Effects of interleukin-11 on the proliferation and cell cycle status of myeloid leukemic cells

Interleukin-11 (IL-11) is a pleiotropic cytokine with effects on many different targets. Within the hematopoietic system, the effects of IL- 11 are largely manifest only through combination with other cytokines, including IL-3 and Steel factor (SF). In the present study, we addressed the question of IL-11 responsiveness within the different types of human leukemic cells, as well as the mechanism of action of IL- 11 at the cellular level. Analysis of a panel of samples from different patients with acute myeloblastic leukemia (AML) and myeloid leukemic cell lines indicated that IL-11 alone was ineffective in supporting myeloid leukemic cell growth but frequently enhanced growth supported by IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), or SF. In contrast, three acute pre-B lymphocytic leukemia (pre-B-ALL) and two acute T lymphocytic leukemia (T-ALL) lines failed to respond to IL- 11 alone or when combined with other cytokines. The growth enhancement of IL-11 among the AML patient samples was dose dependent and remarkably constant with half-efficient concentrations in the range of 0.3 to 0.4 ng/mL. The thymidine suicide studies with the patient samples revealed that 40% to 50% of the blast cells were in S-phase when exposed for 16 hours to IL-3 and this level was increased to 70% to 90% in response to either IL-11 or IL-6. Our data suggest that the latter two interleukins act synergistically with the direct mitogenic factor, IL-3, in triggering AML blast-cell proliferation. Detailed analysis with several patient samples further revealed that SF and IL- 11 both enhance IL-3-supported clonogenic growth of AML blasts and the combination of all three growth factors yields optimal growth. In contrast, IL-6 does not further enhance the effect of IL-11. These results indicate that SF and IL-11 enhance IL-3-dependent clonogenic growth through two distinct pathways, whereas IL-6 and IL-11 may trigger the same pathway.     

Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta

Peripheral T-cell lymphomas consist of a clinically heterogeneous group of malignant disorders whose immunophenotype usually corresponds to that of normal mature T cells. We describe and correlate the clinical, histopathologic, phenotypic, and genotypic findings in two patients with malignant lymphoma presenting with hepatosplenic disease. The morphologic pattern of lymphoma was that of a sinusal/sinusoidal infiltration in spleen, marrow, and liver. This morphologic characteristic was associated with the presence of a productive clonal rearrangement of the T-cell receptor (TCR) delta gene. Lymphoma cells expressed a CD3-TCR-gamma delta- phenotype. They were also double negative (ie, CD4-CD8-) and lacked the CD5 and CD7 antigens. In one patient, tumor progression was associated with phenotypic changes that resulted in a CD3-TCR-gamma delta- phenotype with the same delta-gene rearrangement as initially. These observations suggest the existence of a new type of peripheral T-cell lymphoma characterized by its hepatosplenic presentation, and by the sinusal/sinusoidal tropism and the TCR-gamma delta phenotype of the malignant cells.     

Recombinant human interleukin-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin

Interleukin-11 (IL-11) is a novel multifunctional hematopoietic cytokine capable of stimulating cells of the myeloid, lymphoid, erythroid, and megakaryocytic lineages in vitro. We have tested the pleiotropic properties of this cytokine on the hematopoietic recovery of mice after a combined regimen of sublethal irradiation and carboplatin administration. This regimen results in severe myelosuppression, characterized by a prolonged period of thrombocytopenia and severe anemia. Administration of recombinant human IL-11 (rhIL-11; 250 micrograms/kg/d) had multilineage effects on bone marrow and spleen hematopoietic activity, increasing the number of megakaryocyte, erythroid, granulocyte, and macrophage progenitors compared with the vehicle-treated controls. This was reflected in the peripheral circulation by a reduction of both the platelet and hematocrit nadirs and a significantly reduced period of thrombocytopenia and anemia in the rhIL-11-treated mice. The results from this study support the broad spectrum of biologic activities that have been attributed to rhIL-11 in vitro and suggest that this cytokine may be an effective agent in the treatment of myelosuppression associated with cancer chemotherapy and bone marrow transplantation.     

High-dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma: results of a phase II trial involving 63 patients

Sixty-three patients with high tumor mass multiple myeloma were treated with high-dose chemotherapy and total body irradiation supported by autologous blood stem cell transplantation. After high-dose therapy, they were monitored for a median of 44 months. Seven patients died early from toxicity. All the other patients, including those whose disease was resistant to previous therapies, showed a tumor mass reduction. At 6 months postengraftment, 40 (71%) of the surviving patients had minimal residual disease and 11 (20%) were in apparent complete remission. During follow-up, 25 out of the 63 (39%) patients relapsed and 16 of these died; 31 (49%) had a sustained remission. The median overall and event-free survival times after transplantation were 59 and 43 months, respectively. The initial serum beta 2-microglobulin value (> or < 2.8 mg/L) and length of previous therapy (> or < 6 courses of chemotherapy) were the only significant prognostic factors. In all surviving patients, blood stem cell autograft provided satisfactory and sustained haematopoietic reconstitution most often within 15 days. High dose chemoradiotherapy followed by autologous blood stem cell transplantation is thus an important therapeutic option for young patients with aggressive multiple myeloma.     

