Biomedical subjects

M T Fierro

Publications and source records attributed to M T Fierro.

At least 55 records · Page 3Linked to original sources

PubMed1988

Autocrine or paracrine models of cytokine production and utilization in B-cell chronic lymphocytic leukaemia.

The possibility that autocrine or paracrine mechanisms of cytokine production and utilization may take place in patients with B-cell chronic lymphocytic leukaemia (B-CLL) is discussed. In particular, evidence is provided for a likely role of interleukin 2 (IL2) on the neoplastic B-cell compartment. Furthermore, the possibility that tumor necrosis factor (TNF) may also be involved is suggested.

Humans↗

PubMed1988

In vitro and in vivo susceptibility of human leukemic cells to lymphokine activated killer activity.

The susceptibility of human myeloid and lymphoid leukemic blasts to the lytic action of recombinant interleukin-2 (rIL-2)-generated lymphokine activated killer (LAK) cells was analyzed. With the exception of the K562 cell line, all 9 leukemic cell lines tested were resistant to the natural killer activity of freshly isolated peripheral blood lymphocytes (PBL) from healthy donors but were susceptible to the lytic action of PBL cultured for 3 days in the presence of rIL-2. Of the 32 primary myeloid and lymphoid acute leukemia samples investigated, the great majority were natural killer cell-resistant but were variably sensitive to LAK effectors. Variations in LAK activity were observed according to the donor of PBL, while little or no difference was documented in the capacity to elicit LAK activity of PBL cultured with 100 or 1,000 U of rIL-2/ml. Pretreatment of the leukemic target cells with neuraminidase did not increase substantially their sensitivity to LAK activity. LAK cells generated from the PBL of patients at the onset of the disease or in complete clinicohematological remission lysed Raji cells as efficiently as normal LAK effectors. Finally, LAK cells were capable of abrogating the tumor growth in nude mice of a human leukemic T cell line. These findings demonstrate the susceptibility in vitro and in vivo of human leukemic blasts to the lytic effect of LAK cells and point to a possible clinical exploitment of this new form of adoptive immunotherapy in the management of acute leukemia.

Animals↗

PubMed1987

Chronic T-cell leukaemias. A variant of T-prolymphocytic leukaemias: morphological, immunological and clinical characterization of 2 cases.

In this study we describe 2 patients who appear to suffer from a morphological, cytochemical and clinico-haematological variant of T-prolymphocytic leukaemia (T-PLL). The cells were smaller than typical prolymphocytes, with a regular nucleus containing a smaller and less prominent nucleolus; the alpha-naphthyl acetate esterase (ANAE) and acid phosphatase (AP) cytochemical reactions showed a weaker pattern of positivity in this variant compared to T-PLL. No immunological differences were found between the two conditions with regard to membrane expression and functional behavior of the cells. The clinical course and the outcome of the patients appears to be different: aggressive and rapidly fatal in T-PLL; thus far well-controlled in the T-PLL variant. From a molecular point of view, both cases showed a monoclonal rearrangement of the T-cell receptor beta-chain gene.

Aged↗

PubMed1987

Germ-line configuration of the T-cell receptor beta-chain gene in B-cell chronic lymphoproliferative disorders which co-express T-cell antigens.

In 7 cases of chronic B-cell lymphoproliferative disorders-6 chronic lymphocytic leukaemias and 1 non-Hodgkin lymphoma in leukaemic phase--which co-expressed T-cell markers (CD3, CD2) the clonal origin was investigated at the DNA level. In accordance with the diagnosis, all cases showed a monoclonally rearranged configuration of the immunoglobulin genes. On the contrary, the T-cell receptor beta chain gene always retained a germ-line organization. These findings demonstrate that B-cell chronic lymphoproliferative disorders which co-express T-cell-related markers are truly composed of monoclonal B-cell elements.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1987

Immunoregulatory T-cell defects in B-cell chronic lymphocytic leukemia: cause or consequence of the disease? The contributory role of decreased availability of interleukin 2 (IL-2).

