REPERTOIRE AND AVIDITY OF ANTIvIRAL T CELLS

Sloan-Kettering Institute For Cancer Res, New York NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) and cytomegalovirus (CMV) can cause severe complications in patients undergoing allogeneic bone marrow transplantation. Virus specific T-lymphocytes play a critical role in controlling infection by these viruses. In this grant application we describe studies that will characterize EBV and CMV specific T-cell populations following allogeneic transplantation. The following are our specific aims: 1.) To characterize T-cell receptor repertoires and avidities of EBV and CMV specific CD8 T-cell populations in patients following allo-BMT. We will test the hypothesis that virus specific T-cell populations developing in transplant recipients have a narrower TCR repertoire when compared with the donor repertoire, and that a restricted TCR repertoire results in greater susceptibility to viral infection. We will also estimate relative T-cell avidities for cognate viral antigens by HLA-tetramer staining intensity and dissociation rates. 2.) To characterize effector functions of EBV and CMV specific CD8 T-cells in patients following allo-BMT. These studies will test the hypothesis that EBV or CMV specific T-cells may have deficiencies in effector functions following allo-BMT. We will measure direct antigen specific cytolytic activity and interferon-gamma, TNF and MIP-1Beta expression by virus specific CD8 T-cells. These studies will characterize the function of virus specific CD8 T-cell populations in transplant recipients. 3.) To characterize CD4 T-cell responses to EBV in bone marrow transplant recipients and donors. It is our hypothesis that virus specific CD4 T-cell responses are critical for the return and maintenance of virus specific CD8 T-cell function. We will use recombinant EBV proteins to stimulate PBMCs from transplant recipients and perform intracellular cytokine staining to quantify and characterize CD4 T-cell responses. These studies will provide us with a deeper understanding of virus specific immunity in the transplant patient and potentially lead to improved approaches for immune reconstitution. Additionally, these studies will begin to characterize antiviral immune redevelopment in patients receiving related or unrelated and fully matched or partially mismatched allografts.