Fetal liver cells produce both fetal and adult erythrocytes in semiallogeneic radiation chimeras: possible influence of adult environment

Two kinds of erythrocytes are released in the blood of irradiated adult hybrid mice grafted with parental fetal liver cells: fetal antigen- bearing erythrocytes (Ft+ cells) and adult-type Ft- erythrocytes. Both are of parental origin, as determined by immune lysis using histocompatibility alloantigens. The latter cells make up all the recipient's red blood cells 2 mo after receipt of the graft, Ft+ cells then being no longer detected. The transient duality of erythropoiesis in irradiated adults grafted with fetal liver cells has been confirmed by studying the kinetics of CFU-E populations, as characterized by their ability to give rise to Ft+ or Ft- erythrocytes. The results are discussed in terms of environmental factors that influenc erythroid differentiation.     

Assessment of aldehyde dehydrogenase in viable cells

Cytosolic aldehyde dehydrogenase (ALDH), an enzyme responsible for oxidizing intracellular aldehydes, has an important role in ethanol, vitamin A, and cyclophosphamide metabolism. High expression of this enzyme in primitive stem cells from multiple tissues, including bone marrow and intestine, appears to be an important mechanism by which these cells are resistant to cyclophosphamide. However, although hematopoietic stem cells (HSC) express high levels of cytosolic ALDH, isolating viable HSC by their ALDH expression has not been possible because ALDH is an intracellular protein. We found that a fluorescent aldehyde, dansyl aminoacetaldehyde (DAAA), could be used in flow cytometry experiments to isolate viable mouse and human cells based on their ALDH content. The level of dansyl fluorescence exhibited by cells after incubation with DAAA paralleled cytosolic ALDH levels determined by Western blotting and the sensitivity of the cells to cyclophosphamide. Moreover, DAAA appeared to be a more sensitive means of assessing cytosolic ALDH levels than Western blotting. Bone marrow progenitors treated with DAAA proliferated normally. Furthermore, marrow cells expressing high levels of dansyl fluorescence after incubation with DAAA were enriched for hematopoietic progenitors. The ability to isolate viable cells that express high levels of cytosolic ALDH could be an important component of methodology for identifying and purifying HSC and for studying cyclophosphamide-resistant tumor cell populations.     

Clinical approaches to non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease(NAFLD)ranges from simple steatosis to nonalcoholic steatohepatitis(NASH),leading to fibrosis and potentially cirrhosis,and it is one of the most common causes of liver disease worldwide.NAFLD is associated with other medical conditions such as metabolic syndrome,obesity,cardiovascular disease and diabetes.NASH can only be diagnosed through liver biopsy,but noninvasive techniques have been developed to identify patients who are most likely to have NASH or fibrosis,reducing the need for liver biopsy and risk to patients.Disease progression varies between individuals and is linked to a number of risk factors.Mechanisms involved in the pathogenesis are associated with diet and lifestyle,influx of free fatty acids to the liver from adipose tissue due to insulin resistance,hepatic oxidative stress,cytokines production,reduced very low-density lipoprotein secretion and intestinal microbiome.Weight loss through improved diet and increased physical activity has been the cornerstone therapy of NAFLD.Recent therapies such as pioglitazone and vitamin E have been shown to be beneficial.Omega 3 polyunsaturated fatty acids and statins may offer additional benefits.Bariatric surgery should be considered in morbidly obese patients.More research is needed to assess the impact of these treatments on a long-term basis.The objective of this article is to briefly review the diagnosis,management and treatment of this disease in order to aid clinicians in managing these patients.     

Comparing human and mouse salivary glands: A practice guide for salivary researchers

Mice are a widely utilized in vivo model for translational salivary gland research but must be used with caution. Specifically, mouse salivary glands are similar in many ways to human salivary glands (i.e., in terms of their anatomy, histology, and physiology) and are both readily available and relatively easy and affordable to maintain. However, there are some significant differences between the two organisms, and by extension, the salivary glands derived from them must be taken into account for translational studies. The current review details pertinent similarities and differences between human and mouse salivary glands and offers practical guidelines for using both for research purposes.