Epstein-Barr virus (EBV) is closely associated with the lymphomas and lymphoproliferative disorders (LPD) that arise in patients with acquired immunodeficiency. EBV is associated with the majority of AIDS-related immunoblastic lymphomas and virtually all cases of post-transplant lymphoma and LPD. Latent EBV infection in normal individuals is controlled by EBV-specific CD8+ T cell surveillance, and EBV-associated lymphoma and LPD in the immunodeficient is thus thought to arise as a result of impaired EBV-specific T cell immunity. In the light of these observations, this proposal will explore the potential for EBV-specific CD8+ T cell immunotherapy, using the SCID/hu mouse model of EBV-associated human B cell LPD. The SCID/hu mouse closely resembles the EBV-associated large-cell immunoblastic lymphoma that arise in the immunodeficient. There is in essence a single goal of this proposal; generation of well- characterized EBV-specific T cell lines or clones that can inhibit or reverse EBV-driven tumor development in SCID/hu mice. Two approaches will be considered: 1. Transfer of EBV-specific human CD8+ T cells to SCID mice bearing autologous EBV-induced human B cell tumors arising from injection of EBV- transformed lymphoblastoid cell lines (LCL). 2. Transfer of EBV-specific mouse CD8+ T cells. HLA A2.1/Kb transgenic mice will be primed to give and EBV-specific T cell response that recognizes HLA A2.1-expressing LCL. This strategy has the major advantage of allowing same-species T cell transfer experiments, facilitating reconstitution and evaluation of long-term EBV-specific T cell immunity in the context of severe immunodeficiency. T cell specificity and function will be characterized, and mechanisms of tumor inhibition will be investigated. T cells will be transferred at various times to assess therapy of early or advanced stages of disease; prevention reconstitution of EBV-specific T cell immunity will also be investigated. Strategies for enhancement of T cell engraftment and function in vivo will be explored. The principles established in this study will provide valuable information for the rational design of T cell immunotherapy for prevention or treatment of EBV-associated LPD and lymphoma in the setting of acquired immunodeficiency, most particularly transplant recipients and AIDS patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29CA063931-01
Application #
2106106
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1994-05-01
Project End
1995-01-31
Budget Start
1994-05-01
Budget End
1995-01-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Santin, A D; Bellone, S; Ravaggi, A et al. (2002) Induction of tumour-specific CD8(+) cytotoxic T lymphocytes by tumour lysate-pulsed autologous dendritic cells in patients with uterine serous papillary cancer. Br J Cancer 86:151-7
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Santin, A D; Hermonat, P L; Ravaggi, A et al. (2001) Expression of CD56 by human papillomavirus E7-specific CD8+ cytotoxic T lymphocytes correlates with increased intracellular perforin expression and enhanced cytotoxicity against HLA-A2-matched cervical tumor cells. Clin Cancer Res 7:804s-810s
Khanolkar, A; Yagita, H; Cannon, M J (2001) Preferential utilization of the perforin/granzyme pathway for lysis of Epstein-Barr virus-transformed lymphoblastoid cells by virus-specific CD4+ T cells. Virology 287:79-88
Santin, A D; Bellone, S; Ravaggi, A et al. (2000) Induction of ovarian tumor-specific CD8+ cytotoxic T lymphocytes by acid-eluted peptide-pulsed autologous dendritic cells. Obstet Gynecol 96:422-30
Fu, Z; Cannon, M J (2000) Functional analysis of the CD4(+) T-cell response to Epstein-Barr virus: T-cell-mediated activation of resting B cells and induction of viral BZLF1 expression. J Virol 74:6675-9
Santin, A D; Hermonat, P L; Ravaggi, A et al. (2000) Development and therapeutic effect of adoptively transferred T cells primed by tumor lysate-pulsed autologous dendritic cells in a patient with metastatic endometrial cancer. Gynecol Obstet Invest 49:194-203
Santin, A D; Hermonat, P L; Ravaggi, A et al. (2000) Interleukin-10 increases Th1 cytokine production and cytotoxic potential in human papillomavirus-specific CD8(+) cytotoxic T lymphocytes. J Virol 74:4729-37
Santin, A D; Hermonat, P L; Ravaggi, A et al. (2000) In vitro induction of tumor-specific human lymphocyte antigen class I-restricted CD8 cytotoxic T lymphocytes by ovarian tumor antigen-pulsed autologous dendritic cells from patients with advanced ovarian cancer. Am J Obstet Gynecol 183:601-9

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