Although tumor growth enhances macrophage (m phi) cytotoxic activity by increasing their tumor necrosis factor-alpha (TNF-alpha) production, increased prostaglandin E2 (PGE2) synthesis reduces most immune responses during tumor growth. Macrophages that do not express major histocompatibility complex class II molecules (Ia- m phi) are the predominant suppressor and cytotoxic population and are more abundant in tumor-bearing hosts (TBHs). This study determined if TBH Ia- m phi s are the major population producing TNF-alpha and PGE2 and if these molecules affect Ia- m phi-mediated suppression of alloantigen-stimulated T cell proliferation. Normal host (NH) and TBH splenic Ia(+)-depleted (Ia-) m phi s synthesized more TNF-alpha than their respective whole populations (WPs) when cultured with lipopolysaccharide and interferon-gamma. TBH Ia- m phi s produced the most TNF-alpha. Northern blot analyses showed that Ia- m phi s had higher amounts of TNF-alpha mRNA expression than their respective WP, and TBH Ia- m phi s expressed the highest amounts of TNF-alpha mRNA. When WP and Ia- NH and TBH m phi s were added to alloantigen-stimulated T cells, suppression of T cell proliferation mediated by Ia- m phi s was greater than by their respective WP. TBH Ia- m phi s were most suppressive. The blockage of PGE2 production reduced suppression mediated by TBH Ia- m phi s more than by all other m phi populations. A PGE2-specific enzyme-linked immunosorbent assay showed that PGE2 production was greater in Ia- m phi- than in WP m phi-containing cultures and greatest in cultures containing TBH Ia- m phi s. Because TNF-alpha enhances T cell responses, its effects on Ia- m phi PGE2-mediated suppression was determined. When TNF-alpha was added to m phi-containing T cell cultures, TNF-alpha directly stimulated NH, but not TBH, Ia- m phi s, which enhanced T cell proliferation. However, inhibiting PGE2 production allowed TNF-alpha to stimulate T cell proliferation in TBH Ia- m phi-containing cultures. Collectively, these data show that Ia- m phi s are the major TNF-alpha- and PGE2-producing cells and that these molecules are partly responsible for the tumor-induced increase in m phi-mediated cytotoxicity and suppression, respectively. TNF-alpha not only mediates cytotoxicity but also counteracts Ia- m phi PGE2-mediated suppression. Although tumor growth increases Ia- m phi TNF-alpha production, enhanced PGE2 production blocks TNF-alpha's stimulatory action on Ia- m phi s, which favors their suppressor function during tumor growth.

The histopathology of the thymus and spleen and the response of spleen cells to mitogenic stimuli were evaluated in Sprague-Dawley CF-1 mice infected with Ehrlichia risticii. Intraperitoneal injection of 104 or 106 E. risticii-infected U-937 cells into mice resulted in 100% morbidity and partial mortality. Thymic atrophy became significant between 1 and 2 weeks postinfection and remained for the duration of the study. The atrophy appeared associated with antecedent destruction and rarefaction of lymphocytes, resulting in the loss of corticomedullary demarcation. Splenomegaly was prominent; significantly increased weights were detected 7 days postinfection. Histopathologic examination revealed rarefaction of lymphocytes around central arteries, the presence of necrotic debris in histiocytes, and replacement of erythropoiesis by granulopoiesis in the red pulp. Marked and acute reduction of in vitro proliferative responses of spleen cells to concanavalin A (ConA) and phytohemagglutinin were observed in mice infected with 104 or 106 E. risticii-infected U-937 cells. Interleukin-2 activity in the supernatant of ConA-stimulated spleen cells was also severely reduced. Both changes were time-and dose-dependent and were not associated with decreased spleen cell viability. Neither morbidity nor mortality occurred in mice infected with 102 E. risticii-infected U-937 cells. Although there was temporal reduction in phytohemagglutinin-driven lymphocyte proliferation, reduction in neither ConA-driven lymphocyte proliferation nor interleukin-2 activity was observed with this dosage. All E. risticii-inoculated mice seroconverted between days 18 and 25, as detected by the indirect fluorescent-antibody procedure. The findings indicate for the first time the hypoimmune responsiveness and histopathologic changes in lymphoid organs associated with E. risticii infection.

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The antineoplastic agent paclitaxel (TAXOL) is a potent inhibitor of tumor cell division and a useful chemotherapeutic for the treatment of refractory ovarian and breast carcinoma. Multiple immune system actions have been ascribed to paclitaxel, including the capacity to induce macrophage antitumor cytotoxic molecule production. However, T-cells are susceptible to paclitaxel's cytostatic functions, and no studies have investigated the effects of direct paclitaxel administration on lymphocyte function in the tumor-bearing host (TBH). Because paclitaxel is currently used as an antitumor chemotherapeutic agent and tumor growth alters leukocyte functions, we assessed T-cell function following chemotherapeutic-type paclitaxel treatment. Paclitaxel administration significantly compromised the proliferative capacity of both normal host and TBH lymphocytes in vitro. Although tumor growth impaired T-cell interferon-gamma (IFN-gamma) production, paclitaxel treatment did not alter IFN-gamma. We speculate that the immunostimulatory cytokine interleukin-12 (IL-12), which promoted T-cell activation and proliferation, was capable of reversing paclitaxel-mediated immunosuppression. Exogenous IL-12 fully reconstituted proliferative reactivity and enhanced IFN-gamma production by both normal host and TBH lymphocytes in vitro. Collectively, these data suggest that chemotherapeutic paclitaxel regimens impart significant but reversible inhibition of lymphocyte populations, and IL-12 may be a useful ancillary immunotherapeutic to overcome paclitaxel-induced modulation of lymphocyte activities.

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