Association of NK-cell lymphoproliferative disease and nephrotic syndrome.

A 56-year-old white man with a seven-year history of lymphocytosis of large granular lymphocytes (LGL) developed mild renal insufficiency (serum creatinine 150 mumol/L (1.7 mg/dL) with proteinuria (3.4 g/day).

Lymphocytes of a patient with lymphoproliferative disease of large granular lymphocytes express high natural killer, ADCC, and LAK activity.

The clinical, morphological, immunological, and molecular features of a case of expansion of large granular lymphocytes (LGL) are reported. Surface marker analysis of peripheral blood and spleen mononuclear cells showed that the majority of these cells were CD3-, CD2+, CD16+, and Leu 7-. Ultrastructural characteristics of CD16+ cells revealed a low nuclear/cytoplasmatic ratio, irregularly shaped nucleus, and numerous cytoplasmatic granules.

In vitro and in vivo effects of cisplatin on the generation of lymphokine-activated killer cells.

Pretreatment of human peripheral blood lymphocytes (PBL) with cisplatin (CDDP) before in vitro culture with interleukin-2 (IL-2) inhibited the generation of lymphokine-activated killer (LAK) cells and strongly inhibited proliferation. This inhibition was dose dependent, was significant only at concentrations greater than 6 microM, and it required exposure to the drug for more than 1 hour. This period of IL-2 unresponsiveness was maximum at 6 hours, but was spontaneously recovered within 24-48 hours and was more rapidly restored by increasing dosages of IL-2.

Flavone acetic acid antitumour activity against a mouse pancreatic adenocarcinoma is mediated by natural killer cells.

Flavone acetic acid (FAA) is one of the most active antitumour agents against mouse solid tumours. A number of reports favour the hypothesis that FAA could behave as a biological response modifier; in fact FAA stimulates natural killer (NK) cells, induces secretion of type I interferon and synergizes with interleukin-2 to increase NK/lymphokine-activated killer (LAK) activity in vivo. However, there is no conclusive evidence that the antitumour activity of FAA is mediated via the modulation of NK/LAK cells.

Intraperitoneal and subcutaneous xenografts of human ovarian carcinoma in nude mice and their potential in experimental therapy.

Human ovarian carcinomas (HOC) were established s.c. and i.

T cell receptor delta gene organization and expression in normal and leukemic natural killer cells.

In peripheral blood most NK activity is mediated by CD3- cells with large granular lymphocyte morphology which cannot be assigned to a specific hemopoietic lineage. In accordance with previous studies we have analyzed the organization of the TCR delta gene, which rearranges early in thymic ontogeny, in normal NK cells, and in granular lymphocytes proliferative disorders (GLPD), in an effort to further define their relationship to the T cell differentiation pathway and to identify a possible marker of clonality for CD3- GLPD. The alpha/delta locus was rearranged in five cases of CD3+ GLPD with a biallelic deletion of the C delta region, suggesting V-J alpha rearrangement, whereas CD3- GLPD and normal CD3- NK cells had the delta gene in germ-line configuration, but surprisingly expressed high levels of TCR delta-related mRNA.

Lymphokine-activated killer (LAK) and monocyte-mediated cytotoxicity on tumor cell lines resistant to antitumor agents.

In this study we have examined the susceptibility of tumor cell lines exhibiting different patterns of resistance to chemotherapeutic agents, to the cytotoxic action of lymphokine-activated killer (LAK) cells and activated monocytes. The susceptibility of tumor cells with pleiotropic drug resistance to these cytotoxic mechanisms was not different from that of their parental, chemo-sensitive cell lines. Tumor lines used in this study included three human cell lines (LOVO N and LOVO/Dx, I-407 and I-407/Dx, MCF7 and MCF7a) selected for being resistant to doxorubicin and showing a pleiotropic pattern of resistance, and the murine ovarian reticulum cell sarcoma M5076 and its variants resistant to individual antitumor agents (cisplatin, cyclophosphamide and 5-aza-2'-deoxycytidine).

Stimulation of cytotoxic and non-cytotoxic functions of natural killer cells by bacterial membrane proteoglycans and ribosomes.

The present study was designed to investigate the effect of membrane proteoglycans (MPG) from Klebsiella pneumoniae on the function of human natural killer (NK) cells. MPG combined with bacterial ribosomes from Klebsiella pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes and Haemophilus influenzae, constitute a bacterial immunomodulator (MS D 53), currently in clinical use. Human peripheral blood lymphocytes (PBL) exposed in vitro to MPG or MS D 53 for 20 h showed enhanced NK cytotoxicity.

