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Engineering donor mesenchymal cells with IL-7 hastens naive T cell recruitment in vitro and supports immunologic reconstitution after HSCT in NOD/SCID mice

2005; Elsevier BV; Volume: 11; Issue: 2 Linguagem: Inglês

10.1016/j.bbmt.2004.12.047

1523-6536

Mauro Di Ianni, Beatrice Del Papa, Maria De Ioanni, Adelmo Terenzi, Paolo Sportoletti, Lorenzo Moretti, Franca Falzetti, Ezio Bonifacio, Maria Paola Martelli, Antonio Tabilio,

Hematopoietic Stem Cell Transplantation

Key players in human T-cell development after T- cell-depleted allogeneic stem cell transplants are bone marrow stroma and interleukin-7 (IL-7). We engineered human stromal cells with the IL-7 gene and studied the effects on T cells in vitro and on in vivo immunological reconstitution in NOD/SCID mice. Transduced mesenchymal cells were negative for CD45 and CD14, positive for CD90 (98.15%), CD105 (87.6%), and STRO-1 (86.7%) and stably produced IL-7 (16.37±2SD pg/ml). In cocultures with T cells, IL-7 engineered stromal cells inhibited PHA-induced T cell proliferation (proliferation index, 3.6 vs 8.0 in untransduced cells and 65.8 in PHA alone), and in cocultures with immunoselected naive T cells, they maintained the CD45RA+CD45RO- naive phenotype (resting naive cell count, 4.2 times more than controls). In NOD-SCID mice, they homed to all organs (highest percentages in liver and lung; overlapping signals in spleen, thymus, bone marrow, heart, kidney, skin and gut; traces in brain). In a NOD/SCID model, comparing transplantation of 1× 106 CD34+ cells, cotransplantation of 5× 105 untransduced mesenchymal cells and 1× 106 CD34+ cells and cotransplantation of 5× 105 IL-7 engineered stromal cells with 1× 106 CD34+ cells, the last improved engraftment in terms of CD45+ cells and significantly increased the CD3+ cell count in peripheral blood (1.4± 1.6 vs 7.4± 3; P< .05), bone marrow (0.8± 1 vs 5.5± 2; P< .05) and spleen (0.08± 0.1 vs 6.2± 2; P< .05). No significant differences emerged in CD19+ cell recovery. IL-7 serum concentrations did not vary at any time point posttransplantation. These data demonstrate that IL-7-transduced stromal cells maintain the naive T-cell phenotype (CD45RA+/CD45RO−) in vitro and serve to improve immunologic reconstitution after HSCT in NOD/SCID mice, thus emerging as an ideal scaffold for hastening immunological recovery in T-cell-deficient hosts.