After infection with Epstein-Barr virus (EBV), males with the X- linked lymphorproliferative syndrome (XLP) develop fatal or life- threatening infectious mononucleosis (IM), acquired hypogammaglonbulinemia and bone marrow hypoplasias, or B cell malignant lymphomas. Mortality is 85% by 10 and 100% by 40 years of age. We seek to detect mechanisms responsible for the pathogenesis of EBV-induced immunodeficiency and steps from the premalignant state to malignant lymphoma by: 1) maintaining and updating XLP and Fatal IM Registries, 2) detecting XLP by restriction fragment length polymorphisms linkage analysis with the XLP locus and by assessing antibody responses to bacteriophage OX174 and EBV, and 3) identifying mechanisms of acquired immunodeficiency post-EBV infection and steps in conversion from the premalignant state to malignant lymphoma. Detection of chromosomal translocations by karyotying and/or genetic alterations of c-myc and c-fgr and Ig genes and presence of EBV genome will be achieved by Southern blot analyses. We will measure expression of c-myc protein in lymphoid cells using monoclonal antibodies and flow cytometry. The expression of latent membrane protein and EBV nuclear antigen will be detected in the lymphoproliferative lesions using immunoblotting. Thereby we will determine whether karyotypic and molecular changes in a proliferating B cell endow the cell with enhanced growth (i.e., due to increase c-myc expression) and resistance to cytotoxic T cells (i.e., due to decreased expression of EBV latent membrane protein). These findings will be evaluated and compared to morphological features (i.e., malignant lymphoma vs IM) and clinical behavior. Results of these studies ought to provide improved detection of XLP, prevention, and therapy for EBV-induced lymphoproliferative diseases in immune deficient patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030196-08
Application #
3169127
Study Section
Pathology B Study Section (PTHB)
Project Start
1982-02-01
Project End
1991-08-31
Budget Start
1989-09-01
Budget End
1991-08-31
Support Year
8
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Okano, M; Thiele, G M; Purtilo, D T (1993) Variable presence of circulating cytokines in patients with sporadic or X-linked lymphoproliferative disease with fatal infectious mononucleosis. Pediatr Hematol Oncol 10:97-9
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Grierson, H L; Skare, J; Church, J et al. (1993) Evaluation of families wherein a single male manifests a phenotype of X-linked lymphoproliferative disease (XLP). Am J Med Genet 47:458-63
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Egeler, R M; de Kraker, J; Slater, R et al. (1992) Documentation of Burkitt lymphoma with t(8;14) (q24;q32) in X-linked lymphoproliferative disease. Cancer 70:683-7
Turner, A M; Berdoukas, V A; Tobias, V H et al. (1992) Report on the X-linked lymphoproliferative disease in an Australian family. J Paediatr Child Health 28:184-9
Ellwein, L B; Purtilo, D T (1992) Cellular proliferation and genetic events involved in the genesis of Burkitt lymphoma (BL) in immune compromised patients. Cancer Genet Cytogenet 64:42-8
Pirruccello, S J; Nakamine, H; Beisel, K W et al. (1992) Hemagglutination and graft-versus-host disease in the severe combined immunodeficiency mouse lymphoproliferative disease model. Am J Pathol 140:1187-94
Okano, M; Davis, J R; Brichacek, B et al. (1992) Early activation of the proto-oncogene c-fgr during Epstein-Barr virus immortalization. Cancer Lett 64:11-5
Okano, M; Bashir, R M; Davis, J R et al. (1991) Detection of primary Epstein-Barr virus infection in a patient with X-linked lymphoproliferative disease receiving immunoglobulin prophylaxis. Am J Hematol 36:294-6

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