Interleukin-1 and tumor necrosis factor production in acute non-lymphoid leukemia.

We have investigated interleukin-1 (IL-1) and tumor necrosis factor (TNF) release in 20 patients with acute non-lymphoid leukemia (ANLL) after culture with bacterial lipopolysaccharide (LPS) or in the absence of deliberate stimulation. IL-1 and TNF were identified by appropriate bioassays inhibitable by specific antibodies. The capacity to produce IL-1 was expressed by most ANLL cases investigated irrespective of the FAB (French, American, British) subtype.

Autoimmunity and B-cell dysfunction in chronic proliferative disorders of large granular lymphocytes/natural killer cells.

Clinical and laboratory findings of B-cell immune dysfunction were evaluated in ten patients with a large granular lymphocyte/natural killer cell proliferative disease (LGL/NK-PD). Increased immunoglobulin synthesis with autoantibody formation was documented: polyclonal hypergammaglobulinaemia (six patients), neutrophil autoantibody (one patient), antinuclear antibody (one patient), and rheumatoid factor (five patients). In addition, serum beta 2-microglobulin level was raised in seven patients, a benign monoclonal gammopathy was detected in one, and concurrent B-type hairy cell leukemia in another.

Killing of tumor cells with pleiotropic drug resistance by OK432-activated effector cells.

The inactivate streptococcal preparation OK432 activates the cytotoxic function of natural killer (NK) cells. Moreover, it induces cytotoxic activity against freshly isolated tumor cells. The present study was aimed at assessing whether OK432-activated effector cells expressed cytotoxicity against tumor cells pleiotropically resistant to cancer chemotherapy agents.

Activated adherent large granular lymphocytes/natural killer (LGL/NK) cells change their migratory behaviour.

Unstimulated large granular lymphocytes/natural killer (LGL/NK) cells, unlike small T lymphocytes, exhibit prompt locomotion into nitrocellulose filters in response to chemo-attactrants, but, unlike monocytes, are unable to migrate as adherent cells across polycarbonate filters. Upon activation with 4-B-phorbol 12,13 dibutyrate (PDBU), LGL/NK cells become adherent and change their migratory behaviour, having the ability to migrate as adherent cells across polycarbonate filters. PDBU-treated high-density T lymphocytes did not show, under the same conditions, locomotory activity.

c-fos proto-oncogene expression in human NK/LGL cells: expression is not constitutive and is associated with functional activation.

Unlike mature myeloid and monocytic cells and cell lines committed to terminal myelomonocytic differentiation, highly purified preparations of human natural killer cells/large granular lymphocytes (NK/LGL) did not spontaneously express the c-fos proto-oncogene. Transient expression of c-fos in NK/LGL was associated with functional activation with IL-2, IFN-gamma, LPS and PMA, which increased their cytotoxic activity, lymphokine secretion and in vitro chemotaxis. These results, together with the finding that T-cell receptor genes are in germ-line configuration in the vast majority of peripheral blood NK/LGL, are compatible with the hypothesis that these cells represent a separate hematopoietic lineage.

Association of large granular lymphocyte/natural killer cell proliferative disease and second hematologic malignancy.

We describe the first three patients with a large granular lymphocytosis/lymphocytic leukemia and another blood malignancy. In two, a myeloproliferative disorder developed soon after the diagnosis of abnormal proliferation of large granular lymphocytes-natural killer (LGL-NK) cells, a myelodysplastic syndrome evolving to acute leukemia and a Philadelphia-positive chronic myelogenous leukemia. In these cases, LGLs expressed the phenotype of CD3+ NK and CD3- NK cells, respectively, and were clonal in the first patient as demonstrated by T-cell receptor gene rearrangement study.

Investigation of chronic lymphocytosis in adults.

Thirteen cases of idiopathic chronic lymphocytosis are the subject of this report. Patients showed a lymphocyte count between 4 and 15 X 10(9)/L for at least six months, marrow lymphocytosis not exceeding 25%, absence of lymphomegaly and hepatosplenomegaly, and no associated infections, immune, or neoplastic disease. Morphologic examination of smears revealed a lymphocytosis of large granular lymphocytes in five.

Myelokathexis associated with multiple congenital malformations: immunological study on phagocytic cells and lymphocytes.

A 5-year-old boy was first seen at the age of 11 months when he presented with growth retardation, skeletal dysmorphisms and neutropenia. Since then he has remained leukopenic except when he has pulmonary infections with a marked leukocytosis. Despite his neutropenia, marked myeloid hyperplasia was evident on marrow smear examination; many cells showed abnormally hypersegmented nuclei, with unusual shape or pyknotic nuclei.