Several phenotypic and functional defects have been described within the residual T-lymphocyte population of patients with B-cell chronic lymphocytic leukemia (B-CLL), particularly in those in the more advanced stages of the disease. In this study, we review these abnormalities and discuss their possible effects on the course of the illness. Particular emphasis is devoted to the role of interleukin 2 (IL-2) in B-CLL. Evidence is provided that the IL-2 released by B-CLL T-lymphocytes may be utilized by the neoplastic B-cell clone that expresses the IL-2 receptor and that decreased availability of IL-2 may play a contributory role in some of the T-cell defects encountered in B-CLL.

B-Lymphocytes↗

PubMed1987

Rearrangement of the c-myc oncogene with heavy-chain immunoglobulin enhancer in tumor DNA from an acute lymphoblastic leukemia patient.

The DNA obtained from the leukemia cells of an acute lymphoblastic leukemia (ALL, L3 type) with a pre-B-phenotype and a typical t(8;14) chromosomal translocation showed a rearrangement juxtaposing the c-myc gene and the immunoglobulin (Ig) heavy-chain gene enhancer. This abnormality was only present in the leukemia cells of the patient and correlated with the clinical course of the disease. The breakpoint on chromosome 8 occurred within c-myc intron 1, between 790 and 638 base pairs upstream of c-myc exon 2. This breakpoint position was the nearest to the c-myc exon 2 so far described in Burkitt's type lymphoma-leukemias, and it mapped very near to the location of a major cryptic promoter used by truncated c-myc genes. In spite of what was detected in a human lymphoma cell line (Manca) carrying a similar rearrangement, in this case the amount of c-myc transcript was not increased compared to an Epstein-Barr virus-transformed normal lymphoblastoid cell line obtained from the same patient. This may in part be due to the breakpoint position and to the fact that the efficiency of the major cryptic promoter present within the first intron could have been affected by the translocation event. Finally, as previously suggested by others, the phenotype expressed by the leukemia cells supported the notion that this particular type of rearrangement (linking together the c-myc gene and the Ig heavy-chain gene enhancer element) may be associated with a subgroup of B-ALLs showing an immunologic phenotype relatively more immature than that of classical B-ALL.

Adult↗

PubMed1987

Genotypic characterization of common acute lymphoblastic leukemia may improve the phenotypic classification.

The reactivity of five anti-B monoclonal antibodies (McAb)-OKB2 (CD24), B4 (CD19), Leu12 (CD19), BA1 (CD24), B1 (CD20)--as well as the presence of cytoplasmic immunoglobulins (CyIg) were assessed in 100 cases of common acute lymphoblastic leukemia (cALL) at presentation (TdT+, J5 [CD10]+, HLA-Dr+). All cases studied revealed one or more B-cell related markers and a hierarchy in their expression was documented: OKB2 was positive in all cases tested (100%), B4 was expressed in 96.4% of cases, Leu12 in 95.8%, BA1 in 94.9%, B1 in 18.3%, and CyIg in 23%. Further evidence of the B-cell origin of cALL was obtained by molecular analyses at the DNA level which demonstrated the presence of an Ig heavy chain gene rearrangement in all 37 cases assessed, while 37.8% showed a light chain gene reorganization. A genomic subclassification of cALL demonstrated that the majority of cases showed an immature molecular configuration with one (8.1%) or both (54.1%) Ig heavy chain alleles rearranged and a germ-line configuration of the light chain genes; 27% revealed a heavy chain gene involvement and one k allele rearranged. Only four cases (10.8%) showed a more mature configuration with both k alleles rearranged or a gamma chain gene involvement. This study confirms that cALL is characterized by the proliferation of immature B-lineage-committed elements and indicates that the leukemic cells are blocked at different levels of B-differentiation which may be recognized with the use of multiple phenotypic or genotypic B-cell-related markers.

Alleles↗

PubMed1987

Effect of alpha-interferon on the immune system of patients with hairy cell leukemia.

The role of in vivo administration of lymphoblastoid alpha-interferon (IFN-alpha) on the immune status of 12 patients with hairy cell leukemia (HCL) was studied. In most cases an increase in T3(CD3), T4(CD4), and T8(CD8) lymphocyte subsets was documented at the same time as hairy cells disappeared from the circulation. This led in most cases to an improved T4/T8 ratio. The effect of treatment with IFN-alpha was particularly evident on the natural killer cell compartment, which is often functionally depressed in HCL at diagnosis. After therapy, a progressive increase in the cytotoxic activity was observed in most patients. This was more evident 6-9 months after commencing treatment. These findings suggest that, in addition to the known clinicohematological effects, IFN-alpha can improve both the T and natural killer compartments in patients with HCL.

