thymosin and Leukemia

Topics: Aging; Animals; Autoimmune Diseases; Disease Models, Animal; Humans; Immunity; Immunologic Deficiency Syndromes; Immunologic Techniques; Leukemia; Neoplasms; T-Lymphocytes; Thymosin; Thymus Gland; Thymus Hormones

Thymus tissue implants, thymic epithelial cells obtained from third party donors sharing one HLA-A and -B locus with the recipient, or the thymic hormones thymosin fraction 5 and thymopentin were given to recipients of HLA-identical sibling bone marrow to prevent chronic graft-versus-host disease (GVHD) and accelerate immunologic reconstitution. The clinical courses of 17 patients receiving thymus tissue and 18 patients receiving thymic hormones were reported initially 5 years ago and showed no difference in the incidence of chronic GVHD or immunologic recovery from those of concurrent or historical controls. We report here for the first time nine new patients who received thymus tissue implants with modifications of the culture method to lower the number of lymphocytes in the transplanted tissue with the intent of reducing rejection of the thymus tissue grafts. The clinical outcomes and immunologic functions of these nine patients were similar to those of the recipients of the earlier thymus tissue implants. With follow-up now ranging from 2.2 to 12.3 years (median 6.7) for the total group, 16 patients are alive. Seven never developed chronic GVHD. Nine were treated for chronic GVHD, seven of whom recovered and are leading normal lives, one has chronic pulmonary insufficiency, and one is disabled from chronic GVHD. We conclude that thymus tissue grafts or thymic epithelial cells partially HLA-matched to the recipient, thymosin fraction 5, or thymopentin used as described were not effective in reducing the incidence of chronic GVHD, improving immunologic recovery, or altering long-term survival.

Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Child; Clinical Trials as Topic; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Leukemia; Male; Middle Aged; Peptide Fragments; Thymopentin; Thymopoietins; Thymosin; Thymus Gland; Thymus Hormones

Thymosin alpha1 (Talpha1), a 28-amino acid peptide, is a well-known immune system enhancer for the treatment of various diseases. In the present investigation, the effects of Talpha1 on the proliferation and apoptosis of human leukemia cell lines (HL-60, K562 and K562/ADM) were studied. The proliferation was significantly depressed after 96 h of treatment with Talpha1, and obvious signs of apoptosis, i.e., cell morphology, nuclei condensation and Annexin V binding, were observed thereafter. Moreover, the up-regulation of Fas/Apol (CD95) and decrease in bcl-2 anti-apoptotic gene expression were observed in apoptotic cells. The expression and the function of P-glycoprotein (P-gp) can be slightly inhibited by Talpha1. It is noteworthy that K562 and K562/ADM were more sensitive than HL-60 cells when subjected to Talpha1. Furthermore, HepG-2, the human hepatoma cell line, displayed significant less sensitivity to Talpha1 than all the human leukemia cell lines. D-Tubocurarine (TUB), a nicotinic acetylcholine receptors (nAChRs) antagonist, significantly antagonized the inhibition effects induced by Talpha1, whereas atropine, a muscarinic acetylcholine receptor antagonist, did not exhibit such effects. All the results indicate that Talpha1 was able to significantly suppress proliferation and induce apoptosis in human leukemia cell lines.

Topics: Annexin A5; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Multiple; fas Receptor; Genes, bcl-2; HL-60 Cells; Humans; K562 Cells; Leukemia; Receptors, Cholinergic; Thymalfasin; Thymosin; Time Factors; Tubocurarine

Thymosin beta 4 (beta 4) is an ubiquitous 5-kDa peptide that has been identified as an actin-sequestering peptide. In this work, Northern blot analysis was used to study the beta 4 mRNA levels during the cell cycle of rat thymocytes and hepatocytes as well as in human lymphocytes from patients with leukemia. beta 4 mRNA was found in all the stages of thymocyte and hepatocyte cell cycle, showing an increase in the S-phase which was maintained during the G2 and M phases. Incubation of splenic T-cells with concanavalin A, phorbol myristate acetate or the ionophore A23187 lead to a similar increase of beta 4 transcript during the S-phase. The increase in beta 4 mRNA observed in the G2/M boundary of the cell cycle, together with its ability to inhibit actin polymerization, suggests a possible role of beta 4 in the the morphological changes and actin redistribution occurring during the cytokinesis.

