Allogeneic bone marrow transplantation has emerged as 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 which often ensue as a consequence of efforts to prevent or treat GVHD. Following the resolution of neutropenia early after BMT, infectious risk correlates with the 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. In contrast CD8 counts have the ability to rapidly recover with either form of BMT. GVHD appears to be mediated by T cells bearing cytotoxic effector granules. These cells can be selectively destroyed through the action of Leucyl Leucine Methyl Ester (LLME), which undergoes polymerization by dipeptidyl peptidase-I, one of the components of cytotoxic granules. LLME treatment destroys approximately 90 percent of the CD8 T cells, but only 10 percent of the CD4 cells. After LLME treatment, large numbers of mismatched T cells can be adoptively transferred in animals without GVHD. Prior clinical trials of LLME were 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 been improved, such that the majority of patients can be successfully engrafted with little or no GVHD, even when thetransplants are performed across major histocompatibility barriers. The limitation of these approaches is the prolonged CD4 deficiency and opportunistic infections which ensue. We therefore hypothesize that transplant outcome can be substantially improved by treating recipients of T cell- depleted transplants with donor lymphocyte infusions (DLI) which have been treated with LLME. This will potentially provide safe transfer of large numbers of CD4 T cells and small numbers of CD8 T cells without appreciable GVHD risk. The prior problems of stem cell toxicity will be avoided, as the patients will previously have been engrafted. CD8 recovery would occur through the stem cell graft and CD4 recovery through the DLI. The proposed grant will support a trial to administer increasing numbers of LLME-treated DLI to patients and monitor patients for CD4 recovery and other parameters of immune reconstitution as well as for development of GVHD.
| 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 |
