Tolerance induction by megadose hematopoietic progenitor cells: expansion of veto cells by short-term culture of purified human CD34+ cells

Abstract

Stem cell-dose escalation is one way to overcome immune rejection of incompatible stem cells. However, the number of hematopoietic precursors required for overcoming the immune barrier in recipients pretreated with sublethal regimens cannot be attained with the state-of-theart technology for stem cell mobilization.

The role of donor-derived veto cells in nonmyeloablative haploidentical HSCT

“…The finding that CD34 + stem cells were equipped with veto capability, via TNF-α-mediated deletion, 26,30 was soon followed by the discovery that early myeloid CD33 + cells, which rapidly expand after engraftment, are also endowed with marked veto activity, which is absent from late myeloid cells that express CD14 or CD11b. 27,30 BM-derived immature dendritic cells, formerly described as competent inducers of immune tolerance, were also found to possess veto activity directed against CD8 T cells using a distinct MHCdependent, perforin-based killing mechanism involving activation of Toll-like receptor 7 and signaling through triggering receptor-1 expressed on myeloid cells. 31,32 Natural killer cells, also found to exhibit veto activity on activation with IL-2, develop and appear early during the post-transplant period.…”

“…This was confirmed by the discovery that CD34 + cells are endowed with 'veto activity'. 26,27 The veto effect was first described in 1980 by Miller 28 as the ability to specifically suppress CTLp, directed against antigens (Ags) on the veto cells themselves, but not against third-party Ags. 29 Hence, the veto activity is both Ag-specific and MHC restricted, and results from the unidirectional recognition of the veto cell by the responding T cell, but not vice versa.…”

Haploidentical SCT: the mechanisms underlying the crossing of HLA barriers

“…Several mechanisms, 13,[25][26][27][28][29][30][31][32][33][34] such as clonal deletion and anergy, veto effects, [35][36][37][38][39] Th2 polarization, regulatory T-cell (CD4 þ CD25 þ Foxp3 þ T cells, Tregs)-mediated suppression [40][41][42] and natural killer (NK) cell alloreactivity, 14,43,44 have been implicated in inducing immune tolerance ( Table 1). The mechanisms relevant to haploidentical SCT include: (1) alloreactive TCD and/or B-cell depletion as well as T-cell anergy; (2) veto activity of 'mega-dose CD34 þ cells', 12 which can suppress CTL precursor cells directed against their own Ags, but not those directed against third-party Ags; 45 (3) polarization of T cells from Th1 to Th2 phenotype, the Th2 cells can ameliorate severe GVHD via IL-4 and IL-10 production and potentially via IL-2 consumption and APC modulation.…”

“…The mechanisms relevant to haploidentical SCT include: (1) alloreactive TCD and/or B-cell depletion as well as T-cell anergy; (2) veto activity of 'mega-dose CD34 þ cells', 12 which can suppress CTL precursor cells directed against their own Ags, but not those directed against third-party Ags; 45 (3) polarization of T cells from Th1 to Th2 phenotype, the Th2 cells can ameliorate severe GVHD via IL-4 and IL-10 production and potentially via IL-2 consumption and APC modulation. 29,30,46 In addition, Tregs can ameliorate acute GVHD by modulating IL-10 and TGF-b secretion and polarizing the Treg/Th17 balance toward Treg.…”

Haploidentical haematopoietic stem cell transplantation for acute leukaemia in adults: experience in Europe and the United States

“…[21][22][23][24] Cells within the CD34 þ cell population exhibited 'veto' activity, that is, in bulkmixed lymphocyte reactions they neutralized specific CTL-p s directed against their antigens but not against a third party. 22,23 In 1995, fludarabine was substituted for cyclophosphamide to minimize extra-haematological toxicity of the TBIbased conditioning regimen, 25,26 and CD34 þ cells were positively selected from leukapheresis products to reduce T cells to one log less than in the previous series. The final inocula contained a median of 10 Â 10 6 per kg CD34 þ cells and 2 Â 10 4 T cell per kg.…”