Author(s): Ruggeri L, Mancusi A, Burchielli E, Capanni M, Carotti A,
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Abstract As only 60\% of leukaemia patients find a matched donor, the Perugia Bone Marrow Transplant Centre developed transplantation from HLA haplotype-mismatched family donors to provide a cure for more patients [F. Aversa, A. Tabilio, A. Terenzi, et al., Successful engraftment of T-cell-depleted haploidentical "three-loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum, Blood 84 (1994) 3948-3955] [F. Aversa, A. Tabilio, A. Velardi, et al., Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype, N. Engl. J. Med. 339 (1998) 1186-1193] [F. Aversa, A. Terenzi, A. Tabilio, et al., Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse, J. Clin. Oncol. 23 (2005) 3447-3454]. HLA-mismatches trigger donor vs. recipient NK cell alloreactivity which improves engraftment, protects from GvHD and reduces relapse in AML patients [L. Ruggeri, M. Capanni, E. Urbani, et al., Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants, Science 295 (2002) 2097-2100], [L. Ruggeri, A. Mancusi, M. Capanni, E. Urbani, A. Carotti, T. Aloisi, M. Stern, D. Pende, K. Perruccio, E. Burchielli, F. Topini, E. Bianchi, F. Aversa, M.F. Martelli, A. Velardi, Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value, Blood, in press]. We are using murine transplant models to determine whether NK cell alloreactivity can be exploited to reduce transplant-related mortality (TRM) which remains a major issue. Data from these on-going studies show pre-transplant infusion of alloreactive NK cells: (1) ablates AML cells, (2) kills recipient T cells, permitting a reduced toxicity conditioning regimen, and (3) ablates the recipient dendritic cells (DCs) which trigger GvHD, thus protecting from GvHD while permitting a higher T cell content in the graft. We are designing a clinical haploidentical transplant trial using alloreactive NK cells in the conditioning regimen, with the aim of reducing TRM and improving outcomes and overall survival.
This article was published in Blood Cells Mol Dis
and referenced in Journal of Cell Science & Therapy