Antigens, Differentiation↗

PubMed1987

A human leukemic T cell line (PF-382) inhibits the growth of myeloid and erythroid progenitor cells.

We have recently described a human T cell line, named PF-382, obtained from the pleural effusion of a child with T-acute lymphoblastic leukemia (T-ALL), which expresses phenotypic and functional features of suppression. In this study we report that PF-382 spontaneously releases a factor which inhibits the in vitro growth of myeloid (CFU-GM) and erythroid (BFU-E) progenitor cells. The same effect is obtained when irradiated PF-382 cells are co-cultured with the hemopoietic precursors. In both instances, maximal inhibitory activity is exerted on day 14 CFU-GM and BFU-E obtained from the light density nonadherent fraction of normal human bone marrow and peripheral blood; this finding suggests that the target of the inhibition is represented by the more immature elements within the progenitor cell compartment. Progressive depletion of monocytes, T, B lymphocytes, and NK cells as well as recloning experiments indicate that the inhibitory effect is directly exerted on the target cell and not via an intermediate population of accessory cells. Partial purification by gel filtration and by subsequent high performance liquid chromatography demonstrates that this factor is a protein with a molecular weight of 47 kd. The physicochemical characterization and the specific functional properties suggest that the PF-382 inhibitory factor represents a lymphokine which differs from those so far reported. The PF-382 cell line provides a useful model toward a better understanding of the interrelations between T cell subsets and other hemopoietic compartments.

Colony-Forming Units Assay↗

PubMed1986

Normal T-lymphocyte function in patients with Hodgkin's disease in long-lasting remission.

In 18 patients with Hodgkin's disease (HD) in long-lasting remission (more than 5 years), the distribution of circulating T-lymphocytes was analyzed using a series of monoclonal antibodies (OKT3, T4, T8, Leu-7, Leu-11 and T10) and correlated with cell function (helper capacity in a pokeweed mitogen system and natural killer (NK) activity). A reduced proportion of OKT4 (helper/inducer)-positive cells associated with a normal absolute number was consistently accompanied by a significant increase (p less than 0.005) in the proportion and absolute number of OKT8 (suppressor/cytotoxic)-positive cells. The OKT4-positive cells, despite their moderate percentage reduction, showed normal helper activity. A more extensive characterization of the lymphoid population in these patients documented a preserved cytotoxic function in a 51Cr release assay and increased proportion of cells expressing NK-associated antigens (Leu-7, Leu-11, OKT10) with a high number of cells coexpressing OKT8 and Leu-7. It is suggested that in patients with Hodgkin's disease in long-lasting remission no laboratory (or clinical) evidence of cellular immunodeficiency can be documented.

Adult↗

PubMed1986

Reduced natural killer T-cells in B-cell chronic lymphocytic leukaemia identified by three monoclonal antibodies: Leu-11, A10, AB8.28.

The proportion of E-rosette positive T-lymphocytes capable of reacting with three monoclonal antibodies (MoAbs)--Leu-11, A10, AB8.28--which appear to recognize specifically natural killer (NK) cells, was assessed in a series of untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL). Irrespective of the clinical stage of the disease, the capacity of B-CLL T-lymphocytes to react with all three MoAbs was significantly reduced compared with that of normal circulating T-cells (Leu-11: 2.5% +/- 1.9 SD; A10: 2.3% +/- 1.3; AB8.28: 7% +/- 6.6 v Leu-11: 13.5% +/- 4.5; A10: 8.5% +/- 4.6; AB8.28: 12% +/- 5.5). Furthermore, a marked difference was demonstrated between the reactivity with the Leu-11, A10, AB8.28 MoAbs and the proportion of Leu-7 positive T-cells, which in B-CLL is significantly higher than in normal blood (23% +/- 12.1 v 11.9% +/- 5.9). These findings are in agreement with previous evidence of a discrepancy in B-CLL between the phenotypic expression, assessed by Leu-7 positivity, and the true functional activity of NK T-cells, and suggest that the Leu-11, A10 and AB8.28 MoAbs correlate well with the depressed NK function found in this disease.