Patterns of T cell receptor gamma gene rearrangement and expression in B and T lymphoid malignancies.

The frequency and pattern of T gamma gene rearrangement and expression was investigated in hematopoietic neoplasms including T and B lymphoid and myeloid malignancies. 39 of 39 T lymphoid neoplasms, including fresh cases and cell lines, were found to display clonal T gamma gene rearrangements. There was heterogeneity with respect to utilization of the two T gamma constant region genes, T gamma C1 and T gamma C2.

Lymphocytes infiltrating ovarian carcinoma: modulation of functional activity by intraperitoneal treatment with biological response modifiers.

A better understanding of the immunobiology of tumor-associated lymphocytes (TAL) may have considerable bearing on the therapeutic perspective of human neoplasia. We have identified ovarian cancer as a clinical condition privileged for studies on immunity and its in vitro and in vivo modulation. Our previous studies on the mechanisms of natural resistance have shown that TAL from ovarian carcinoma have defective natural killer cell activity when compared to peripheral blood lymphocytes from the same patient.

Proliferative response of lymphocytes from ovarian cancer patients to autologous tumor cells.

Peripheral blood lymphocytes (PBL) from 43 patients with histologically confirmed ovarian carcinoma were stimulated in mixed lymphocyte-tumor culture (MLTC) with purified autologous tumor cells. Positive results, assessed as lymphocyte proliferation, were observed in 21 cases (48.8%).

DR antigen expression on ovarian carcinoma cells does not correlate with their capacity to elicit an autologous proliferative response.

Expression of HLA-DR antigens by purified preparations of human ovarian carcinoma cells freshly isolated from surgical specimens was examined in parallel with the capacity of tumor cells to elicit a blastogenic response from autologous lymphocytes in mixed lymphocyte-tumor culture (MLTC) assay. Of 21 tumor preparations, 11 (52%) reacted with monoclonal antibodies 279 and/or 949 specific for a monomorphic determinant of HLA-DR antigens, with heterogeneous positivity, ranging between 30% and 95%. In this series of patients positive MLTC occurred in 8/21 individual experiments.

T cell receptor (alpha, beta, gamma) gene rearrangements and expression in normal and leukemic large granular lymphocytes/natural killer cells.

The large granular lymphocyte (LGL) population, which effects a natural killer (NK) function, consists of cells whose lineage derivation has not been clearly established on the basis of phenotypic and functional properties. To clarify the relationship of LGL/NK cells to T cells we studied patterns of rearrangement and expression of the T cell receptor (Ti) genes alpha, beta, and gamma in normal human LGLs; in CD8+, CD8-, Mol+, and Mol- LGL subsets; and in 17 cases of leukemic LGL proliferations (T gamma LPD). T alpha, T beta, and T gamma genes were not expressed, nor were T beta and T gamma genes rearranged in normal LGLs or LGL subsets.

T-cell receptor gene rearrangements and expression in normal human large granular lymphocytes (LGL) and their pathological expansions.

The lineage to which normal large granular lymphocytes/natural killer (LGL/NK) cells belong is controversial; in fact they share some surface markers and functional activities with monocytes, but also with T lymphocytes. The relationship of LGL to the T cell lineage by analysis with the T cell receptor (T-rec) gene has been investigated. Pure preparations of human LGL and their CD11(+) CD8(-) and CD11(-) CD8(+) subsets had the Tβ gene in its unrearranged germline configuration.

Human tumor cell lines with pleiotropic drug resistance are efficiently killed by interleukin-2 activated killer cells and by activated monocytes.

Two human cell lines, the colon carcinoma Lovo and the transformed intestinal I-407, and their variants (Lovo/Dx and I-407/Dx), with pleiotropic resistance to cancer chemotherapeutic drugs, were examined for their susceptibility to human Interleukin-2-activated killer cells and to activated monocytes. These non-specific or broadly specific effector cells expressed cytotoxicity levels on pleiotropically resistant tumor cells comparable to those of the parental cell populations. This finding provides a rationale for immunological approaches designed to eradicate residual tumor cells surviving and resistant to cytotoxic chemotherapy.

In vitro susceptibility of different human T-cell subpopulations and resistance of large granular lymphocytes to HTLV-I infection.

T4 subpopulation of T lymphocytes is the preferential target of infection with human T leukemia/lymphoma virus of subgroup I (HTLV-I). In this study we attempt to determine whether different T-cell subsets exhibit differences in susceptibility to virus infection. T cells from cord or peripheral blood were separated according to cell densities and T-cell surface markers by Percoll gradient and Sepharose anti-Fab immunoadsorbent affinity column (IAC), respectively.