first seven patients were treated with an initial 5-FU dose of 7.5 mg/kg intravenously (IV) on days 1 through 5, which was escalated to 11.5 mg/kg IV after the first course and to 13 mg/kg IV after the second course. The next eight patients were treated with an initial 5-FU dose of 11.5 mg/kg IV on days 1 through 5, which was escalated to 13 mg/kg IV on days 1 through 5. No major responses (complete or partial) were documented. Median survival for all evaluable patients was 33 weeks. Toxicity was predominantly gastrointestinal and hematologic and was considered moderate. Our data suggest that 5-FU and ISO, at the doses used, were ineffectual in the treatment of metastatic colorectal carcinoma.

Analysis of CD4-positive T cell subpopulation in sarcoidosis.

Double-labelling immunofluorescence analysis within the CD4+ cell subset was carried out in 27 bronchoalveolar lavage fluids and 11 peripheral blood samples of sarcoidosis patients with anti-TQ1, anti-2H4 and anti-4B4 monoclonal antibodies. Helper/inducer CD4+TQ1-/4B4+ cells were strongly increased in the lung and slightly, but significantly, decreased in the blood of sarcoidosis patients with respect to normal controls. No differences were found in the number of both lung and blood CD4+2H4+ cells between sarcoidosis patients and controls. The findings are further evidence for a compartmentalization of T cell subsets in sarcoidosis.

Distinct alpha-L-fucosidase isoenzyme profiles in human leukemic cells.

alpha-L-Fucosidase (EC 3.2.1.51; FUS) activity and isoenzyme characteristics were analyzed in normal lymphocytes, normal granulocytes (PMNs) and myeloid and lymphoid leukemic cells, (AML, AMMoL, ALL, CLL and CML). CLL lymphocytes had a lower mean specific activity than normal lymphocytes (2.5 v 4.0, p less than 0.05). ALL blasts had a higher mean specific activity compared to normal lymphocytes (9.7 v 4.0; p less than 0.001), CLL lymphocytes (9.7 v 2.5; p less than 0.001) and AML blasts (9.7 v 7.6 p = NS). Normal PMNs had a higher mean specific activity than normal lymphocytes (7.0 v 4.0 p less than 0.05) but similar activity when compared to CML cells or AML blasts. Blasts from AMMoL patients had higher activity than normal PMNs (9.0 v 7.0; p less than 0.05). The isoenzyme patterns of normal and leukemic granulocytes and lymphocytes were obtained by automated chromatofocusing on PBE-94 microcolumns with normal and leukemic lymphocyte lysates. With normal and leukemic lymphoid lysates two major isoenzyme components (B and A) were isolated. The isoenzyme pattern of PMN, AML, CML and AMMoL revealed 3 major peaks (B, A, I), totally different from that seen in lymphoid cells. The patterns of AML, CML and PMN appeared to be similar to each other; however, the isoenzyme pattern obtained from AMMoL cells could be distinguished from the others by a prominent I peak. Thus the FUS isoenzyme profile distinguishes the blasts of AMMoL from AML, and AMMoL and AML from ALL.

Thymic hormone modulation of CD38 (T10) antigen on human cord blood lymphocytes.

We studied the in vitro effect of three different thymic factors on the expression of CD38 (T10) antigen on cord T-lymphoid cell surface. The results showed that cord mononuclear cell populations contain variable percentages of CD38+ cells. The CD38 molecule was expressed on cord T and B lymphocyte and monocyte surfaces. Incubation with thymic agents induced a significant increases in the CD38+ cell percentage only in the samples with low CD38 antigen expression, and this modulation was mainly attributable to the T-cell subset. The effect seems to be specific and not correlated with the known high spontaneous DNA synthesis rate of cord mononuclear cells.

Phenotypic and functional abnormalities of T lymphocytes in pathological hyperprolactinemia.

The phenotype and function of T cells circulating in patients with pathological hyperprolactinemia were analyzed and compared to those in sex- and age-matched control subjects. Two-color immunofluorescence study revealed an increased number of CD4+ TQ1+ cells and the presence of phenotypically immature CD1+ T cells, also exhibiting transferrin surface receptor, in peripheral blood of the hyperprolactinemic patients. After chronic treatment with the dopamine agonist bromocriptine, T-cell abnormalities disappeared. In addition, some untreated patients showed enhanced T-cell suppressor activity in an in vitro pokeweed mitogen-driven B-cell transformation assay. These immunological findings confirm a link between neuroendocrine and immune systems in humans.

Immunoregulatory T cells in alcoholic liver disease: phenotypical dissection of circulating Leu3+/T4+ inducer T-lymphocytes.

Alcoholic liver disease (ALD) patients had normal absolute lymphocyte counts, increased percentage of Leu3+/T4+ cells (p less than 0.001) and raised T4/T8 ratio (p less than 0.01). Double-colour immunofluorescence analysis using isotype-specific goat anti-mouse immunoglobulins, fluorescein or rhodamine-conjugated, demonstrated that the rise in inducer (Leu3+/T4+) T-cells was almost entirely represented by an expanded population of T4+TQ1- and 5/9+ true helper lymphocytes. T4+ cells also expressed IL2 receptors, as detected by the anti-Tac monoclonal antibody (range 1-18%). On the other hand, the percentage of Leu3+/T4+ cells which bind the K562 cell-line or co-express NK markers on their surface, such as Leu7 (HNK-1), was within the normal range in the majority of ALD patients. Functional studies on patients' cultured total or B-enriched lymphocytes in a pokeweed-mitogen-driven B-cell differentiation assay showed an enhanced plasma cell generation even in unstimulated cultures. Co-culture experiments with normal enriched-B lymphocytes demonstrated that both irradiated and non-irradiated patient T cells led to an increased plasma cell generation. These findings indicate that helper T cells and B cells are all simultaneously activated in vivo, and that the suppressor T lymphocyte function is normal in ALD.

[Immuno-allergic reactions to cotrimoxazole in a hospital population]. / Reazioni immuno-allergiche a cotrimoxazolo in una popolazione ospedalizzata.

By a study of 87 oncologic hospitalized patients, affected by serious infectious complications and treated with high-dose antibiotic therapy including co-trimoxazole, the authors evaluate the allergic and immunologic reactions to the drug on clinical and serological basis and try to outline the pathogenic implicated mechanisms.