Antibodies, Monoclonal↗

PubMed1986

Phenotypic and functional characterization of the circulating NK compartment in hairy cell leukaemia.

A phenotypic and functional analysis of the circulating natural killer (NK) cell population was carried out in a series of patients with hairy cell leukaemia (HCL). The overall mean NK activity of both the mononuclear and T cell fractions was reduced compared to that of normal controls (466 lytic units (lu) v 573 lu and 226 lu v 381 lu, respectively), though this difference did not reach statistical significance (P less than 0.05). Individual analysis of the data showed that in five out of 15 and in seven out of 16 cases the K562 killing by the mononuclear and T cells respectively was below the lowest s.d. limit for normal subjects. This reduced NK function was associated with a decreased ability of the effector cells to bind the target. The NK response to exogenous human leucocyte interferon was also generally depressed in cases with a low basal NK activity. The functional studies were complemented with the evaluation of the membrane expression of NK associated antigens. The percentage of circulating T cells recognized by the monoclonal antibody (MoAb) Leu-7 was significantly higher (P less than 0.001) in HCL than in normal blood (25.2% +/- 10.2 v 11.9 +/- 5.9 s.d.). However, the reactivity with two other NK-related MoAb, Leu-11 and AB8.28, was significantly lower (7.1% +/- 6.9 and 9.8% +/- 8.5; P less than 0.002) than with Leu-7 and moderately reduced compared with that of normal circulating T cells (11.7% + 6.1 & 12% + 5.5). These findings suggest that in a proportion of patients with HCL there is an impairment of the NK compartment, which may contribute towards the occurrence of the infective complications which are the primary cause of death in this disease.

Antibodies, Monoclonal↗

PubMed1985

A novel leukemia T-cell line (PF-382) with phenotypic and functional features of suppressor lymphocytes.

A human leukemia T-cell line (PF-382) spontaneously derived from the pleural effusion of a child with T-cell acute lymphoblastic leukemia is described. The cell line, which has been maintained in culture for over 10 months, has a modal number of 46 chromosomes and is characterized by a chromosomal abnormality, present in most of the cells, consisting of a translocation between chromosome X and chromosome 15 (46X,Xq-,15p+). The cells are not recognized by the OKT3 and OKT11 monoclonal antibodies (MoAb), nor do they form rosettes with sheep erythrocytes. By contrast, they react with the OKT6, Leu-1, and Leu-9 MoAb, which detect early T-lymphocytes, and express the more mature OKT8 antigen. The presence of the OKT8 marker is associated with suppressor activity on the pokeweed mitogen-induced proliferation and differentiation of normal B-cells, both by the PF-382 cells and by their supernatant. However, no cytotoxic activity against natural killer (NK)-sensitive target cells (K562) was found, indicating that the proliferating cells do not correspond to the subset of NK cells expressing the OKT8 antigen. Furthermore, the cells are incapable of both spontaneous and mitogen-induced interleukin-2 and interferon production. The ability of the PF-382 cell line to release a soluble factor(s) capable of modulating the differentiation of the B-cell compartment suggests that this new cell line represents a valuable model for the investigation of the interrelationships between T-cell subsets and other hematopoietic cell lineages.

Antigens, Viral↗

PubMed1985

Interleukin 2 (IL 2) and interferon-gamma production by T lymphocytes from patients with B-chronic lymphocytic leukemia: evidence that normally released IL 2 is absorbed by the neoplastic B cell population.

The capacity of T lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) to release interleukin 2 (IL 2) and interferon (IFN)-gamma was assessed following various stimuli. The spontaneous release of IL 2 and IFN-gamma was practically absent both with B-CLL and normal T lymphocytes. By contrast, after stimulation with phytohemagglutinin (PHA) or with PHA plus 12-O-tetradecanoylphorbol-13-acetate, the production of IL 2 and IFN-gamma by B-CLL T lymphocytes was similar to that of normal T lymphocytes, irrespective of the reversed T lymphocyte subset distribution (OKT4/OKT8 ratio) observed in B-CLL. However, the titer of IL 2 was greatly reduced when autologous leukemic B cells were added to the culture system. Unlike IL 2, the presence of leukemic B cells did not affect the titer of IFN-gamma in the culture supernatants. The indication that IL 2 may be adsorbed in vivo by the neoplastic B cells was further confirmed by the demonstration of the IL 2 receptor (revealed by anti-Tac monoclonal antibody) on the leukemic B cells, particularly following mitogenic stimulation, and by the evidence that exogenous IL 2 can be directly absorbed by untreated B-CLL T lymphocytes to release IFN-gamma and IL 2 is preserved, but that IL 2 may be rapidly removed by the neoplastic B-CLL cells, thus contributing to the well-documented T lymphocyte abnormalities present in this disease.

