Distinct clinical and laboratory activity of two recombinant interleukin-2 preparations. (1/335)

Interleukin-2 (IL-2) is a potent lymphokine that activates natural killer cells, T cells, and other cells of the immune system. Several distinct recombinant human IL-2 preparations have shown antitumor activity, particularly for renal cell cancer and melanoma. Somewhat distinct immune and clinical effects have been noted when different IL-2 preparations have been tested clinically; however, the regimens and doses used were not identical. To compare these more directly, we have evaluated two clinical recombinant IL-2 preparations in vitro and in vivo using similar regimens and similar IUs of IL-2. We used the Food and Drug Administration-approved, commercially available Chiron IL-2 and the Hoffmann LaRoche (HLR) IL-2 supplied by the National Cancer Institute. Using equivalent IUs of IL-2, we noted quantitative differences in vitro and in vivo in the IL-2 activity of these two preparations. In patients receiving comparable IUs of the two preparations, HLR IL-2 induced the release of more soluble IL-2 receptor alpha into the serum than Chiron IL-2. In addition, more toxicities were noted in patients receiving 1.5 x 10(6) IU of HLR IL-2 than were seen in patients treated with 1.5 x 10(6) or even 4.5 x 10(6) IU of Chiron IL-2. These toxicities included fever, nausea and vomiting, and hepatic toxicity. In vitro proliferative assays using IL-2-dependent human and murine cell lines indicated that the IU of HLR IL-2 was more effective than Chiron IL-2 at inducing tritiated thymidine incorporation. Using flow cytometry, we also found quantitative differences in the ability of these two preparations to bind to IL-2 receptors. These findings indicate that approximately 3-6 IU of Chiron IL-2 are required to induce the same biological effect as 1 IU of HLR IL-2.  (+info)

Mice with early onset of death (EOD) due to lupus glomerulonephritis. (2/335)

Both MRL-lpr/lpr (lpr) and BXSB mice fall victim to autoimmune disease as a function of age. To combine their properties, brother-sister mating of (female lpr x male BXSB)F1 mice was done. Mice for mating were selected according to indicators of early onset of glomerulonephritis and subsequent early death (i.e., EOD). This mating was continued for more than 16 generations. The EOD mice thus established had homozygous H-2k/k, lpr/lpr, and possible yaa/- (in the case of males). The average life span of males was 83 days while that of females was 126 days. After 12 weeks of age, the majority (> 80%) of male EOD mice were characterized by the abnormality of urine due to glomerulonephritis. We then characterized how glomerulonephritis was evoked, especially in terms of expanding lymphocyte subsets in various immune organs. Similar to the case of parental lpr mice, the major expanding cells were CD4-8-B220+ TCRint cells in the immune organs and kidney. In addition, myeloid cells were found to infiltrate the kidney. This massive infiltration of both TCRint cells and myeloid cells might be responsible for the onset of acute glomerulonephritis. Even after more than 50 generations, these EOD mice still carry both lpr and yaa genes. These results suggest that EOD mice might be a very useful tool for the study of acute lupus glomerulonephritis which is evoked by the genetic abnormalities.  (+info)

Reactive plasmacytoses are expansions of plasmablasts retaining the capacity to differentiate into plasma cells. (3/335)

Circulating plasma cells in 10 cases of reactive plasmacytosis had a shared phenotype with early plasma cell (CD19(+) CD38(+) CD138(+) CD40(+) CD45(+) CD11a+ CD49e- CD56(-)). In most cases, a minor subpopulation of CD28(+) plasma cells was also detected. Reactive plasma cells were highly proliferative, suggesting the presence of circulating progenitors (plasmablasts). After CD138(+) plasma cell removal, highly proliferative CD138(-) plasmablasts differentiated into CD138(+) plasma cells within a few days. This differentiation, which was associated with increased CD38 and decreased HLA-DR expression, was further confirmed by a large increase in intracellular Ig content (associated with Ig secretion) and was concomitant with extensive secretion of interleukin-6 (IL-6). The addition of neutralizing anti-IL-6 and anti-CD126 (IL-6 receptor) monoclonal antibodies totally prevented Ig secretion and cell differentiation by inducing apoptosis of plasmablasts, which indicates that IL-6 is an essential survival factor for plasmablasts. This report provides the first characterization of normal plasmablasts and shows that their phenotype is not exactly that of multiple myeloma cells.  (+info)

