Harnessing the immune system to recognize and destroy tumor cells has been the central goal of anti-cancer immunotherapy. In recent years, there has been an increased interest in optimizing this technology in order to make it a clinically feasible treatment. One of the main treatment modalities within cancer immunotherapy has been adoptive T cell therapy (ACT). Using this approach, tumor-specific cytotoxic T cells are infused into cancer patients with the goal of recognizing, targeting, and destroying tumor cells. In the current review, we revisit some of the major successes of ACT, the major hurdles that have been overcome to optimize ACT, the remaining challenges, and future approaches to make ACT widely available.
Adoptive immunotherapy (AIT) can mediate durable regression of cancer, but widespread adoption of AIT is limited by the cost and complexity of generating tumor-specific T cells. Here we develop an Enrichment + Expansion strategy using paramagnetic, nanoscale artificial Antigen Presenting Cells (aAPC) to rapidly expand tumor-specific T cells from rare naïve precursors and predicted neo-epitope responses. Nano-aAPC are capable of enriching rare tumor-specific T cells in a magnetic column and subsequently activating them to induce proliferation. Enrichment + Expansion resulted in greater than 1000-fold expansion of both mouse and human tumor-specific T cells in one week, with nano-aAPC based enrichment conferring a proliferation advantage during both in vitro culture and after adoptive transfer in vivo. Robust T cell responses were not only seen for shared tumor antigens, but also for computationally predicted neo-epitopes. Streamlining the rapid generation of large numbers of tumor-specific T cells in a cost-effective fashion through Enrichment + Expansion can be a powerful tool for immunotherapy.
These data demonstrate that CTGF is expressed by corneal cells after stimulation by TGF-beta, that CTGF expression increases significantly during corneal wound healing, and that CTGF mediates the effects of TGF-beta induction of collagen synthesis by corneal fibroblasts. These data support the hypothesis that CTGF promotes corneal scar formation and imply that regulating CTGF synthesis and action may be an important goal for reducing corneal scarring.
The mechanisms that contribute to inflammatory damage following ischemic stroke are poorly characterized, but studies indicate a role for both complement and P-selectin. In this study, we show that compared with wild-type mice, C3-deficient mice showed significant improvement in survival, neurological deficit, and infarct size at 24 h after middle cerebral artery occlusion and reperfusion. Furthermore, P-selectin protein expression was undetectable in the cerebral microvasculature of C3-deficient mice following reperfusion, and there was reduced neutrophil influx, reduced microthrombus formation, and increased blood flow postreperfusion in C3-deficient mice. We further investigated the use of a novel complement inhibitory protein in a therapeutic paradigm. Complement receptor 2 (CR2)-Crry inhibits complement activation at the C3 stage and targets to sites of complement activation. Treatment of normal mice with CR2-Crry at 30 min postreperfusion resulted in a similar level of protection to that seen in C3-deficient mice in all of the above-measured parameters. The data demonstrate an important role for complement in cerebrovascular thrombosis, inflammation, and injury following ischemic stroke. P-selectin expression in the cerebrovasculature, which is also implicated in cerebral ischemia and reperfusion injury, was shown to be distal to and dependent on complement activation. Data also show that a CR2-targeted approach of complement inhibition provides appropriate bioavailability in cerebral injury to enable complement inhibition at a dose that does not significantly affect systemic levels of serum complement activity, a potential benefit for stroke patients where immunosuppression would be undesirable due to significantly increased susceptibility to lung infection.