Absorption↗

PubMed1984

Immature T lymphocytes in human cord blood identified by monoclonal antibodies: a model for the study of the differentiation pathway of T cells in humans.

The reactivity of human cord blood lymphocytes was assessed against a panel of monoclonal antibodies (MoAb). The mean proportion of OKT3+ cells (pan-T) was significantly lower in cord blood (52 +/- 13.8%; mean +/- SD) compared with that of adult blood (75 +/- 8.9%) and paralleled well with the E-rosette-forming capacity (50 +/- 16.3%). Both the proportions of OKT4+ cells (helper/inducer phenotype) and of OKT8+ cells (suppressor/cytotoxic phenotype) were significantly reduced in cord blood (43 +/- 11.8% vs 50.3 +/- 7.4% and 20 +/- 10.3% vs 25.6 +/- 6.0%, respectively), while the overall OKT4/OKT8 ratio was increased compared with adult blood (2.87 +/- 1.83 vs 2.04 +/- 0.61). Unlike adult blood, in 30 of the 35 samples of cord blood an overlap was observed between the total proportion of OKT4+ and OKT8+ cells (65 +/- 15.2%) and that of OKT3+ cells (52 +/- 14.3%). Although small numbers of cells coexpressing both antigens were occasionally found, double-staining analysis showed that the overlap in cord blood was mostly due to an expanded proportion of OKT3 (Leu-4)-/OKT8 (Leu-2)+ cells. Relevant proportions of OKT6+ (common thymocyte antigen) and OKT10+ (thymocytes, activated T cells, precursor cells) cells were found in cord blood as opposed to adult blood (10.8 +/- 8.6% vs 0.6 +/- 0.6% and 67 +/- 18.0% vs 8 +/- 2.1%, respectively), while terminal deoxynucleotidyl transferase-positive cells were observed only in two samples of cord blood. A small proportion of T cells (E-rosette+) reacted with the MoAb OKIa1 (HLA-DR). Finally, the proportion of cord blood cells recognized by the MoAb Leu-7 (HNK-1 clone) was almost negligible compared with adult blood (2.8 +/- 2.4% vs 15 +/- 7.5%). These data confirm the immaturity and heterogeneity of cord blood lymphocytes and demonstrate the presence at birth of circulating lymphocytes which express a surface phenotype reminiscent of that found in the late stages of intrathymic differentiation and in some human T-cell leukemias. Human cord blood may thus represent a suitable model for the study of the differentiation pathway of normal and pathological T-cells in humans.

Antibodies, Monoclonal↗

PubMed1984

B-chronic lymphocytic leukaemia patients with stable benign disease show a distinctive membrane phenotype.

The circulating B cells of 98 patients with B-CLL were analysed with a panel of conventional markers and monoclonal antibodies including RFA-1 and RFA-4. A subgroup of patients was defined with a distinctive double membrane marker phenotype (RFA-1+, RFA-4+). These patients showed features of clinical stability. Their physical signs, haematological features and lymphocyte counts remained unchanged for 5-10 years: therefore, the RFA-1+, RFA-4+ membrane phenotype appears to identify a subgroup of B-CLL patients with a particularly non-progressive disease.

Aged↗

PubMed1984

Discrepancy between phenotypic and functional features of natural killer T-lymphocytes in B-cell chronic lymphocytic leukaemia.

