PREVENTION AND ANTIVIRAL TREATMENT FOR EBV LYMPHOMAGENESIS

EBV 淋巴生成的预防和抗病毒治疗

• 批准号: 8502416
• 负责人: JOSEPH S PAGANO
• 金额: $ 17.86万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502416
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adult; Adverse effects; Affect; Alternative Therapies; Animal Model; Animals; Antiviral Agents; B-Cell Lymphomas; B-Lymphocytes; Blinded; Body Weight decreased; Cell Transplants; Cells; Clinical Trials Design; Controlled Study; Cytomegalovirus; Development; Disease; Dose; Epstein-Barr Virus Infections; Gene Rearrangement; Generations; Genomics; Hematopoietic stem cells; Human; Human Herpesvirus 4; Immune response; Immune system; Individual; Infection; Lymphoid; Lymphoid Cell; Lymphoma; Lymphomagenesis; Lymphoproliferative Disorders; Lytic; Lytic Phase; MS4A1 gene; Malignant Neoplasms; Modeling; Mus; Natural Killer Cells; Organ Transplantation; Pathogenesis; Patients; Pharmaceutical Preparations; Phase; Phenotype; Placebo Control; Placebos; Prevention; Signal Transduction; Stem cells; System; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissue Donors; Transplant Recipients; Transplantation; Variant; Viral; Viral Load result; Virus; acquired immunodeficiency; antitumor agent; arm; base; cohort; control trial; design; dosage; effective therapy; experience; inborn immunodeficiency; infected B cell; latent infection; maribavir; mouse model; pilot trial; placebo controlled study; prevent; prospective; reconstitution; rituximab; standard of care; transmission process; tumor

DESCRIPTION (provided by applicant): Fifty years after discovery of Epstein - Barr virus there is still no effective treatment to interrpt pathogenesis of any EBV infections including those that result in fatal B-cell lymphomas in patients with acquired or inborn immunodeficiency. Rapid development of humanized mice models engrafted with transplanted human hematopoietic stem cells that generate human B, T, and NK cells and a reconstituted human immune system have now provided small animal models suitable for treatment of studies human EBV disease. Infection of humanized NOD/SCID ?C-/- (NSG) mice with EBV produces infection that proceeds from a subclinical phase during which virus is replicated to development of polyclonal EBV B-cell lymphoproliferative disease and ultimately lethal CD20+, EBV EBER-positive, large-cell monoclonal B-cell lymphomas. In a single Aim we will infect with EBV cohorts of NSG mice reconstituted with stem cells from single donors for controlled trials designed to test whether an anti-EBV drug, Maribavir (MBV) alone or together with Rituximab can abort or retard progression from the reversible polyclonal lymphoproliferative phase of disease, when there is cell-to-cell transmission of virus, to irreversible monoclonal lymphoma. Polyclonal and monoclonal phases will be distinguished both by IgH gene rearrangements and EBV genomic terminal probe analyses. Basis for comparisons between treatment and placebo groups will be survival of animals analyzed with Kaplan-Meier survival curves and for statistical significance. These studies will be conducted in blinded fashion and will provide the first prospective, placebo-controlled trials of whether an antiviral drug, either alone or together with the nontoxic anti-tumor agent Rituximab, can affect the course of an EBV malignancy. Results may provide the basis for a nontoxic alternative therapy for these ultimately lethal post-transplant lymphomas. Results may also be of use in patients with AIDS who have rising EBV viral loads that may herald genesis of B-cell lymphomas.

描述（由申请人提供）：