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Titolo:
ALLOANTIGEN-INDUCED UNRESPONSIVENESS IN CORD-BLOOD T-LYMPHOCYTES IS ASSOCIATED WITH DEFECTIVE ACTIVATION OF RAS
Autore:
PORCU P; GADDY J; BROXMEYER HE;
Indirizzi:
INDIANA UNIV,SCH MED,WALTHER ONCOL CTR,DEPT IMMUNOL MICROBIOL,1044 W WALNUT ST,ROOM 302 INDIANAPOLIS IN 46202 INDIANA UNIV,SCH MED,WALTHER ONCOL CTR,DEPT IMMUNOL MICROBIOL INDIANAPOLIS IN 46202 INDIANA UNIV,SCH MED,DEPT MICROBIOL IMMUNOL INDIANAPOLIS IN 46202 INDIANA UNIV,SCH MED,DEPT MED HEMATOL ONCOL INDIANAPOLIS IN 46202 WALTHER CANC INST INDIANAPOLIS IN 46202
Titolo Testata:
Proceedings of the National Academy of Sciences of the United Statesof America
fascicolo: 8, volume: 95, anno: 1998,
pagine: 4538 - 4543
SICI:
0027-8424(1998)95:8<4538:AUICTI>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
VERSUS-HOST DISEASE; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNAL-TRANSDUCTION; CELLS; RECEPTOR; CD28; STIMULATION; ANTIGEN; ANERGY; TRANSPLANTATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
30
Recensione:
Indirizzi per estratti:
Citazione:
P. Porcu et al., "ALLOANTIGEN-INDUCED UNRESPONSIVENESS IN CORD-BLOOD T-LYMPHOCYTES IS ASSOCIATED WITH DEFECTIVE ACTIVATION OF RAS", Proceedings of the National Academy of Sciences of the United Statesof America, 95(8), 1998, pp. 4538-4543

Abstract

Human umbilical cord blood T lymphocytes (CBTL) respond to primary allostimulation but they do not proliferate upon rechallenge with alloantigen. Using PKH-26-labeled cells created a proliferative block that was observed only in CBTL that have divided during primary stimulation (PKH-26(dim)) but not in unstimulated (PKH-26(bright)) CBTL. CBTL's secondary unresponsiveness resembles anergy and can be overcome by treatment with phorbol myristate acetate (PMA) and ionomycin or by high doses (50-100 units/ml) of interleukin 2. Addition of interleukin 2 to the primary cultures does not prevent the induction of secondary unresponsiveness. Defective Ras activation is detected in PKH-26(dim) CBTL during secondary response to alloantigen or after antibody-mediated T cell receptor stimulation whereas Ras is activated and proliferation is induced in CBTL during primary alloantigenic stimulation. Upon stimulation with PMA plus ionomycin, PMA plus alloantigen, but not alloantigen plus ionomycin, Ras is activated in PKH-26(dim) CBTL, and the block in proliferation is overcome. Correction of PKH-26(dim) CBTL's proliferative defect correlates with PMA-induced Ras activation, suggesting adefect in the signaling pathway leading to Ras. Ras-independent signals, necessary but not sufficient to induce PKH-26(dim) CBTL proliferation, are provided by alloantigen exposure, as evident by the ability of PMA plus alloantigen but not PMA alone to overcome the proliferativeblock. Functional signal transduction through CD28 in PKH-26(dim) CBTL is supported by detectable CD28-mediated PI-3 kinase activation after PKH-26(dim) CBTL's exposure to alloantigen or CD28 cross-linking. These results suggest that defective activation of Ras plays a key role in PKH-26(dim) CBTL's secondary unresponsiveness and point to a defectalong the T cell receptor rather than the CD28 signaling pathway.

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Documento generato il 07/04/20 alle ore 21:59:02