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Biomedical subjects

F Caligaris-Cappio

Publications and source records attributed to F Caligaris-Cappio.

At least 37 records · Page 2Linked to original sources
PubMed1997

Relationship between autoimmunity and immunodeficiency in CLL.

B-CLL patients have a high prevalence of autoimmune phenomena due to polyclonal autoantibodies (Abs) restricted to blood cell self-antigens (Ag) and progressively develop a severe hypogammaglobulinemia. Autoimmunity and immunodeficiency have been related to B-CLL biological properties and cellular origin. Three major issues have emerged: 1) the relevance of B cell receptor abnormalities. More specifically, the importance of the defective expression of CD79b which may explain the faint to virtually undetectable amounts of monoclonal sig, the anomalous signal transduction and the failure to present antigens (Ag). 2) the possibility that the relentless accumulation of B-CLL cells is also under microenvironmental influences. These are brought about by the interplay of cytokines produced through cell/cell contacts among malignant B cells, macrophages and T cells. 3) the view that the very properties of accumulating anergic self-reactive CD5+ B lymphocytes may provide a bridge between autoimmunity and immune incompetence. CD5+ malignant B cells influence the cytokine production by T cells, but are inefficient Ag presenting cells (APC). As such they are a hurdle to the production of normal Ab. However, by stimulating in vitro the CD40 molecule on the membrane of CLL cell with the CD40 ligand the inefficient APC is turned into an efficient APC. In vivo, such an activation may conceivably occur in specific environments like the spleen and favour the production by normal residual B-cells of polyclonal autoAb against red cell or platelet self Ag.

Animals↗
PubMed1997

Fludarabine ability to down-regulate Bcl-2 gene product in CD5+ leukaemic B cells: in vitro/in vivo correlations.

CD5+ B-chronic lymphocytic leukaemia (B-CLL) and mantle cell lymphoma (MCL) in leukaemic phase are characterized by defects in cell death induction that primarily involves the Bcl-2 family of genes. Fludarabine (9-beta-D-arabinofuranosyl-2-fluoradenine, F-ara-A) is a potent inducer of apoptosis in CLL cells. This study aimed to determine whether F-ara-A-induced apoptosis might be related to Bcl-2 modifications and to evaluate in vitro/in vivo correlations. Peripheral blood lymphocytes from eight B-CLL and four leukaemic MCL were cultured in the presence of different concentrations of F-ara-A +/- methylprednisolone (MP). F-ara-A down-regulated the expression of Bcl-2 in 5/12 cases. mRNA down-regulation was maximal at 48 h; protein down-regulation was prominent after 48 h. Both events were dose-dependent. The amount of apoptosis was significantly higher in the samples treated with F-ara-A than in those exposed to MP alone. In the seven remaining cases, no Bcl-2 down-regulation was observed after exposure to F-ara-A and the degree of F-ara-A-induced apoptosis overlapped that induced by MP. The in vivo outcome after treatment with three to six courses of F-ara-A was evaluable in 10 patients: 4/5 cases, whose cells had shown in vitro Bcl-2 down-regulation and prominent apoptosis after exposure to F-ara-A, had a complete response (CR) and a partial response (PR) was observed in the remaining patient. Of the five patients whose cells had shown no in vitro Bcl-2 modulation after exposure to F-ara-A, two had a PR, but the other three did not show any in vivo clinical response.

Aged↗
PubMed1997

Autoimmune phenomena and hepatitis C virus in lymphoproliferative and connective tissue disorders.

Since hepatitis C virus (HCV) infection is frequently detected in patients with lymphoproliferative or autoimmune disorders and since the virus may infect lymphocytes, the question is raised whether malignant transformation and autoimmune manifestations in the presence of HCV are HCV-related or merely fortuitous. A close association has been firmly established between HCV infection and essential type II mixed cryoglobulinemia (ECM), an indolent lymphoproliferative disorder characterized by cryoprecipitable immune-complexes (IC) that may evolve into classical non Hodgkin's lymphomas (NHL) retaining the ability to produce cryoprecipitable rheumatoid factor (RF). It is reasonable to consider HCV as one cofactor in lymphomagenesis, even if the precise pathogenetic relationship between HCV infection, the chronic presence of cryoprecipitable IC and the development of NHL have not been established yet. Several epidemiological studies have documented the ability of chronic HCV infection to favour the production of autoAb. It is not clear why only some patients with HCV infection develop autoAb, nor why the most frequent autoAb detected in HCV-infected subjects are cryoglobulins. Though a high prevalence of anti-HCV has been found in a variety of systemic and organ-specific autoimmune diseases, it is likely that several of these associations are fortuitous with the notable exception of membranoproliferative glomerulonephritis. As HCV can provoke or exacerbate inflammatory signs and cause the production of RF, it is reasonable to suspect that HCV infection may be able to trigger the development of some connective tissue diseases or to exacerbate their clinical course. Nonetheless, it is clinically prudent to conclude that the pathogenetic relationships of Sjögren syndrome, rheumatoid arthritis and polyarthritis with HCV infection are more likely to be regarded as mediated via the intermediate development of ECM.

