2002 Fiscal Year Final Research Report Summary
Analysis on the activated T-cells in lymphoproliferative diseases
| Project/Area Number |
13670814
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kyushu University |
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Principal Investigator |
OHGA Shouichi Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Lecturer, 医学部附属病院, 講師 (60233053)
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| Co-Investigator(Kenkyū-buntansha) |
TAKADA Hidetoshi Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Assistant Professor, 医学研究院, 助手 (70294931)
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| Project Period (FY) |
2001 – 2002
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| Keywords | lymphoproliferative diseases (disorders) / perforin / activated T cell / Fas / activation-induced cell death (AICD) / hemophagocytic lymphohistiocytosis (HLH) / autoimmune lymphoproliferative syndrome (ALPS) / hyper-IgE syndrome (HIES) |
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| Research Abstract |
Lymphoproliferative disease (LPD) is defined as a clonal disorder of lymphocytes without histopathological evidence of malignancy. Epstein-Barr virus (EBV) is reactivated and associated with the development of B-cell LPD in immunodeficient patients. This virus infects T/NK cells in immunocompetent subjects and induces EBV^+ T-cell LPD including chronic active EBV infection (CAEBV) and hemophagocytic lymphohistiocytosis (HLH). On the other hand, there is a group of inherited LPD caused by the defective functional molecule of T cells. Patients with primary HLH or autoimmune lymphoproliferative syndrome (ALPS) show hypercytokinemia or autoimmunity, because the cytotoxcity and activation-induced cell death (AICD) are impaired by the defects of perforin and Fas, respectively. Hyper-IgE syndrome (HIES) is a congenital immunodeficiency characterized by recurrent infections, marked IgE elevation, and increase of activated T cells. The defective IFNγ production is implicated in the pathogenesis
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of HIES. The present study revealed that the cytokines released from persistently activated T cells could contribute to the pathophysiology of these diseases.
1) primary HLH: Perforin gene defects were found in 2/8 Japansese patients with familial HLH (FHL), and 1/7 patients without affected siblings (4 novel mutations). The protein was not expressed in CD8^+/CD56^+ cells of the patient. The frequency of mutation was 〜20% of FHL in Japan.
2) ALPS: Patients with CD4^-CD8^- double negative (DN) αβT-cell expansion showed high serum IL-10 levels. IL-10-expressing DNT cells were increased in patients with lymphoproliferation. Real-time PCR revealed 〜100 times higher IL-10, but not, IFNγ or TGFβ in DN than in single positive T-cells. IL-10 was exclusively expressed in DN αβ but not γδ-cells. Circulating DN αβT-cells may constitutively express IL-10 and contribute to the ALPS phenotype.
3) HIES: Cytokine profile of HLA-DR^+ and DR^- T-cells was analyzed. IFNγ/IL-4 or IFNγ/IL-10 ratio in DR^+ T-cells of HIES was lower than each of chronic granulomatous disease (CGD). TGFβ/IL-4 ratio in DR^+ T-cells of HIES was lower than that of atopy or CGD. TGFβ/IL-4 in DR^- T-cells of HIES was also lower than that of atopy. The statistical analysis revealed that TGFβ/IL-4 ratios in DR^+ or DR^- T-cells were the most powerful parameters to distinguish HIES from atopy and/or CGD. The in vivo activated T-cells of HIES might not sufficiently express IFNγ and TGFβ genes to counteract on the IL-4 dependent IgE production. The reduced TGFβ expression may imply the indigenous T-cell defects of HIES. Less
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[Publications] Kimura H, Morishima T, Kanegane H, Ohga S, Hoshino Y, Maeda A, Imai S, Okano M, Morio T, Yokota S, Tsuchiya S, Yachie A, Imashuku S, Kawa K, Wakiguchi H, and Members of the Japanese Association for Research on Esptein-Bar Virus and related Diseases:: "Prognostic factors for chronic active Epstein-Barr virus infection."J Infect Dis. 187. 527-533 (2003)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Ohga S, Ohara A, Hibi S, Kojima S, Bessho F, Tsuchiya S, Ohshima Y, Yoshida N, Kashii Y, Nishimura S, Kawakami K, Nishikawa K, Tsukimoto J for the Aplastic Anemia Committee of the Japanese Society of Pediatric Hematology:: "Treatment responses of childhood aplastic anemia with chromosomal aberrations at diagnosis."Br J Haematol. 118. 313-319 (2002)
Description
「研究成果報告書概要(欧文)」より
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