Rationale: Donor brain death (BD) is an unavoidable occurrence in heart transplantation and results in profound physiological derangements that render the heart more susceptible to ischemia/reperfusion injury in the recipient and likely has negative long-term consequences to allograft survival. Objective: We developed a novel mouse model of BD and investigated the role of complement in BD-induced myocardial inflammation and injury. Methods and Results: BD was induced by inflation of a balloon catheter in the cranial cavity. BD in wild-type mice resulted in a significant increase in serum concentrations of the complement activation product complement component ( Key Words: complement Ⅲ brain death Ⅲ heart transplantation Ⅲ inflammation Ⅲ mouse model H eart transplantation has become a highly successful treatment for end-stage heart disease. Advances in immunosuppression have led to dramatic improvements in first-year survival, in large part, because of better modulation of the alloimmune response. However, despite these improvements, primary graft failure, acute rejection, and cardiac allograft vasculopathy are still major limitations to short and long-term survival. The precise mechanisms involved in the development of primary graft failure and chronic rejection are not well understood. Recently, brain death and ischemia/ reperfusion injury (IRI) have been implicated in graft endothelial activation and injury, which, in turn, have been linked to the pathogenesis of graft dysfunction and chronic rejection. 1-3 Clinical studies of renal transplant recipients and, to a lesser extent, domino donation in heart transplant recipients have highlighted the deleterious impact that donor brain death (BD) has on transplant outcome. 4 Recipients receiving allografts from living donors experience fewer rejection episodes, are less susceptible to primary graft failure, and, as a consequence, survive significantly longer than patients receiving organs from cadaveric sources. 2-5 Initially, it was proposed that these significant improvements were a result of reduced ischemic times, but recent evidence points toward the effects of BD as a stimulating factor in priming the donor organ and rendering it proinflammatory. 2,6,7 BD results in the outpouring of catecholamines, which promotes intense vasoconstriction, leading to chaotic swings in blood pressure, hypothermia, coagulopathies, hormone depletion, and electrolyte abnormalities. The effects on blood pressure are 2-fold: an initial hypertensive phase is followed by hypotension, resulting in an increase in oxygen supply to the heart. However, the increase is still insufficient to cover the enhanced demand and results in transient global myocardial ischemia. 8,9 The imbalance in myocardial oxygen demand and supply renders peripheral organs ischemic, which may activate the endothelium by processes similar to that associated with IRI. The mechanism(s) of donor organ activation has yet to be fully elucidated, but much of the available data from animal studies suggest that imbalances...
The excitability of hippocampal pyramidal neurons is regulated by activation of metabotropic glutamate receptors, an effect that is mediated by modulation of R-type calcium channels.
A documented consequence of poxvirus infections is global inhibition of host protein synthesis and reduction in mRNA levels. We examined this mRNA decrease by infecting A549 cells, derived from a human lung carcinoma, with rabbitpox virus (RPV), or RPV deleted for the serine protease inhibitor SPI-1 (RPVDeltaSPI-1), which exhibits a growth defect on A549 cells. At various times postinfection, mRNA profiles were analyzed using Affymetrix U95AV2 microarrays. There was a decline in overall cellular mRNA levels beginning at 2.5 hpi, and by 5 hpi, mRNA levels were drastically reduced for the majority of genes. However, several mRNAs increased, including those of heat-shock genes. Finally, a comparison of host mRNA profiles of RPV- to RPVDeltaSPI-1-infected cells revealed subtle differences in mRNA levels at 5 and 12 hpi. In summary, while there was a global decrease of host mRNA levels, the induction of selected mRNAs may be required for a successful poxvirus infection.
Conflicting evidence exists regarding the importance of routine abdominal ultrasound (US) with hepatic and splenic fine needle aspiration (FNA) cytology during staging of canine mast cell tumours (MCT). The objective of this study was to correlate ultrasonographic and cytologic findings in dogs with strictly defined high-risk MCTs and to determine the influence on outcome. Our hypothesis was that US poorly predicts visceral metastasis in high-risk MCTs and that early metastasis is associated with improved outcome when compared to overt metastasis. US of liver and spleen correlated to cytologic results, categorized as no metastasis, early metastasis or overt metastasis. Of 82 dogs prospectively enrolled, 18% had early visceral metastasis and 7% had overt metastasis on cytology; 67% with visceral metastasis had regional LN metastasis. US was a poor predictor of metastasis with sensitivity, specificity, positive predictive value and negative predictive value for the spleen of 67%, 68%, 21% and 94%, respectively and for the liver of 29%, 93%, 56% and 82%, respectively. Median time to progression (TTP) for dogs with no metastasis, early metastasis and overt metastasis was not reached, 305 and 69 days, respectively (P < .001). Median survival time (MST) for the 3 groups were not reached, 322 and 81 days, respectively (P < .001). High Patnaik or Kiupel grade, early metastasis, overt metastasis and adequate local control were significantly associated with outcome. Early visceral metastasis was associated with poorer outcome compared to dogs without metastasis, however, a subset of dogs experienced long-term control.
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