PROCUREMENT OF TISSUE FOR MAKING EPSTEIN-BARR VIRUS (EBV) SPECIFIC CYTOTOXIC T

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a procurement only protocol This is a companion protocol to the following GCRC supported research studies: H-9935, 6676, 9454, 8216 Using blood obtained from eligible subjects, will enable the ability to produce EBV specific cytotoxic T lymphocytes (CTLs). The objective of this protocol is to obtain tissue (blood) for the purpose of making EBV specific cytotoxic T lymphocytes (CTLs). If successful, these cells may be given back to the patient in the future should they become eligible for one of the EBV-CTL research studies being conducted. Epstein-Barr virus (EBV) is a human lymphotropic herpes virus able to infect and immortalize human B lymphocytes. In the primary infection, occurring via saliva exchange, EBV infects oropharyngeal epithelial cells that support the lytic replication and allow the transmission of the virus to circulating B cells. Once in the B cells, the EBV genome is maintained in a latent form. B cells infected with EBV in vitro undergo transformation as result of the expression of latency-associated transforming proteins. These B cells always express a number of EBV gene products including the nuclear antigens EBNA1, EBNA2, EBNA3A, EBNA3B, EBNA 3C, EBNA LP and the latent membrane proteins LMP1 and LMP2. The proliferation of EBV-infected cells expressing these latency-associated transforming proteins is controlled by specific T cells. Hence, in a majority of the population, primary infection is asymptomatic or results in a mild and self-limiting illness (infectious mononucleosis, IM). Following infection, individuals are life-long virus carriers. Unlike patients with a normal immune system, people with congenital or acquired immunodeficiency are highly susceptible to the development of EBV driven lymphoproliferative disease (EBV-LPD) since the reactivation of EBV is less tightly controlled by a cell-mediated response. Evidence suggests that EBV specific CD8+ CTLs are the most important defense mechanism against outgrowth of EBV infected B cells. These cells recognize peptide fragments derived from viral antigens expressed in association with MHC molecules on the surface of B cells. The state of reduced or suppressed T cell activity in immunosuppressed individuals interferes with the immunosurveillance system and increases the risk of EBV-driven proliferation of the infected cells, allowing Bcell clones with a growth advantage to emerge and result in one or more clonal populations. Another syndrome associated with defective immune control of EBV is severe chronic active EBV (SCAEBV) infection syndrome where patients present with chronic fatigue, fever, hepatosplenomegaly and lymphoadenopathy . Patients characteristically have elevated antibody titers to the viruscapsid antigen and low or absent antibody to EBNA and free virus in serum or other body fluids. EBV is also associated with other malignancies and is found in the malignant cells of 40% of patients with Hodgkin Disease, and most cases of nasopharyngeal carcinoma. Studies in animals and humans have shown that EBV specific T-cells can be generated ex-vivo to produce an anti- EBV infected cell immune response. We have used this approach in patients post bone marrow transplant where donor derived EBV-specific CTLs have been effective both in preventing and treating EBV lymphoproliferation. We are now extending this approach to other EBV-associated diseases including EBV lymphomas arising after solid organ transplant, EBV positive Hodgkin disease, nasopharyngeal carcinoma and severe chronic EBV infection.