Animals↗
PubMed1997

Increased nitric oxide in exhaled air of patients with systemic lupus erythematosus.

OBJECTIVE: In experimental animals, elevated nitric oxide (NO) production has been implicated in the pathogenesis of a lupus-like syndrome. Abnormalities of lung function tests are reported in a high proportion of patients with systemic lupus erythematosus (SLE). We investigated whether NO output in exhaled air might be increased in patients with SLE and whether it is related to disease activity and to respiratory function abnormalities. METHODS: Lung volume, maximal expiratory flow at 50 and 25% of vital capacity (MEF50 and MEF25), diffusion coefficient for carbon monoxide (KCO), and NO in the exhaled air were measured in 27 outpatients with SLE (23 women, age 39.2 +/- 16.3). NO in exhaled air was also measured in 30 healthy control subjects. Disease activity was assessed by the European Consensus Lupus Activity Measurement (ECLAM) scoring system. RESULTS: Mean values of peak concentrations of NO exhaled air were 64.8 +/- 27.9 parts per billion (ppb) in patients and 31.6 +/- 7.7 ppb in controls, p < 0.001. Peak NO concentration was directly related to ECLAM activity score (p < 0.05) and inversely related to MEF25 (p < 0.05). CONCLUSION: NO in exhaled air is significantly increased and correlated with disease activity in patients with SLE. Whether increased NO output depends on respiratory tract inflammation, as the relationship with MEF25 may suggest, or on circulating cytokines produced elsewhere remains to be investigated.

Adolescent↗
PubMed1996

B cells and their fate in health and disease.

A recent meeting discussed advances in our understanding of germinal centers, B-cell malignancies and B-cell signal transduction. Such developments have yielded a more refined view of the role of B-cells in health and disease.

B-Lymphocytes↗
PubMed1996

High prevalence of autoimmune phenomena in hepatitis C virus antibody positive patients with lymphoproliferative and connective tissue disorders.

The aim of this study was to investigate whether hepatitis C virus (HCV) may perturb the immune system towards autoreactivity. We studied the relationship between the prevalence of anti-HCV and the presence of laboratory and/or clinical autoimmune features in 300 patients: lymphoid malignancies (167) and autoimmune disorders (connective tissue diseases 100; idiopathic thrombocytopenic purpura (ITP) 33). As a control, hepatitis B surface antigen (HBV) and anti-hepatitis B core antigen (anti-HBc) were related to the same parameters. Anti-HCV and anti-HBV were detected in 68/300 (22.6%) and 70/300 (24.6%) patients, respectively. HCV prevalence was 18% in lymphoproliferative disorders (anti-HBc 28.1%) and 26% in connective tissue disease (anti-HBc 16.3%). Among ITP cases, 12/33 (36.4%) were anti-HCV+ and 10/33 (30.3%) anti-HBc+. In 24/30 (80%) anti-HCV+ patients with lymphoproliferative disorders at least one serologic or clinical autoimmune abnormality was detected. To the contrary, only 10/45 (22.2%) anti-HBc+ patients with lymphoproliferative disorders had at least one serologic or clinical abnormality (P < 0.0001). A statistically significant correlation was observed between HCV prevalence and the number of autoimmune alterations in both lymphoproliferative and connective tissue disorders, which was not found for anti-HBc. These data suggest that HCV may skew the immune system toward the production of autoantibodies and also support the possibility that some cases of ITP may be linked to both HCV and HBV infection.

Adolescent↗
PubMed1996

In leukaemic CD5+ B cells the expression of BCL-2 gene family is shifted toward protection from apoptosis.

This study further investigated the mechanisms that control apoptosis in leukaemic CD5+ B cells, and focused on the Bcl-2 gene family. The pattern of expression of Bcl-2, Bcl-xL, Bcl-xS and Bax genes, selected because of their interrelated role in the control of apoptosis, was analysed in a series of CD5+ B-cell chronic lymphoid leukaemias. Cells from 34 patients with chronic lymphoid leukaemia of B-cell type (23 B-chronic lymphocytic leukaemia (B-CLL) and 11 mantle cell lymphoma (MCL) in leukaemic phase) were investigated. High levels of Bcl-2 mRNA were observed by Northern blot and high levels of Bcl-2 protein were detected by cytofluorograph analysis with a specific monoclonal antibody (MAb) in all cases. Strong Bax expression was detected by RT-PCR in 20/23 B-CLL cases; Bax was also observed in 8/11 MCL in leukaemic phase with variable degree of intensity. In both B-CLL and MCL samples the presence of Bax protein was confirmed by cytofluorograph analysis. RT-PCR detected high levels of Bcl-xL in 16/23 B-CLL and in 8/11 MCL in leukaemic phase, whereas Bcl-xS was detectable in low to trace amounts respectively in 13/23 B-CLL and in 6/11 MCL in leukaemic phase. According to the functional role of Bcl-2, Bcl-xL, Bcl-xS and Bax, these data indicate that the pattern of Bcl-2 family genes expression in leukaemic CD5+ B cells is skewed toward prevention of apoptosis and may thus favour the relentless accumulation of CD5+ leukaemic B cells.

