T cell depletion (TCD) of allogeneic stem cell transplants (SCT) dramatically reduces the risk of graft vs host disease (GVHD) but results in a heightened risk for infectious complications, two of the most serious being Epstein Barr virus (EBV) induced lymphoproliferative disease and cytomegalovirus (CMV) infection. Previous studies have shown that cytotoxic T lymphocytes can be cultured and infused into SCT recipients resulting in antigen specific immune reconstitution, but this can be impractical due to the need of expanding CTL with separate antigen presenting cells. Preliminary studies have demonstrated the feasibility of retroviral transduction of B lymphoblastoid cell lines (BLCL) to achieve expression of CMV pp65, and stimulation with BLCL expressing pp65 results in expansion of CTL recognizing both CMVpp65 and EBV antigens. In this proposal, we will compare the clinical, immunologic, and virologic effects of prophylactic CMV/EBV specific CTL in recipients of allogeneic, TCD SCT with a control group of TCD SCT patients randomized to not receive CTL. CD4 and CD8 antigen specific immune reconstitution (CTL precursor frequencies) and CMV and EBV DNA levels (by real time PCR) will be compared in these groups at intervals post-transplant. We will determine which CMVpp65 epitopes are immunodominant in stem cell donors using recombinant vaccinia encoding pp65 deletion mutations, and then the exact epitopes will be determined using synthetic peptides pulsed onto APC. Dominant epitopes of the CTL donors will be compared with those found in CTL recipients post-infusion, to determine whether immunodominant epitopes recognized by the donor are retained in the recipient, and if not, which epitopes are most relevant post-transplant. Also of interest are the types of effector cells and the dynamic changes in CD4 and CD8 CMV specific T cells during CMV reactivation in recipients of CTL and the control group. These studies will determine the impact on viral reactivation and immune reconstitution of prophylactic antigen-specific CTL and will serve as a groundwork for extending this system of antigen presentation and T cell expansion to other pathogens as well as tumor antigens in the future. ? ? ?
| Bao, Lei; Cowan, Morton J; Dunham, Kimberly et al. (2012) Adoptive immunotherapy with CMV-specific cytotoxic T lymphocytes for stem cell transplant patients with refractory CMV infections. J Immunother 35:293-8 |
| Horn, Biljana; Bao, Lei; Dunham, Kimberly et al. (2009) Infusion of cytomegalovirus specific cytotoxic T lymphocytes from a sero-negative donor can facilitate resolution of infection and immune reconstitution. Pediatr Infect Dis J 28:65-7 |
| Bao, Lei; Dunham, Kimberly; Stamer, Mindy et al. (2008) Expansion of cytomegalovirus pp65 and IE-1 specific cytotoxic T lymphocytes for cytomegalovirus-specific immunotherapy following allogeneic stem cell transplantation. Biol Blood Marrow Transplant 14:1156-62 |
| Bao, Lei; Sun, Qi; Lucas, Kenneth G (2007) Rapid generation of CMV pp65-specific T cells for immunotherapy. J Immunother 30:557-61 |