Impaired expression of MHC class II molecules in response to interferon-gamma (IFN-gamma) on human thymoma neoplastic epithelial cells. (4/335)

A human thymoma is a neoplasm derived from the thymic epithelial cell, and is well known for its association with autoimmune diseases, especially myasthenia gravis. The neoplastic epithelial cells of thymoma clearly retain thymic epithelial functions, but the development of T cells in thymoma is somewhat impaired. In this study, we quantified by flow cytometry the in vitro expression of MHC molecules on neoplastic epithelial cells precultured with IFN-gamma. While MHC class I expression was comparable with that on normal thymic epithelial cells, the level of MHC class II molecules on neoplastic epithelial cells was lower than in controls, and also varied greatly from case to case. Additionally, there was a significant positive correlation between the expression level of MHC class II and the proportion of mature CD3+ cells in the CD4+CD8- subset. Thus, accumulation of CD3-CD4+CD8- cells in thymoma may result from impaired expression of the MHC class II molecules, suggesting that the function of the neoplastic epithelial cells might determine the maturation and the positively selected repertoire of T cells in thymomas.  (+info)

Lymphocytic colitis: a distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis. (5/335)

BACKGROUND AND AIMS: It is not known whether lymphocytic colitis and collagenous colitis represent different clinical entities or constitute part of a spectrum of disease. METHODS: Detailed clinical features and histological findings were compared in a large series of patients with confirmed lymphocytic and collagenous colitis. RESULTS: Histological diagnosis was confirmed in 96 patients with collagenous colitis and 80 with lymphocytic colitis. Twenty eight per cent of patients with collagenous colitis and 26% of patients with lymphocytic colitis had overlapping but less pronounced histological features. Both groups were equal in terms of age, use of aspirin and non-steroidal anti-inflammatory drugs, associated autoimmune conditions, arthritis, diarrhoea, and abdominal pain. The male:female ratio was 27:73 for collagenous colitis and 45:55 for lymphocytic colitis (p=0.013). Twenty five per cent of patients with collagenous colitis compared with 14% of patients with lymphocytic colitis were active smokers; only 8.3% of patients with collagenous colitis had stopped smoking compared with 23% of patients with lymphocytic colitis (p=0.013). Drug induced disease was suspected for ticlopidine (two collagenous colitis, four lymphocytic colitis) and flutamide (four lymphocytic colitis). Mean duration of symptoms before diagnosis was two months for lymphocytic colitis and four months for collagenous colitis. Overall prognosis was generally mild; 84% of patients with lymphocytic colitis and 74% of patients with collagenous colitis reported resolution or significant improvement (p=0.033). CONCLUSIONS: Collagenous and lymphocytic colitis are similar but not identical. Patients with lymphocytic colitis present somewhat earlier and are less likely to be active smokers. Symptoms are milder and more likely to disappear in lymphocytic colitis. Ticlopidine and flutamide should be added to the list of drugs inducing colitis.  (+info)

Effects of Helicobacter pylori eradication on the natural history of lymphocytic gastritis. (6/335)

BACKGROUND: Lymphocytic gastritis is characterised by an accumulation of lymphocytes in the surface epithelium of the stomach. Lymphocytic gastritis has been linked to coeliac disease and Helicobacter pylori infection. AIMS: To determine whether H pylori eradication leads to resolution of the lymphocytic infiltrate and clinical improvement in patients with lymphocytic gastritis, and to determine their HLA status. METHODS: The Leeds Dyspepsia Questionnaire (LDQ) was administered to 13 patients with lymphocytic gastritis. H pylori serology, (13)C urea breath test (UBT), and upper gastrointestinal endoscopy with sampling of the duodenum, antrum, and corpus were done in all cases and the HLA status was determined. Eleven patients had at least one positive test for H pylori. Patients with lymphocytic gastritis and H pylori infection were treated with a one week course of omeprazole, clarithromycin, and metronidazole. Gastric and duodenal intraepithelial lymphocyte (IEL) counts were performed, along with histological assessment of gastric and duodenal biopsies before and after H pylori eradication. RESULTS: Two months after treatment there was a significant reduction in gastric IEL counts in both antrum and corpus. There was no significant change in duodenal IEL counts before and after eradication. According to the Sydney grading there was significant improvement in corpus inflammation after eradication. The patients histologically H pylori positive before treatment became H pylori negative. Dyspepsia scores also improved significantly after treatment. CONCLUSIONS: H pylori eradication treatment in patients with lymphocytic gastritis causes significant improvement in the gastric IEL infiltrate, corpus inflammation, and dyspeptic symptoms. H pylori serology is frequently positive when histology and UBT are negative. Lymphocytic gastritis may represent a specific immune response to H pylori infection.  (+info)