Apoptosis↗
PubMed1996

Respiratory function in systemic lupus erythematosus: relation with activity and severity.

The objective of this study was to examine the relation between respiratory function tests, disease activity and disease severity in ambulatory patients with systemic lupus erythematosus (SLE) who did not present with overt respiratory problems. Lung volumes, maximal expiratory flows at 50% and 25% of vital capacity (MEF50 and MEF25), bronchial threshold to methacholine (PD15FEV1), transfer factor CO (KCO) were measured in 24 consecutive SLE outpatients (22 women, age 41 +/- 14.8 years) and in 24 healthy controls matched for age and sex. In SLE patients alveolar-arterial oxygen gradient (AaO2) was also measured. Disease activity was assessed by European Consensus Lupus Activity Measurement (ECLAM) scoring system and disease severity by Lupus Severity of Disease Index. In comparison to controls SLE patients showed a significant decrease of total lung capacity (TLC) (91.7 +/- 16.5 vs 102.7 +/- 12.9% predicted, P < 0.01), MEF25 (58.4 +/- 25.2 vs 73.5 +/- 19.5% predicted, P < 0.005) PD15FEV1 (2164 +/- 1122 vs 4230 +/- 1014 micrograms methacholine, P < 0.0001) and KCO (77.1 +/- 20.5 vs 96.3 +/- 12.4% predicted, P < 0.001). AaO2 (mean value 13.2 +/- 8.4) was abnormally high (> 20 mmHg) in 12 patients. The ECLAM score of activity was inversely related with KCO (r = 0.48, P < 0.02). The severity index was significantly related with FEV1/VC ratio (r = 0.43, P < 0.05), MEF50 (r = 0.51, P < 0.01), MEF25 (r = 0.40, P < 0.05) and PD15FEV1 (r = 0.51, P < 0.01). In eight patients, evaluated also after treatment intensification, there was a significant increase in KCO (from 71.8 +/- 24.7 to 84.9 +/- 22.3% predicted, P < 0.01) along with a decrease in ECLAM score (from 3.0 +/- 1.34 to 0.69 +/- 0.75, P < 0.01). The relation between disease activity and KCO suggests a relation between systemic and alveolar inflammation whereas the relation between severity index, airway patency and reactivity indices suggests a cumulative damage to the airways in SLE patients, even in the absence of overt respiratory manifestations.

Adult↗
PubMed1995

CD30 and type 2 T helper (Th2) responses.

CD30 is one of the members of the tumor necrosis factor receptor superfamily, originally described as a marker of Reed-Sternberg and Hodgkin's cells in Hodgkin's lymphoma. CD30 appears to be preferentially expressed on, and its soluble form (sCD30) released by, CD4+ and CD8+ T cell clones capable of producing T helper 2 (Th2)-type cytokines. In noneoplastic conditions, CD30+ T cells are barely detectable in vivo; however, a few allergen-specific CD4+CD30+ T cells inducible to the production of Th2-type cytokines could be sorted out from the circulation of allergic subjects after allergen exposure. Moreover, high numbers of CD30+ T cells were found in the lymph node of a patient suffering from Omenn's syndrome, a rare congenital Th2-mediated immunodeficiency disorder. More importantly, high serum levels of sCD30 were observed in some conditions in which a pathogenetic role for Th2 cells has been suggested, such as Omenn's syndrome, atopy, systemic lupus erythematosus, and after infection with measles virus or human immunodeficiency virus. Thus, detection of CD30+ T cells and/or of increased levels of sCD30 may reflect the presence of immune responses or immune alterations characterized by the prevalent activation of Th2-like cells.

HIV Infections↗
PubMed1995

Failure of B cells of chronic lymphocytic leukemia in presenting soluble and alloantigens.

B-cell-type chronic lymphocytic leukemia (B-CLL) patients have immunological abnormalities of both B and T lymphocytes. Since T cell defects might depend upon a defective accessory function of neoplastic B lymphocytes, we analyzed the ability of peripheral blood B cells of seven B-CLL patients to stimulate allogenic normal T cells in mixed lymphocyte reaction (MLR) and to present tetanus toxoid (TT) to autologous T cells. In both systems, neoplastic B lymphocytes show a defective antigen-presenting function, which is more evident with disease progression. Such a defect cannot be ascribed to a decreased MHC class II molecule expression nor to an abnormal IL-1 beta production, but it can be partially accounted for by a low B7 expression. Pretreatment of neoplastic B cells with interleukin-4 (IL-4) restores primary MLR, but has little effect on the response to TT. The effect of IL-4 is not mediated by quantitative modifications of class II and B7 molecule expression or of IL-1 beta production.

