NK cell alloreactivity and allogeneic hematopoietic stem cell transplantation.
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.
Ruggeri
Loredana
L
Department of Clinical and Experimental Medicine, IRCCS Foundation on Transplantation Biotechnologies, University of Perugia, Italy.
Mancusi
Antonella
A
Burchielli
Emanuela
E
Capanni
Marusca
M
Carotti
Alessandra
A
Aloisi
Teresa
T
Aversa
Franco
F
Martelli
Massimo F
MF
Velardi
Andrea
A
D000818:Animals; D002986:Clinical Trials as Topic; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods / Q000401:mortality*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D017710:Lymphocyte Transfusion; D051379:Mice; D023421:Models, Animal; D018448:Models, Immunological; D014184:Transplantation, Homologous