Prolonged defects of interleukin-2 production, responsiveness, and receptor expression in patients with acute lymphoblastic leukemia.

The proliferative responsiveness to, production of, and the expression of cell-surface receptors for interleukin-2 (IL-2) were examined in 14 children with acute lymphoblastic leukemia (ALL) in remission and receiving maintenance chemotherapy for 6 to 35 months; in 19 children with ALL in remission and off all therapy for 2 to 138 months; and 15 control subjects. Short-term concanavalin A (Con A)-activated, purified T lymphocytes from patients on, as well as patients off, therapy had a significantly decreased proliferative responsiveness to a saturating amount of exogenous, recombinant IL-2 as compared to control subjects (P less than 0.005 and less than 0.05, respectively). Phytohemagglutinin (PHA)-stimulated IL-2 production by peripheral blood mononuclear cells (PBMC) was also substantially decreased in both patient groups with the median values of IL-2 produced being 2.2, 2.1, and 8.1 U/mL in the on therapy, off therapy, and control groups, respectively. In addition, PHA-induced expression of cell-surface receptors for IL-2 on PBMC was significantly decreased in both patient groups as compared to control subjects (P less than 0.01). Lymphocyte proliferation to mitogens (PHA, Con A, and pokeweed mitogen) was similar in all three groups studied. These results demonstrate that substantial quantitative and qualitative abnormalities of the IL-2-T lymphocyte system are present in the majority of treated patients with ALL, not only during maintenance therapy, but also for a prolonged period after the cessation of all chemotherapy. These long-lasting defects of the IL-2 system are most likely a late effect of chemotherapy and may result in increased complications in some long-term survivors of ALL.

Immunological phenotype of lymphoid cells in regenerating bone marrow of children after treatment for acute lymphoblastic leukemia.

Bone marrow samples from 8 children treated for acute lymphoblastic leukemia (ALL) were investigated at cessation of cytostatic treatment and during 18 months thereafter. The course of the percentage of lymphoid cells and characterization of these cells by means of monoclonal antibodies, peanut agglutinin (PNA) binding and S-phase determination are shown. The percentage of lymphocytes rises in the first 1.5 months, followed by a non-significant decline. The percentage of cells in S-phase is higher at 0 months than at 6, 15 and 18 months. The percentage of T-cells does not change significantly. In the first 1.5 months a sudden rise in the percentage of common-ALL-antigen (cALLA)-positive lymphocytes occurs. The number of B-cells rises to a peak at 6 months. PNA positively increases to a maximum at 3 months and is correlated with positivity for markers of the B-cell lineage. The percentages of B-cells, cALLA-positive, and PNA-positive lymphocytes do not change significantly after they reach their maximum values and are still high at 18 months. Our results show that after cessation of chemotherapy for ALL a lymphoid cell regeneration occurs in the bone marrow consisting of cells of the B-cell lineage; many of these are cALLA-positive, but are discernible from their malignant counterparts by PNA-positivity.

Spontaneous proliferation of peripheral blood lymphocytes increased in patients with HTLV-I-associated myelopathy.

We found unstimulated (spontaneous) peripheral blood lymphocyte (PBL) proliferation significantly increased in 14 patients with human T-lymphotropic virus (HTLV)-I-associated myelopathy (HAM) compared with findings in HTLV-I seropositive non-HAM carriers (N = 8) or HTLV-I seronegative controls (N = 16). The proliferative response to phytohemagglutinin, concanavalin A, or pokeweed mitogen was decreased in the HAM patients. Cell clusters were frequent in cultures of unstimulated PBL from the HAM patients, but much less common in the controls or carriers. This spontaneous PBL proliferation was depressed when adherent-cell populations were depleted from the cultures. IL-2 activity increased in the supernatant of 3-day cultured cells from HAM patients, but not in cultured cells from the controls. Since IL-2 receptor positive cells increased in HAM, this spontaneous PBL proliferation is probably a response to IL-2 through the expression of IL-2 receptors.

Diabetes in transgenic mice resulting from over-expression of class I histocompatibility molecules in pancreatic beta cells.

A class I histocompatibility gene, H-2Kb, linked to the rat insulin promoter, is overexpressed in the pancreatic beta cells of transgenic mice. The mice, whether syngeneic or allogeneic to the transgene, develop insulin dependent diabetes without detectable T cell infiltration, suggesting a direct, non-immune role for the transgenic class I molecules in the disease process.