Antigen Presentation↗
PubMed1995

Osteoclast precursors circulate in the peripheral blood of patients with aggressive multiple myeloma.

Osteolysis resulting in extensive bone damage is a major clinical manifestation of patients with multiple myeloma (MM). The mechanisms of bone resorption in MM are incompletely understood. The final pathway is the generation of activated osteoclasts within bone marrow (BM) microenvironment. To investigate the mechanisms of bone resorption in MM we established an experimental system that, including bone marrow (BM) stromal cells and bone slices, closely mimicks in vitro the in vivo BM microenvironment. Peripheral blood mononuclear cells (PBMC) from nine patients with MM, three monoclonal gammopathy of undetermined significance (MGUS), and nine normal controls were cultured in this system. PBMC from patients with aggressive and bone devastating MM gave rise to multi-nucleated cells with the morphology and phenotype of osteoclasts. These cells induced bone resorption in vitro which was inhibited by the addition of calcitonin. No bone resorption was observed in cultures of PBMC from patients with MM and limited bone damage, with MGUS and from normal subjects. These findings indicate that patients with aggressive MM have a population of circulating precursors that develop into functionally active osteoclast-like cells once they come in contact with the BM microenvironment. These cells may contribute to the wide-spread and generalized bone erosion observed in the patients.

Aged↗
PubMed1994

Characterization of bone marrow stromal cells from multiple myeloma.

We have cultured multiple myeloma (MM) bone marrow (BM) stromal cells that are able to sustain the in vitro growth of monoclonal B-cells. Our aim was to evaluate which adhesion molecules are expressed and which extracellular matrix proteins are produced by these cells and whether they differ from the stromal cells that can be grown under the same experimental conditions from the BM of monoclonal gammopathies of undetermined significance (MGUS) and of normal donors. MM BM stromal cells that support malignant B-cell development have a striking proliferative ability that is absent in MGUS and normal donors of the same age group and are formed by four major different cell populations. Two kinds of HLA-DR+, CD10+ fibroblast-like cells can be recognized through the expression (or the lack) of alpha-smooth muscle actin isoform; further, macrophages and osteoclasts can be identified. Fibroblast-like cells that express alpha-smooth muscle actin isoform, often organized along stress fibers in a periodic fashion, may be considered as myofibroblasts. Fibroblast-like cells react strongly with antibodies to CD54 (ICAM-1), integrin beta 1, beta 3, beta 5 and some of associated alpha chains. Integrin beta 1 is diffusely exposed on the surface while beta 3 is clustered in focal contacts in association with vinculin. A still undetermined subpopulation of fibroblasts is highly positive for alpha v beta 5 that is clustered at focal contacts as shown by association with stress fiber termini and by interference reflection microscopy. A major difference between MM and normal donor BM stromal cells involves lower deposition and simpler organization of the extracellular matrix proteins (fibronectin, laminin, collagen type IV) deposited by MM fibroblast-like cells. CD14+ macrophages from MM, MGUS and normal donor BM are CD11a+ (alpha L), CD11b+ (alpha M), CD11c+ (alpha X), CD54+ (ICAM-1), CD56+ (N-CAM), beta 1 and beta 2 (CD18) integrin positive. The integrin beta 1 is diffusely expressed on the surface, while beta 2 is concentrated in podosomes. MM osteoclasts show a weak diffuse staining with CD54 and CD56 MoAbs; beta 1 integrin has a diffuse surface expression, while beta 3 integrin is concentrated in the podosomes. Normal donor osteoclasts are CD54- and the staining with CD56 is barely visible. These findings lead us to suggest that the microenvironment provided by MM BM may be significantly different from that of normal BM indicating its potential role in controlling the local proliferation and differentiation of malignant B-lineage cells.

Aged↗
PubMed1994

Recent progress in chronic lymphocytic leukemia. International Workshop on chronic Lymphocytic Leukemia.

The data we discuss indicate substantial recent progress in understanding and treating CLL. However, despite considerable new information, many of the intriguing issues we posed at previous IWCLL meetings remain unanswered. Prominent among these are the questions of what causes CLL, what is the relation between CLL and normal B-cell development, are T-cell abnormalities a cause of consequence of CLL, why are auto-immune features so prominent and how is CLL best treated? Although these gaps in our knowledge are unfortunate, they give us the opportunity for yet another IWCLL meeting: 1996 in Greece. More to follow.

Antigens, CD↗