Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred therapy for a variety of disorders. Unfortunately, outcome is limited by development of graft-versus-host disease (GVHD) and by the opportunistic infections (OI) which often ensue as a consequence of efforts to prevent or treat GVHD. Following resolution of neutropenia early after HSCT, infectious risk correlates with patients' CD4 counts, much as is the case in HIV infected patients. CD4 counts remain low for 4-6 months after either T-cell depleted or T-cell replete marrow transplants, while CD8 counts often rapidly recover. Late OI cause significant morbidity and mortality following allogeneic HSCT. ? ? GVHD appears to be mediated by T cells bearing cytotoxic effector granules. L-Leucyl-L-Leucine Methyl Ester (LLME) is polymerized by one of the enzymes within cytotoxic granules, resulting in the destruction of approximately 90% of the CD8 T cells, but only 10% of the CD4 cells. After LLME treatment, large numbers of mismatched T cells can be adoptively transferred in animals without GVHD. A prior clinical trial of LLME was successful in preventing GVHD, but limited by stem cell toxicity and graft failure when the marrow was treated. Since that time, T cell depletion techniques have improved, such that the majority of patients can be successfully engrafted with little or no GVHD.These approaches are limited by the prolonged CD4 deficiency and OI which ensue. We hypothesize that, after T cell depleted transplant, administration of LLME treated donor lymphocyte infusions will correct the quantitative CD4 deficiency and the associated functional deficiency of T cell mediated help. LLME treated T cells will be given in a murine model of T cell depleted stem cell transplantation. We will use this system to determine whether LLME treated cells can provide functional help to allow improved survival, expansion, and efficacy of virus or leukemia specific cytotoxic T cells and antibody secreting B cells in these animals. We will also perform in vitro studies using human peripheral blood samples to determine whether LLME treated CD4 cells provide effective help for the generation of CD8 cytotoxic T cells directed against allogeneic cells and viruses. ? ? The candidate is a junior faculty member of the Jefferson Blood & Marrow Transplant Program. These efforts will allow her to improve skills relevant to the design, implementation, and critical review of laboratory experiments, and to test potential solutions for clinical problems in appropriate laboratory settings.
| Filicko-O'Hara, Joanne; Grosso, Dolores; Flomenberg, Phyllis R et al. (2009) Antiviral responses following L-leucyl-L-leucine methyl esther (LLME)-treated lymphocyte infusions: graft-versus-infection without graft-versus-host disease. Biol Blood Marrow Transplant 15:1609-19 |
| Friedman, Thea M; Filicko-O'Hara, Joanne; Mookerjee, Bijoyesh et al. (2007) T cell repertoire complexity is conserved after LLME treatment of donor lymphocyte infusions. Biol Blood Marrow Transplant 13:1439-47 |
| Kakhniashvili, Irina; Filicko, Joanne; Kraft, Walter K et al. (2005) Heterogeneous clearance of antithymocyte globulin after CD34+-selected allogeneic hematopoietic progenitor cell transplantation. Biol Blood Marrow Transplant 11:609-18 |