Mononuclear cell infiltrate and HLA-DR expression in low grade astrocytomas. An immunohistological study of 23 cases.

Frozen samples from 23 low grade (grade I and II) astrocytomas were studied by means of a panel of monoclonal antibodies to macrophages, lymphocytes (and their subsets) and HLA-DR antigens. Macrophages were present in low to moderate numbers in 38%-86% of cases, the variance in figures depending on the antibody used. T lymphocytes, the majority of CD8 phenotype, were detected in low numbers in 78% of tumours. B lymphocytes were scanty in 22% (5/22) and totally absent in the remaining cases. HLA-DR antigen was expressed by tumour cells in 35% (6/17) of cases. These findings indicate that in some low grade astrocytomas there is a mononuclear cell infiltrate with macrophages and secondarily CD8+ lymphocytes playing the major role. The significance of these findings remains speculative at present.

Early cellular events in pulmonary fibrosis.

In this review we have surveyed recent investigations of early cellular events in pulmonary fibrosis both in animal models and in human diseases. Analysis of the interactions of the numerous cell types in the lung following injury is an almost overwhelmingly complex enterprise. In the animal models experimental design has a profound effect on results, making it difficult to compare studies when species, fibrogenic agent, dose, route of exposure, schedule of administration, time course, and analytical methods may not be equivalent. In human diseases we are rarely able to obtain data at precisely the same time point in the course of the disease even among patients in the same study, and possible confounding variables present are legion. Transcending these difficulties for the moment, can we draw any conclusions from our current knowledge of early cellular interactions in pulmonary fibrosis? What is striking is not that there are so many agents that can potentially induce pulmonary fibrosis, but that the lung has such capabilities for recovery. Although the major effector cells may all initially participate in damaging the lung and initiating fibrosis, there is evidence that they may also have the capacity to participate in subsequent repair. Macrophages may initially recruit fibroblasts and stimulate them to proliferate, only to suppress them subsequently. Macrophage production of prostaglandins can lead to suppression of macrophage, neutrophil and lymphocyte responses, thus attenuating tissue injury and the development of fibrosis. Neutrophils may initially release toxic metabolites and enzymes that damage parenchyma. However, there is evidence that they may later play a role in attenuating fibrosis, perhaps through collagenase secretion, or through as yet unknown mechanisms. Lymphocytes may initially participate in a number of damaging ways by secreting chemoattractants for other cells and participating in destructive autoimmune processes. However, there is evidence that subpopulations of T cells may dramatically shift during the course of fibrosis, leading to attenuation of the process. It may thus be useful to consider irreversible pulmonary fibrosis as the end result of a process in which the balance of normal injury/repair mechanisms is disrupted. There is clearly no single "fibrogenic event." Rather, there seem to be a number of places where disruption of balance/repair processes may begin. In diseases of unknown etiology such as sarcoidosis or IPF, loss of control may occur at the genetic level, leading to the destructive alveolitis that is the apparent precursor of fibrosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Kinetic studies on lymphocytes labelled with indium 111-oxine in patients with chronic lymphocytic leukaemia.

The kinetics of 111Indium-oxine-labelled autologous blood lymphocytes were studied in normal subjects and 10 patients with chronic lymphocytic leukaemia (CLL). In both normal and leukaemic subjects, intravascular survival of lymphocytes was characterized by two exponential decreases, the first being a rapid one and the second slow phase. T 1/2 of the second phase for normal T lymphocytes (52.0 +/- 3.2 h: mean +/- SEM) was longer than that for B lymphocytes (31.6 +/- 2.8 h). T 1/2 of the second phase in patients with CLL was 15.1 to 192.6 h, which correlated well with the clinical stage of CLL by the Rai classification. Body surface scanning revealed prominent splenic accumulation of labelled cells in normal individuals and patients with CLL. Lymph node visualization was recognized in all patients with T-cell CLL; however, there was no visualization in 8 of the 9 patients with B-cell CLL. The longer survival time and splenic and lymph node visualization suggest that an expansion of the extravascular lymphocyte pool may be important in the pathophysiology of CLL.

Sister chromatid exchanges in leukemic patients.

