Control of in vivo differentiation of myeloid leukemic cells. III. Regulation by T lymphocytes and inflammation.

Mouse and human (HL-60) MGI+D+ myeloid leukemic cells were induced to differentiate to mature cells in diffusion chambers implanted into the peritoneal cavity of normal mice when a xenogeneic source of serum was added to the diffusion chambers. Differentiation was inhibited in immune deficient mice including congenitally athymic nude and neonatally thymectomized mice, and mice treated with cyclophosphamide, hydrocortisone, or X-irradiation. There was no such inhibition of differentiation in mice with various genetic defects in their B lymphocytes, granulocytes, erythrocytes and natural killer cells. Differentiation in cyclophosphamide-treated mice was restored by a single intravenous injection of normal spleen cells highly enriched for T lymphocytes. Conditions permissive for differentiation were associated with a higher number of eosinophils in the peritoneum that conditions that inhibited differentiation. Intraperitoneal injections of inflammatory peritoneal exudate cells, peritoneal granulocytes, or the inflammation inducer sodium caseinate, restored the ability of defective mice to induce differentiation. Injections into defective mice of the normal mouse macrophage and granulocyte differentiation-inducing protein (MGI-2) restored differentiation of the mouse myeloid leukemic cells but not of the human myeloid leukemic cells. Differentiation of normal mouse bone marrow myeloid precursors to mature cells and of differentiation-defective (MGI-D-) mouse myeloid leukemic cells to intermediate stages of differentiation were not affected by the conditions that inhibited differentiation of the MGI+D+ myeloid leukemic cells. The results indicate: 1) that the intraperitoneal accumulation of inflammatory cells, including eosinophils, can induce differentiation of MGI+D+ leukemic cells in the peritoneal cavity; 2) that this response requires T lymphocytes and can be regulated by xenogeneic serum in the chamber; 3) that in vivo differentiation of normal and MGI+D+ myeloid leukemic cells can be regulated in different ways; and 4) that the in vivo differentiation of the mouse MGI+D+ leukemic cells, human MGI+D+ leukemic cells and mouse MGI-D- leukemic cells were induced by different compounds, so that differentiation of different types of leukemic cells may be differently regulated in vivo depending on which compounds induce differentiation.