https://ogma.newcastle.edu.au/vital/access/ /manager/Index ${session.getAttribute("locale")} 5 https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:46366 in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.]]> Wed 16 Nov 2022 08:57:15 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:33081 -/-) mice, one with a targeted deletion and another mutant expressing an major histocompatibility complex (MHC) transgene. To determine the importance of RelB in DCs, RelB-sufficient DCs (RelB^-/- or RelB^-/-) were adoptively transferred into RelB^-/- mice. Both strains had increased pulmonary inflammation compared to their respective wild-type (RelB^-/-) and heterozygous (RelB^-/-) controls. RelB^-/- mice also had increased inflammatory cell influx into the airways, levels of chemokines (CCL2/3/4/5/11/17, CXCL9/10/13) and Th2-associated cytokines (IL-4/5) in lung tissues, serum IgE and airway remodelling (mucus secreting cell numbers (MSCs), collagen deposition and epithelial thickening). Transfer of RelB^-/- CD11c⁺ DCs to RelB^-/- mice decreased pulmonary inflammation, with reduced lung chemokine and Th2-associated cytokine (IL-4/5/13/25/33, thymic stromal lymphopoietin) levels, serum IgE, numbers of type 2 innate lymphoid cells, myeloid DCs, γδ T cells and lung Vß13⁺ T cells, MSCs, airway collagen deposition and epithelial thickening.These data indicate that RelB deficiency may be a key pathway underlying AAI and that DC-encoded RelB is sufficient to restore control.]]> Wed 02 Mar 2022 14:25:08 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:9358 Sat 24 Mar 2018 08:36:33 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:18254 Sat 24 Mar 2018 08:04:34 AEDT ]]> https://ogma.newcastle.edu.au/vital/access/ /manager/Repository/uon:22084 Chlamydia trachomatis is a sexually transmitted obligate intracellular pathogen that causes inflammatory reactive arthritis, spondylitis, psoriasiform dermatitis, and conjunctivitis in some individuals after genital infection. The immunologic basis for this inflammatory response in susceptible hosts is poorly understood. As ZAP-70^W163C–mutant BALB/c (SKG) mice are susceptible to spondylo-arthritis after systemic exposure to microbial β-glucan, we undertook the present study to compare responses to infection with Chlamydia muridarum in SKG mice and BALB/c mice. Methods: After genital or respiratory infection with C muridarum, conjunctivitis and arthritis were assessed clinically, and eye, skin, and joint specimens were analyzed histologically. Chlamydial major outer membrane protein antigen–specific responses were assessed in splenocytes. Treg cells were depleted from FoxP3-DTR BALB/c or SKG mice, and chlamydial DNA was quantified by polymerase chain reaction. Results: Five weeks after vaginal infection with live C muridarum, arthritis, spondylitis, and psoriasiform dermatitis developed in female SKG mice, but not in BALB/c mice. Inflammatory bowel disease did not occur in mice of either strain. The severity of inflammatory disease was correlated with C muridarum inoculum size and vaginal burden postinoculation. Treatment with combination antibiotics starting 1 day postinoculation prevented disease. Chlamydial antigen was present in macrophages and spread from the infection site to lymphoid organs and peripheral tissue. In response to chlamydial antigen, production of interferon-γ and interleukin-17 was impaired in T cells from SKG mice but tumor necrosis factor (TNF) responses were exaggerated, compared to findings in T cells from BALB/c mice. Unlike previous observations in arthritis triggered by β-glucan, no autoantibodies developed. Accelerated disease triggered by depletion of Treg cells was TNF dependent. Conclusion: In the susceptible SKG strain, Chlamydia-induced reactive arthritis develops as a result of deficient intracellular pathogen control, with antigen-specific TNF production upon dissemination of antigen, and TNF-dependent inflammatory disease.]]> Mon 06 Aug 2018 11:11:21 AEST ]]>