Activated lymphocytes trigger lymphoblast extravasation.

Intraperitoneal stimulation of adoptively sensitized rats with bacterial antigen promotes the localization of lymphoblasts at the site of antigen deposition. Lymphoblast extravasation activity (LEA) is generated only when specifically immune donor lymphocytes and the recipients of these cells share at least on Ag-B haplotype. However, if the specificity criteria for its formation are satisfied, LEA promotes the local development of lymphoblasts of all available specificities and irrespective of their Ag-B genotype. Allogeneic lymphoblasts do not participate actively in the delayed inflammatory reaction even when they are passively recruited into exudates. The results suggest that LEA is a T cell-derived mediator that amplifies the delayed type hypersensitivity reaction by directing recently activated lymphocytes into lesions.     

BVDV and innate immunity.

Infection with bovine viral diarrhea virus (BVDV) is prevalent in the cattle population worldwide. The virus exists in two biotypes, cytopathic and non-cytopathic, depending on the effect of the viruses on cultured cells. BVDV may cause transient and persistent infections which differ fundamentally in the host's antiviral immune response. Transient infection may be due to both cytopathic and non-cytopathic biotypes of BVDV and leads to a specific immune response. In contrast, only non-cytopathic BVD viruses can establish persistent infection as a result of infection of the embryo early in its development. Persistent infection is characterized by immunotolerance specific for the infecting viral strain. In this paper we discuss the role of innate immune responses in the two types of infection. In general, both transient and persistent infections are associated with an increased frequency of secondary infections. Associated with the increased risk of such infections are, among others, impaired bacteria killing and decreased chemotaxis. Interestingly, non-cytopathic BVDV fails to induce interferon type I in cultured bovine macrophages whereas cytopathic biotypes readily trigger this response. Cells infected with non-cytopathic BVDV are also resistant to induction of interferon by double stranded RNA, a potent interferon inducer signalling the presence of viral replication in the cell. Thus, non-cytopathic BVDV may dispose of a mechanism suppressing a key element of the antiviral defence of the innate immune system. Since interferon is also important in the activation of the adaptive immune response, suppression of this signal may be essential for the establishment of persistent infection and immunotolerance.     

Concurrent or sequential use of cytotoxic chemotherapy and hormone treatment in advanced breast cancer: report of the Swiss Group for Clinical Cancer Research.

In a trial of combined hormone treatment and cytotoxic chemotherapy 464 patients with advanced breast cancer were randomly allocated to either concurrent or sequential treatment. Cytotoxic drugs were given only if the antitumour activity of the hormone treatment was inadequate. Hormone treatment consisted of oophorectomy for premenopausal and tamoxifen administration for postmenopausal patients. Length of survival was better, though not significantly, in premenopausal patients (p = 0.29) treated concurrently and in postmenopausal women (p = 0.17) treated sequentially; the difference was highly significant (p = 0.003) only for postmenopausal women in the low-risk category. The findings suggest that postmenopausal women with metastatic breast cancer should probably be treated primarily by carefully monitored hormone treatment.     

IGG-stimulated and LPS-stimulated monocytes elaborate transforming growth factor type beta (TGF-beta) in active form

Mononuclear cells (MNC) stimulated either with lipopolysaccharide (LPS) or with surface-adsorbed IgG elaborated significant amounts of tumor necrosis factor (TNF) bioactivity, as well as immunoenzymatically detectable TNF-alpha and interleukin-1 beta. (IL1-beta). In contrast, IgG-stimulated cells released little IL1 bioactivity, but released an IL1 inhibitor, as determined by the thymocyte costimulatory assay (LAF assay). This inhibition was not due to an inhibitory effect of cyclooxygenase products, e.g. prostaglandin-E2 in the LAF assay. In contrast, antibodies against transforming growth factor type beta (TGF-beta), which is an important inhibitor of the LAF assay, augmented the LAF activity of supernatants from LPS-stimulated and IgG-stimulated MNC. Anti-TGF-beta-modulated LAF inhibition was enhanced by acid treatment of supernatants from mononuclear cells, but not of those from purified monocytes. Antibody blocking experiments point for the first time to a TGF-beta species other than type 1 as a monocyte-derived TGF-beta activity. Thus, TGF-beta released in active form from monocytes may be the more important antagonist of IL1 than cyclooxygenase-derived mediators. It implies that the LAF assay, in the absence of anti-TGF-beta antibodies, is an inadequate indicator of IL1 activity.     

Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model

Bone tissue has an exceptional quality to regenerate to native tissue in response to injury. However, the fracture repair process requires mechanical stability or a viable biological microenvironment or both to ensure successful healing to native tissue. An improved understanding of the molecular and cellular events that occur during bone repair and remodeling has led to the development of biologic agents that can augment the biological microenvironment and enhance bone repair. Orthobiologics, including stem cells, osteoinductive growth factors, osteoconductive matrices, and anabolic agents, are available clinically for accelerating fracture repair and treatment of compromised bone repair situations like delayed unions and nonunions. Preclinical and clinical studies using biologic agents like recombinant bone morphogenetic proteins have demonstrated an efficacy similar or better than that of autologous bone graft in acute fracture healing. A lack of standardized outcome measures for comparison of biologic agents in clinical fracture repair trials, frequent off-label use, and a limited understanding of the biological activity of these agents at the bone repair site have limited their efficacy in clinical applications.     

Allogeneic restriction of acquired antimicrobial resistance in the rat.

Allogeneic restriction of acquired antimicrobial resistance was demonstrated by infusing Listeria-immune thoracic duct lymphocytes (TDL) into syngeneic, semisyngeneic, or allogeneic recipients that had been infected i.v. with Listeria monocytogenes (LM). Syngeneic and semisyngeneic recipients enjoyed a high level of protection (3 to 5 log10 reduction in viable organisms within 64 hr, whereas allogeneic recipients were poorly protected (0.5 to 2.5 log10 reduction). Sharing one haplotype between TDL-donors and challenged recipients resulted in a 4- to 8-fold increase in the level of resistance transferred. Histoincompatibility reactions could be excluded as a cause of the observed allogeneic restriction. Therefore, it is likely that LM-immune TDL are unable to respond efficiently to the antigens of this organism in an allogeneic environment. But allogeneic immune TDL do confer a low level of protection that cannot be ascribed to B cell activity nor to GvH and/or HvG reactions. Evidence is provided that the modest protection afforded by allogeneic lymphocytes is conveyed by the same T cell subset that operates with much higher efficiency in genetically related rats.     

Low-affinity interaction of fibrinogen carboxy-gamma terminus with human monocytes induces an oxidative burst and modulates effector functions

The interaction of highly purified, monomeric fibrinogen (Fg) with human monocytes (MO) was investigated. In contrast to commercial Fg, no high-affinity binding of monomeric Fg to MO or mononuclear cells could be demonstrated. MO preincubated with Fg in the presence or absence of Ca++ elicited an oxidative burst when triggered with anti-Fg antibodies. Divalency of the antibody and specificity were required, but an intact Fc portion was not. Surface-adsorbed monomeric Fg also promoted an oxidative burst. Evidence is presented that Fg-MO interaction is mediated by the carboxy-gamma terminus of Fg. MO treated with monomeric Fg or exposed to Fg-coated surfaces show a reduced oxidative burst upon triggering with unrelated stimuli. Thus, MO function may be modulated upon interaction with surface-adsorbed Fg or with fibrin.     

CD36-mediated signal transduction in human monocytes by anti-CD36 antibodies but not by anti-thrombospondin antibodies recognizing cell membrane-bound thrombospondin

Mononuclear cells (MNC) treated with anti-CD36 Fab or F(ab')2 fragments and then stimulated with anti-rabbit (F(ab')2 displayed an oxidative burst, suggesting that the crosslinking of CD36 promotes signal transduction in the absence of an Fc receptor involvement. Moreover, intact anti-TSP mediates a weak oxidative burst in MNC, which was strongly enhanced upon pretreatment of monocytes (but not lymphocytes) with TSP. This response, however, was mediated by Fc receptors, not by an involvement of CD36. Other means of crosslinking cell-bound TSP and exposure of MNC to surface-bound TSP failed to promote an oxidative burst. Crosscompetition tests confirmed that the interaction site(s) of TSP with monocytes are distinct from the signal-promoting sites recognized by polyclonal and 3 monoclonal anti-CD36 antibodies.     

Targeting the cell cycle in breast cancer: towards the next phase

Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.