IN VITRO INDUCTION OF TUMOR-SPECIFIC IMMUNITY : I. PARAMETERS OF ACTIVATION AND CYTOTOXIC REACTIVITY OF MOUSE LYMPHOID CELLS IMMUNIZED IN VITRO AGAINST SYNGENEIC AND ALLOGENEIC PLASMA CELL TUMORS

Induction of tumor-specific immunity in vitro was accomplished by cocultivation of cortisone-resistant murine thymocytes or spleen cells with irradiated syngeneic plasma cell tumors (PCT). The cytotoxic activity generated could be detected in a short-term 51Cr-release assay. Optimal cytotoxic activity against PCT-associated transplantation antigens (TATA) was generated after 7 days in culture. Unlike cytotoxic responses to tumor allografts in which the cytotoxic activity was directed against allogeneic transplantation antigens, the cytotoxic activity obtained in the syngeneic tumor system was specific to the immunizing syngeneic PCT. Similar parameters of induction of cytotoxic responses in in vitro tumor allograft responses and in the syngeneic tumor system suggested that both reactions are cell-mediated cytotoxic immune responses. With regard to the magnitude of cytotoxic responses obtained, allogeneic transplantation antigens induced about a 30-fold higher cytotoxic immune response than plasma cell TATA. The results are consistent with the concept that in vitro tumor allograft responses and in vitro responses against TATA of PCT are similar in quality, but differ in the magnitude of the cytotoxic response provoked

Tumor necrosis factor-α\alpha in combination with interferon-γ\gamma, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes

We have previously shown that during an infection with Leishmania major, susceptible BALB/c mice, as opposed to mice of a resistant strain (C57BLl6), are primed by lipopolysaccharide for the production of high levels of tumor necrosis factor-$\alpha$ (TNF-$\alpha$) which is known to be a potent maerophage M$\Phi$ stimulator in other parasitic diseases. In the present study we investigated whether TNF-$\alpha$ activates M$\Phi$ for killing of L. major parasites. In the absence of interferon-y (IFN-$\gamma$) or lipopolysaccharide, TNF-$\alpha$ (0.025-25000 U/ml) failed to activate peritoneal exudate M$\Phi$ from BALB/c mice for killling of L. major amastigotes. In the presence of suboptimal doses of IFN-$\gamma$ (5 or 10 Vlml), however, TNF-$\alpha$ mediated a rapid elimination of intracellular parasites, which was highly significant compared to IFN-$\gamma$ alone. Tbe combination of TNF with interleukin 4, in contrast, was inactive in this respect and allowed survival of intracellular parasites. From these data we conelude that the presence of IFN-$\gamma$ is crucial for TNF-$\alpha$-mediated killing of L. major parasites by M$\Phi$. Disease progression in susceptible mice therefore seems to be a consequence of a deficiency of IFN-$\gamma$ and a predominance of interleukin 4 rather than the result of an excess amount of TNF-$\alpha$

Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by the recruitment of leukocytes and the accumulation of inflammatory mediators within the synovial compartment. Release of the chemokine CCL18 has been widely attributed to antigen-presenting cells, including macrophages and dendritic cells. This study investigates the production of CCL18 in polymorphonuclear neutrophils (PMN), the predominant cell type recruited into synovial fluid (SF). Microarray analysis, semiquantitative and quantitative reverse transcriptase polymerase chain reaction identified SF PMN from patients with RA as a novel source for CCL18 in diseased joints. Highly upregulated expression of other chemokine genes was observed for CCL3, CXCL8 and CXCL10, whereas CCL21 was downregulated. The chemokine receptor genes were differentially expressed, with upregulation of CXCR4, CCRL2 and CCR5 and downregulation of CXCR1 and CXCR2. In cell culture experiments, expression of CCL18 mRNA in blood PMN was induced by tumor necrosis factor α, whereas synthesis of CCL18 protein required additional stimulation with a combination of IL-10 and vitamin D3. In comparison, recruited SF PMN from patients with RA were sensitized for CCL18 production, because IL-10 alone was sufficient to induce CCL18 release. These results suggest a release of the T cell-attracting CCL18 by PMN when recruited to diseased joints. However, its production is tightly regulated at the levels of mRNA expression and protein synthesis

Lymphocytes play the music but the macrophage calls the tune

No abstract availabl

Resistance to murine cutaneous leishmaniasis is mediated by TH_H1 cells, but disease-promoting CD4+^+ cells are different from TH_H2 cells

No abstract availabl

T-cell reactivity to purified lipophosphoglycan from Leishmania major: A model for analysis of the cellular immune response to microbial carbohydrates.

The major macromolecule on the surface o/Leishmania majorpromastigotes is a lipophosphoglycan (LPG). This glycoconjugate plays a key role in determining infectivity and survival of para-sites in the mammalian host cell. In addition, L. major LPG is able to induce a host-protective immune response. In this article, we summarise the evidence for recognition of highly purified LPG by T cells and we discuss the potential mechanisms of T-cell Stimulation by this non-protein antigen

Parasitism of epidermal Langerhans cells in experimental cutaneous leishmaniasis with Leishmania major

Murine epidermal Langerhans cells (LC) have been demonstrated to stimulate a vigorous T cell response to Leishmania major, a cause of human cutaneous leishmaniasis. It was therefore of interest to analyze whether LC can take up viable parasites. Epidermal cells were obtained from mouse ear skin for incubation with L. major and subsequent detection of intracellular parasites by cytochemistry. Freshly isolated LC, but not cultured LC, phagocytosed L. major and the uptake was inhibited by antibodies to the complement receptor type 3. Electron microscopic studies revealed the presence of viable amastigotes within Le. Moreover, with double-Iabeling techniques, L. major-containing LC could also be detected in infected skin. The results demonstrate that LC can internalize L. major. Since the number of organisms per infected LC remained consistently low, the prime task of LC may not be the promotion of parasite spreading but the presentation of L. major antigen to T cells and, thus, the regulation of the cellular immunity during cutaneous leishmaniasis

Toll-Like Receptors: Sentinels of Host Defence against Bacterial Infection

Innate immunity provides a fi rst line of host defence against infection through microbial recognition and killing while simultaneously activating a defi nitive adaptive immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition and function mainly by detection of structural patterns that do not exist in the host. TLR2 and TLR4 were the fi rst members of this innate immune receptor family to be strongly implicated in antibacterial host defence. Following the initial description of the mammalian TLR family, susceptibility to infection with numerous human microbial pathogens has been intensively studied using mice with engineered deletions of each of these molecules. While it has become quite clear that TLR activation is necessary for optimal host defence, a comprehensive understanding of the mechanisms by which this family of pattern recognition receptors engages protective immunity, particularly the adaptive response, is still evolving