The cellular events leading to proliferation of cultured human lymphocytes after in vitro stimulation with phytomitogens or allogeneic cells are poorly understood. Little is known on the nature of the proliferating lymphocytes, or whether interactions between different cell types are required for blastogenic transformation of the eventually responding lymphocytes. Investigating these questions, attention has to focus primarily on monocytes, and the different lymphocyte subpopulations.The role of the monocyte (or the monocyte-derived maerophage [1,2], respectively) in antigen-induced lymphocyte activation continues to be of great interest. Lymphocyte response to many antigens requires the presence of monocytes. Removal of glassadherent cells abolishes the in vitro antibody formation by mouse spleen cells against sheep erythrocytes (3) and antigen-induced transformation of human lymphocytes (4); addition of macrophages restores the lymphocyte reactivity (5, 6). Macrophagelymphocyte interaction is also required for lymphocyte activation by allogeneic histoincompatible lymphocytes in vitro, the mixed leukocyte culture (MLC) 1 (7-11). In contrast, lymphocyte activation by plant mitogens such as phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM) is widely attributed to direct interaction of the soluble mitogen with lymphocyte membrane receptors (12-15). Opinions about the role of monocytes in the mitogen-induced lymphocyte proliferation are controversial: reports that phagocytic cells inhibit the lymphocyte response to PHA (16) conflict with others that removal of phagocytic cells decreases lymphocyte activation by this mitogen (17, 18). Alter and Bach described potentiation of PHA-induced lymphocyte proliferation by monocytes (11), whereas Oppenheim and co-workers (4) observed this effect only at suboptimal doses of PHA.Lymphocytes can be separated into thymus-dependent (T) and thymus-independent (B) cells on the basis of ontogeny, function, and cell surface differentiation markers. Relatively small fractions of B or T cells from immunized animals will respond to the sensitizing antigens (19,20), whereas a large fraction of the lymphocyte inoculum will be stimulated in vitro by phytomitogens (21,22). Therefore, the lymphocyte response to phytomitogens is generally considered to be nonspecific, 1 Abbreviations used in this paper: Con A, concanavalin A; HBSS, Hanks' balanced salt solution; MLC, mixed leukocyte culture; N-SRBC, neuraminidase-pretreated sheep erythrocytes; PHA, phytohemagglutinin; PWM, pokeweed mitogen.

Fig 3.-Section of thymoma removed at surgery (hematoxylineosin, x40

The optimum treatment conditions of interferon (IFN) a therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CMLstudy I and it had been planned in advance to add the HU patients of study I (n ¼ 194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n ¼ 21), major in 14% (n ¼ 24), and at least minimal in 35% (n ¼ 59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (Po0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P ¼ 0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.

No abstract