Biomedical subjects

Paolo Ghia

Publications and source records attributed to Paolo Ghia.

23 records · Page 2Linked to original sources

PubMed2002

The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression.

Chronic lymphocytic leukemia (CLL) has a variable clinical course. CD38 expression and IgV(H) gene mutational status are independent predictors of prognosis, but their relationships and the CD38 cutoff level are unknown. Using cytofluorography, we analyzed CD38 in 148 patients, in 108 of whom we were able to evaluate IgV(H) mutations, make correlations with disease history, and assess cumulative survival. Three different patient groups were identified by the CD38 expression pattern: a group homogeneously CD38(-), a group homogeneously CD38(+), and a group characterized by a bimodal profile, because of the concomitant presence of variable proportions of 2 distinct populations, one CD38(+) and one CD38(-). In CD38 bimodal expression patients the CD38(+) subset was significantly more represented in the bone marrow than in the peripheral blood. For IgV(H) mutations, 11.4% of CD38(-), 84.6% of CD38(+), and 68.0% of CD38 bimodal expression patients had no mutation. CD38 expression, IgV(H) mutational status, and traditional prognostic factors were concordant. The progression rate was 12.9% for CD38(-), 75.0% for CD38(+), and 63.3% for CD38 bimodal expression patients. Only 25.8% of the CD38(-) patients but 63.3% of the bimodal and 75.0% of CD38(+) patients were treated. The presence of a CD38(+) population, albeit small, correlated with the development of autoimmune manifestations. The CD38(-) group has not yet reached the median survival, which is 183 months in the CD38(+) group and 156 months in the CD38 bimodal expression group, regardless of the size of the CD38(+) population. The presence of a distinct CD38(+) population within the leukemic clone, rather than a numerical cutoff definition, correlates with IgV(H) gene mutational status and, irrespective of its size, identifies CLL patients who will have progressive disease.

ADP-ribosyl Cyclase↗

PubMed2002

Chronic lymphocytic leukemia B cells are endowed with the capacity to attract CD4+, CD40L+ T cells by producing CCL22.

The natural history of B-chronic lymphocytic leukemia (CLL) is not entirely explained by intrinsic defects of the neoplastic cell, but is also favored by microenvironmental signals. As CLL cells retain the capacity to respond to CD40 ligand (CD40L) and as CD4(+) T cells are always present in involved tissues, we asked whether malignant CLL cells might produce T cell-attracting chemokines. We studied the chemokine expression of CD19(+)/CD5(+) malignant B cells from peripheral blood (PB), lymph nodes (LN) or bone marrow (BM) of 32 patients and found a major difference. LN- and BM-, but not PB-derived cells, expressed a readily detectable reverse transcription-PCR band for CCL22 and one for CCL17 of variable intensity. CD40 ligation of PB cells induced the mRNA expression of both CCL22 and CCL17. CCL22 was also released in the culture supernatants. These supernatants induced the migration of activated CD4(+), CD40L(+) T cells expressing the CCL22 receptor, CCR4. T cell migration was abrogated by anti-CCL22 antibodies. Immunohistochemistry and cytofluorography studies revealed that a proportion of CD4(+) T cells in CLL LN and BM expressed CD40L. Our data demonstrate that malignant CLL cells chemo-attract CD4(+) T cells that in turn induce a strong chemokine production by the leukemic clone, suggesting a vicious circle, leading to the progressive accumulation of the neoplastic cells.

Aged↗

PubMed2002

Chronic B cell malignancies and bone marrow microenvironment.

Chronic B-lymphoid malignancies depend upon supportive interactions within specific microenvironments. Follicular lymphoma (FL), chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) cells accumulate in the bone marrow (BM) where they receive survival or growth signals from by-stander cells. However, they deeply differ in their interaction with the microenvironment. We propose a model where FL and CLL recreate in the BM the microenvironment most suitable to their growth by 'importing' the normal cells that usually nurse them in secondary lymphoid organs. In contrast, MM takes advantage of the actual BM microenvironment by 'instructing' it through an abnormal activation state.

Bone Marrow↗

PubMed2002

CXCL13 (BCA-1) is produced by follicular lymphoma cells: role in the accumulation of malignant B cells.

Follicular lymphomas (FLs) localize in lymphoid tissues and recapitulate the structure of normal secondary follicles. The chemokine/chemokine receptor pair CXCL13/CXCR5 is required for the architectural organization of B cells within lymphoid follicles. In this study, we showed that CXCL13 was secreted by FL cells. FL cells expressed CXCR5 and migrated in response to CXCL13. Furthermore, we observed a synergistic effect between CXCL13 and CXCL12 (SDF-1), a chemokine produced by stromal cells in lymphoid tissues. The production of CXCL13 by FL cells and CXCL12 by stromal cells probably directs and participates in the accumulation of FL cells within specific anatomic sites.

Apoptosis↗

PubMed2002

Chronic lymphocytic leukaemia: a model for investigating potential new targets for the therapy of indolent lymphomas.

We address two key issues whose investigation may help to define new prognostic parameters and new potential targets for therapeutic intervention. First, which are the conceptual implications of the cellular origin of indolent lymphomas? Second, how may deciphering the biology of chronic lymphocytic leukaemia (CLL) lead to the development of new modalities of treatment? The latter issue is articulated in the following three key questions. (1) Which are the molecular pathways through which the microenvironment exerts its influence on the malignant clone? (2) What are the relationships between proliferation and defective apoptosis? (3)Is there any evidence of a role for antigenic stimulation?

Apoptosis↗