Sister chromatid exchange (SCE) was studied in PHA-stimulated peripheral blood lymphocytes from 36 newly diagnosed and untreated leukemic patients: 16 with acute lymphoblastic leukemia (ALL), 10 with acute nonlymphocytic leukemia (ANLL), and 10 with chronic myelocytic leukemia (CML). The metaphases analyzed show no chromosomal abnormalities. The mean SCE frequency (mean +/- SE) for each group of patients was: 6.8 +/- 0.4, 6.6 +/- 0.3, and 7.0 +/- 0.6 per mitosis, respectively, which was significantly lower than the mean SCE score for 30 controls (8.7 +/- 0.2). No differences in SCE score among ALL, ANLL, and CML and a similar SCE frequency by chromosome number and group allowed consolidation of all the cases into a single group of 36 leukemic patients (6.8 +/- 0.3). When the frequency of SCE was compared by chromosome number and group between the leukemic patients with the control group, a significant decrease in SCE frequency was observed due to a low SCE score in almost all the complements, except chromosome #1. It is suggested that the low SCE rate is related to the leukemic process itself.

The effect of experimental hyperlipidemia on the angiogenic activity of rabbit peripheral blood lymphocytes.

Peripheral blood lymphocytes from young rabbits with experimentally evoked hyperlipidemia and atherosclerosis express enhanced angiogeneic activity. It seems that angiogenesis-enhancing factor in the sera of cholesterol fed rabbits is not present.

Lymphocyte locomotion in experimental allergic thyroiditis.

Experimental allergic thyroiditis was produced in rats by immunization with homologous thyroglobulin (Tg). The mechanisms of lymphocyte accumulation of the thyroid lesion were analyzed by using this experimental model. The sensitized lymph node cells were cultured with Tg. After 72 hr, the cell-free supernatant was found to contain a chemotactic factor for sensitized lymphocytes. Lymph node lymphocytes from animals immunized 3 weeks previously were the best source of such sensitized lymphocytes while the cells at the latter stage could not produce the factor. The culture supernatant was applied to a Sephadex G-100 gel filtration column. The results indicate that the molecular weight of the factor is around 12,400. Among lymph node lymphocytes, nylon-wool column nonadherent lymphocytes were the most responsive; adherent lymphocytes were not responsive. Thyroglobulin itself did not chemoattract lymphocytes obtained from rats immunized with Tg. This phenomenon was in contrast to macrophage chemotaxis in the same model in which macrophage itself can move toward Tg. In any event, these results seem to indicate that a chemotactic lymphokine may be playing an important role in the pathogenesis of lymphocyte accumulation of the thyroid lesion.

Viability of cultured peripheral blood mononuclear cells from atopic individuals.

The viability of cultured peripheral blood mononuclear cells (MNC) from atopic children was found to be subnormal. After 3 days of culture, less than 5% of cells from nonatopic children had died as judged by trypan blue exclusion tests, whereas more than 4 times as many dead cells were observed in cultures of cells from atopics with high IgE levels (greater than 400 units/ml). MNC from atopics with low or moderately increased IgE levels did not display any significantly decreased viability. Low cell viability was observed primarily in cultures from patients with atopic dermatitis, but also in cases with respiratory allergy with high IgE levels but without concomitant atopic dermatitis, there was a decreased viability. There was no evidence that low cell viability was causally related to occurrence of cytotoxic serum factors. Results of experiments where dibutyryl cyclic AMP or theophylline was included in the cultures suggested that a possible explanation for the decreased viability might be altered sensitivity of the cells to inactivation by cyclic AMP promoting substances.

Further studies on the inflammatory response induced by zinc wire implants in the central nervous system of rats.

Implantation of zinc wires into the central nervous system of adult Lewis rats initiates an inflammatory reaction with a predominantly mononuclear cell profile. Extensive cuffs of small lymphocytes, mature plasma cells, macrophages, and histiocytes are found around the site of the wire implant and around adjacent blood vessels. The inflammatory response persists for at least 35 weeks but, with time , is gradually replaced by extensive fibrosis, collagen deposition, and proliferation of glial cells in the adjacent neuropil. The Lesion is not necrotic, nor is it characteristic of a foreign body granuloma, since neither giant cells nor organized epithelioid cells are found. No obvious clinical effect is observed. The fact that the implantation of zinc wire initiates an inflammatory response which resembles certain immune-mediated reactions is consistent with the reports of others that zinc affects immunological responses both in vivo and in vitro. Other metals (Be, Co, Mg, Pt, and Ni), implanted to control for the effect of zinc, initiated responses that were both distinct for the metal used and reproducible, and thus underscore the significance of studying the role of metals in both acute and chronic diseases.