ABSTRACT
New, potentially tumor-specific antigens have been described in Bcr/Abl positive leukemias. Besides the main BCR/ABL hybrid fusion transcripts, a small number of transcripts derived from alternative splicing between BCR exons 1, 13, and 14 with ABL exons 4 and 5 have been identified. These variants are expressed in chronic myelogenous leukemia and acute lymphocytic leukemia patients. The transcriptional products were characterized at their C-terminus by a large amino acid portion derived from out of frame (OOF) reading of the ABL gene. This OOF peptide is expressed only in leukemic cells and has no homology with known human proteins. In order to study an in vivo model, three 39-amino acid peptides, each corresponding to a third of the whole human OOF peptide sequence, were tested for their capacity to elicit specific immune responses in HLA A2.1 transgenic mice. Peptides A and B, but not C, induced the production of specific antisera, while A and C induced the generation of specific cytotoxic T lymphocytes.
Subject(s)
Alternative Splicing , Cancer Vaccines/immunology , Frameshift Mutation/immunology , Fusion Proteins, bcr-abl/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Amino Acid Sequence , Animals , Antigens, Neoplasm/genetics , Antigens, Neoplasm/immunology , Cell Line, Tumor , Enzyme-Linked Immunosorbent Assay , Frameshift Mutation/genetics , Fusion Proteins, bcr-abl/genetics , HLA-A2 Antigen/genetics , Humans , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Molecular Sequence Data , Peptides/genetics , Peptides/immunology , Proto-Oncogene Proteins c-bcr/genetics , Proto-Oncogene Proteins c-bcr/immunology , T-Lymphocytes, Cytotoxic/immunologyABSTRACT
Somatostatin (SST) regulates the function of the central and peripheral nervous system, the endocrine and exocrine organs, as well as the vascular and immune system. These actions are mediated by five specific membrane somatostatin receptors. This study compares the effects on human lymphocytes of two long-acting somatostatin analogues that have different receptor affinity: octreotide and pasireotide. Both analogues have an antiproliferative effect on human lymphocyte proliferation, but they act at different concentration and, while octreotide enhances IL10 and inhibits gamma IFN pasireotide inhibits IL2 and gamma IFN. In both sets of experiment the different behaviour of the two analogues could be due to their different affinity to the SSTR subtypes. Finally this study suggest that the growth inhibitory action of somatostatin analogues is an apoptotic phenomenon and it can be mediated by SSTR2a, in the case of octreotide, and by SSTR3 when pasireotide is used or it can be mediated by the heterodimerization of the two receptor.
Subject(s)
Lymphocyte Activation/drug effects , Octreotide/pharmacology , Oligopeptides/pharmacology , Adult , Apoptosis/physiology , Binding, Competitive , Cells, Cultured , Dose-Response Relationship, Drug , Humans , Interferon-gamma/antagonists & inhibitors , Interleukin-10/metabolism , Interleukin-2/antagonists & inhibitors , Lymphocytes/drug effects , Lymphocytes/metabolism , Lymphocytes/physiology , Octreotide/administration & dosage , Octreotide/metabolism , Oligopeptides/administration & dosage , Oligopeptides/metabolism , Osmolar Concentration , Receptors, Somatostatin/metabolism , Somatostatin/analogs & derivativesABSTRACT
BIM 23A761, selective for somatostatin receptors subtypes 2, 5 and the dopamine receptor subtype 2, and BIM 23A757 with affinity for SSTR2 and DAR2 were studied on human PBL proliferation and activation. BIM 23A761 was significantly more potent than specific SSTR and DAR2 agonists in suppressing lymphocyte proliferation induced by mitogen or alloantigen, while BIM 23A757 was more potent than specific SSTR2 and DAR2 agonists in suppressing antigen induced proliferation only. Both molecules displayed enhanced potency in suppressing IFNgamma and IL-6 secretion compared with the SSTR and DAR2 analogs, while only BIM 23A761 was able to inhibit IL-2 secretion and its effect is more potent than the control analogs. Furthermore BIM 23A761 inhibit cell progression into the S phase and then into the G2/M, while BIM 23A757 inhibited bromodeoxyuridine incorporation only during the S phase. Both chimeric molecules resulted significantly more effective than the respective controls.