Elevated levels of beta-chemokines in bronchoalveolar lavage fluid (BALF) of individuals infected with human T lymphotropic virus type-1 (HTLV-1). (7/335)

Pulmonary complications are known to develop in HTLV-1 carriers, including T lymphocytic alveolitis, and increased IL-2 receptor alpha (CD25)-bearing T cells have been found in BALF. Several chemokines may contribute to accumulation of T lymphocytes in the lungs of HTLV-1 carriers. Here, we compared the distribution of T lymphocyte subsets and beta-chemokines, such as macrophage inflammatory peptide-1alpha (MIP-1alpha), regulated on activation normal T expressed and secreted (RANTES), and macrophage chemoattractant protein-1 (MCP-1), in BALF and peripheral blood between HTLV-1 carriers and non-infected healthy normal subjects. Flow cytometric analysis with MoAbs to cell surface antigens was used to identify T lymphocyte subsets in BALF samples from HTLV-1 carriers (n = 13) and non-infected healthy controls (n = 10). The levels of different beta-chemokines were estimated by ELISA. High percentages of CD3+ cells, CD3 expressing HLA-DR antigen and CD3+CD25+ cells were detected in BALF of HTLV-1 carriers compared with non-infected controls. The concentration of MIP-1alpha in BALF of patients was significantly higher than in non-infected healthy controls and correlated well with the percentage of CD3+CD25+ cells. The level of RANTES in BALF was also significantly high in HTLV-1 carriers, but did not correlate with the percentage of CD3+CD25+ cells. On the other hand, the level of MCP-1 in BALF of HTLV-1 carriers was not different from that of controls. Our results suggest a possible interaction between activated T cells bearing CD25 and beta-chemokines, especially MIP-1alpha, which may contribute to the pulmonary involvement in HTLV-1 carriers.  (+info)

Reactive and neoplastic lymphocytes in human bone marrow: morphological, immunohistological, and molecular biological investigations on biopsy specimens. (8/335)

BACKGROUND: Slight, diffuse or focal lymphocyte proliferation is relatively common in bone marrow biopsy specimens. It may be impossible to determine whether this represents a reactive lymphocytosis or low grade non-Hodgkin lymphoma (NHL) on the basis of routine investigations alone. AIM: To investigate the supplementary use of molecular biological techniques in this situation. METHODS: 529 formalin fixed, paraffin embedded bone marrow biopsy specimens from the iliac crest were subjected to histological and immunohistochemical staining to determine the number and nature of the lymphocytes present. The cases were divided into three groups according to the lymphocyte count: normal (< 10% of nucleated bone marrow cells), slightly increased (10-30%), and markedly increased (> 30%). All of the last group could be diagnosed as NHL from the morphological findings alone. The clonality of rearrangements of the IgH and TCR gamma genes was investigated by polymerase chain reaction (PCR). RESULTS: Monoclonality was observed in 7.5% of the 372 cases with a normal lymphocyte count, in 50% of the cases with a modest increase in lymphocyte numbers (suggesting a diagnosis of low grade NHL not detected by immunostaining), and in 77% of the cases with markedly increased lymphocyte numbers. CONCLUSIONS: If PCR is used in addition to the immunohistochemical investigation of bone marrow biopsies, considerably more cases of NHL can be identified, making this of particular use in staging and detection of recurrences.  (+info)