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Josef Prchal

Publications and source records attributed to Josef Prchal.

5 recordsLinked to original sources
PubMed2006

Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera.

We attempted to determine whether the immune reactions elicited by aberrantly expressed testis antigens contribute to the beneficial responses to interferon (IFN)-alpha therapy and other therapies in patients with polycythemia vera (PV). We screened a human testis cDNA library using SEREX (serological analysis of tumor antigens by screening an expression cDNA library with sera from three patients with PV who had undergone IFN-alpha-induced or other therapeutics-induced remission). We identified two novel PV associated tumor antigens, PV65 (eIF-2alpha) and PV13 (protamine 2). These 2 antigens elicited IgG antibody reactions in a subset of PV patients but not in healthy donors, suggesting that they are authentic tumor antigens. Increased phosphorylation of PV65 in response to stimulation of IFN-alpha, and upregulation of PV13 in tumor cells might enhance their abilities in elicitation of immune reactions in patients. These findings provide new insights into the mechanism underlying the regulation of the self-antigen repertoire in eliciting anti-tumor immune reactions in patients with polycythemia vera, and suggest their potential as the targets of novel immunotherapy.

Antibodies, Neoplasm↗
PubMed2006

An unconventional antigen translated by a novel internal ribosome entry site elicits antitumor humoral immune reactions.

Self-tumor Ags that elicit antitumor immune responses in responses to IFN-alpha stimulation remain poorly defined. We screened a human testis cDNA library with sera from three polycythemia vera patients who responded to IFN-alpha and identified a novel Ag, MPD6. MPD6 belongs to the group of cryptic Ags without conventional genomic structure and is encoded by a cryptic open reading frame located in the 3'-untranslated region of myotrophin mRNA. MPD6 elicits IgG Ab responses in a subset of polycythemia vera patients, as well as patients with chronic myelogenous leukemia and prostate cancer, suggesting that it is broadly immunogenic. The expression of myotrophin-MPD6 transcripts was up-regulated in some tumor cells, but only slightly increased in K562 cells in response to IFN-alpha treatment. By using bicistronic reporter constructs, we showed that the translation of MPD6 was mediated by a novel internal ribosome entry site (IRES) upstream of the MPD6 reading frame. Furthermore, the MPD6-IRES-mediated translation, but not myotrophin-MPD6 transcription, was significantly up-regulated in response to IFN-alpha stimulation. These findings demonstrate that a novel IRES-mediated mechanism may be responsible for the translation of unconventional self-Ag MPD6 in responsive to IFN-alpha stimulation. The eliciting antitumor immune response against unconventional Ag MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy.

Amino Acid Sequence↗
PubMed2004

Polycythemia and oxygen sensing.

Polycythemias can be differentiated based on the responsiveness of erythroid progenitors to circulating cytokines. Primary polycythemias are characterized by an augmented response due to acquired somatic or inherited germ-line mutations that are expressed within hematopoietic progenitors causing increased proliferation or decreased apoptosis and resulting in accumulation of red blood cells. In terms of oxygen requirements, primary polycythemias can be viewed as the production of hemoglobin fully dissociated from the tissue oxygen needs and from the oxygen sensing pathway. Polycythemia vera (PV) is the most common primary polycythemia. PV bone marrow progenitors cells can form erythroid colonies in the absence of exogenous erythropoietin in vitro. These endogenous erythroid colonies (EEC) are useful in differentiating PV and secondary polycythemias. They also can differentiate PV where this feature is independent of Epo signalling from primary familial and congenital polycythemia. In this autosomal dominant primary polycythemia, at variance with PV, EEC formation is abolished by anti-Epo and anti-Epo receptor neutralising antibodies. Mutations of the EPOR have been described and resulted in nine cases in truncated EPORs lacking the cytoplasmic carboxy-terminal of the receptor which possesses a negative growth regulatory domain. However, recent data suggest that different mutations may cause PFCP in most cases. Secondary polycythemia can be viewed as either physiological response to satisfy the oxygen needs of the tissues, resulting for instance from high affinity hemoglobins or BPG mutase deficiency, or as the result of germ-line or somatic mutations disturbing the oxygen sensing pathway or its target: Epo. Chuvash polycythemia is a frequently symptomatic disorder with an autosomal recessive inheritance and inappropriately high Epo levels. The erythroid progenitors are hypersensitive to Epo linking this condition to both primary and secondary polycythemia. A germline missense mutation at nucleotide 598 in both alleles of the von Hippel-Lindau gene results in increased hypoxia inducible factor-1 (HIF-1) expression in normoxic conditions. HIF-1 controls the expression of many genes including Epo. Identifying causal defects in other situations like post-renal transplant erythrocytosis and cases of autosomal dominant polycythemia with high Epo levels will help further understanding of the regulation of erythropoiesis.

Erythrocytes↗
PubMed2002

Excessive erythrocytosis, chronic mountain sickness, and serum cobalt levels.

In a subset of high-altitude dwellers, the appropriate erythrocytotic response becomes excessive and can result in chronic mountain sickness. We studied men with (study group) and without excessive erythrocytosis (packed-cell volume >65%) living in Cerro de Pasco, Peru (altitude 4300 m), and compared them with controls living in Lima, Peru (at sea-level). Toxic serum cobalt concentrations were detected in 11 of 21 (52%) study participants with excessive erythrocytosis, but were undetectable in high altitude or sea-level controls. In the mining community of Cerro de Pasco, cobalt toxicity might be an important contributor to excessive erythrocytosis.

Adult↗