Topics: Actins; Animals; Calcimycin; Cell Division; Concanavalin A; Gene Expression; Humans; Leukemia; Liver; Liver Regeneration; Lymphocytes; Peptides; Rats; Rats, Sprague-Dawley; RNA, Messenger; Tetradecanoylphorbol Acetate; Thymosin; Thymus Gland; Time Factors

Thymosin beta 4 (T beta 4) was originally isolated as a thymic hormone. Its functional properties remain obscure; however, the N-terminal peptidic sequence could have a regulatory function on hematopoietic stem cell proliferation. To investigate the mechanism of T beta 4 expression, we studied T beta 4 gene expression in various leukemic cells and in established cell lines. Among leukemic cell samples obtained from leukemia patients, the T beta 4 gene was highly expressed in a lymphoid lineage, especially in adult T-cell leukemia (ATL) cells, rather than in a granulocyte lineage. The T beta 4 gene was more transcriptionally active in chronic B-cell leukemia than in acute B-cell leukemia, while it was inactive in plasma cell leukemia. We also found that cells from one of the ATL patients transcribed a heterogeneous message. T beta 4 messenger RNA increased in MOLT-3 during differentiation by 12-O-tetradecanoylphorbol-13-acetate (TPA), in HL60 cells induced by TPA or dimethylsulfoxide and K562 cells stimulated by cytosine arabinoside or hemin. The genomic sequence of T beta 4 is considered to be highly conserved. Only 1 of 20 genomes from normal or hematopoietic malignant cells showed restriction fragment length polymorphism. These findings, along with previous data, suggest that T beta 4 may be a new marker of differentiation of hematopoietic cells.

Topics: Adult; Cell Differentiation; Cell Line; Female; Gene Expression Regulation; Hematopoietic Stem Cells; Humans; Kinetics; Leukemia; Leukocytes; Male; Middle Aged; Reference Values; RNA, Messenger; Tetradecanoylphorbol Acetate; Thymosin; Transcription, Genetic

We isolated the cDNA for human prothymosin alpha (ProT alpha) from a human peripheral T-cell library using two synthetic oligonucleotides as probes. Hybridization studies with this cDNA showed that the ProT alpha mRNA is detectable in all the rat tissues studied but is most abundant in thymus and within this gland mainly synthesized by thymocytes. In the T-cell lineage, its expression is higher in proliferative immature thymocytes than in pre- and post-thymic T lymphocytes. A quite similar pattern was obtained with the proliferation-related protein proliferating cell nuclear antigen/cyclin. These data show that ProT alpha mRNA levels change with the maturation stage of T-cells. Moreover, the amount of ProT alpha transcript is increased in lymphocytes from human patients with leukemias. Our findings indicate a role for ProT alpha linked to lymphocyte proliferation.

Topics: Amino Acid Sequence; Animals; Base Sequence; Cells, Cultured; DNA; Gene Expression Regulation; Genes; Humans; Leukemia; Lymphocyte Activation; Molecular Sequence Data; Protein Precursors; Rats; Reference Values; Restriction Mapping; RNA, Messenger; T-Lymphocytes; Thymosin; Transcription, Genetic

In acute leukemia, the frequency of the E+ cells among the blood mononuclears before and after their incubation with human serum thymic factor was investigated by means of the E rosette assay. In 4 of 24 patients tested, the thymic factor incubation of their peripheral blood cells increased the number of the E+ cells among the mononuclears. Prospective importance of the test either in investigating whether a T0 leukemia might really exist, or in monitoring possible variations of the immature T cell counts in relationship to the patient's treatment and his disease course, are discussed.

Topics: Acute Disease; Adolescent; Adult; Cell Differentiation; Child; Child, Preschool; Diagnosis, Differential; Female; Humans; Leukemia; Male; Middle Aged; Remission, Spontaneous; Rosette Formation; T-Lymphocytes; Thymosin; Thymus Hormones