Cytokines and cytotoxic pathways in engraftment resistance to purified allogeneic hematopoietic stem cells.

The way that allogeneic hematopoietic cells are rejected is not completely understood. Regimen-resistant populations, including natural killer (NK) cells and lymphocytes, are thought to mediate the allograft barrier. In this report, the mechanism by which recipient cell populations resist engraftment of purified allogeneic hematopoietic stem cells (HSCs) was examined in mice. To define the immunoregulatory pathways involved in allogeneic hematopoietic cell resistance, HSC transplantations were performed in immune-defective recipients. Recipients were wild-type mice treated with alpha-NK cell antibodies or knockout strain mice lacking expression of CD8, perforin, Fas ligand, or 1 of the following cytokines: tumor necrosis factor alpha, transforming growth factor beta, interferon gamma, interleukin 4, or interleukin 10. Elimination of a single cytotoxic pathway was ineffective in reducing engraftment resistance, although mice treated with a polyclonal antibody that recognizes NK-cell determinants or CD8 expression showed a profound reduction in the engraftment barrier. Posttransplantation chimerism analysis revealed regeneration of host hematopoiesis in some experimental groups. These studies show, for the first time, that elimination of selected cytokines does not alter allogeneic hematopoietic resistance. Furthermore, the chimerism data reinforce the importance of competition for HSC niches in conjunction with immune mechanisms in resistance to long-term HSC engraftment.