The phenotypic expression and functional capacity of natural killer (NK) T-lymphocytes (E+, OKT3+) were analysed in a series of untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL). The mean value of NK activity of B-CLL T-lymphocytes, tested against the K562 cell line, was significantly depressed (P less than 0.01) in the 20 cases studied, compared with that of normal T-cells. Incubation with human leucocyte interferon produced an increase (P less than 0.05) in NK activity, although the mean value was still significantly lower (P less than 0.05) than that obtained with normal T-cells. Furthermore, the formation of effector-target conjugates was significantly lower (P less than 0.01) among B-CLL T-cells compared with normal T-lymphocytes. Despite the reduced NK functions observed in the majority of B-CLL patients, the capacity of T-cells to react with the monoclonal antibody (MoAb) Leu-7 (HNK-1 clone), assessed in 60 patients, was significantly higher (P less than 0.001) in B-CLL than in normal blood (mean 24% +/- 10.6 SD v 9% +/- 4.2), irrespective of the clinical stage of the disease. These findings suggest that the reduced cytotoxic ability of B-CLL T-lymphocytes may be due either to an expanded population of immature T-cells which already express a cytotoxic-like phenotype (E+, OKT3+, HNK-1+) but which lack adequate cytotoxic functions, or, alternatively, to an intrinsic defect of the natural effectors present within the T-cell population of B-CLL. The T-cell functional abnormalities documented in this study, together with other defective functions previously described, may be implicated in some of the complications frequently associated with B-CLL, particularly the high incidence of secondary neoplasms. There is growing evidence that natural cytotoxicity may play a major role in the immune surveillance system, both against tumour cells and virus-infected cells (Herberman & Ortaldo, 1981). Natural killer (NK) cells are a morphologically homogeneous population of large granular lymphocytes with azurophilic granules in the cytoplasm (Timonen et al, 1981), which are non-adherent and express receptors for the Fc portion of IgG. About 50% of these cells form rosettes with sheep red blood cells (E-rosettes) (West et al, 1977). A monoclonal antibody (MoAb) which appears to react with practically all human NK cells (HNK-1 clone, Leu-7; Becton Dickinson) has been recently produced (Abo & Balch, 1981).(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗

PubMed1984

Different stages of B cell differentiation in non-T acute lymphoblastic leukemia.

Immunoglobulin heavy chain gene rearrangement was evaluated in 19 cases of acute lymphoblastic leukemia (ALL) and correlated with the immunological phenotypic expression on primary or phorbol diester (12-O-tetradecanoylphorbol-13-acetate [TPA])-induced cells. One case of common ALL (cALL), one case of T-ALL, and one undifferentiated acute leukemia that responded to anti-myeloid drugs after unsuccessful anti-lymphoid induction therapy, had germ line heavy chain genes. Rearranged immunoglobulin genes were instead found in 15 of the 16 cALL cases studied and in a case of non-T, non-B, non-common ("null") ALL, which suggested the B cell origin of the neoplastic cells. All cases bearing a heavy chain gene rearrangement were HLA-DR positive. However, the unique cALL case with a germ line configuration was also HLA-DR positive, which confirmed that both the cALL antigen and HLA-DR antigen were not per se expression of B cell commitment. On the other hand, a complete search for B cell-related markers (BA-1 and B1 monoclonal antibodies, as well as cytoplasmic immunoglobulins [CyIg]) in the cALL cases showed that at least one B cell marker could be detected either on primary or on TPA-induced cells in all cases in which a gene rearrangement had occurred. Incubation with TPA allowed the detection of one B cell marker in a case in which the primary cells were negative, and increased the expression of B cell markers in all but one of the cALLs tested. The only cALL case that was not rearranged expressed no B cell markers either on primary or on TPA-induced cells. The non-T, non-B, non-common ("null") case that was rearranged also showed no phenotypic evidence of B cell markers on primary and induced cells. These findings indicate that: (a) practically all cases of cALL appear to be of B cell origin as shown by gene rearrangement analysis; (b) DNA studies are relevant for a more precise characterization of individual cases of undifferentiated acute leukemia; (c) a complete survey for B cell markers may establish the B cell origin of the cALL blasts, as long as the analysis on primary cells is complemented by differentiation induction assessment; and (d) most cases of non-T ALL appear to be characterized by the expansion of neoplastic cells "frozen" at different levels along the B cell differentiation pathway, the first detectable marker being heavy chain gene rearrangement, followed by BA-1, B1, and CyIg expression.

Antigens, Surface↗