Mice lacking the secreted extracellular superoxide dismutase (EC-SOD) or the cytosolic copper-and zinc-containing SOD (CuZn-SOD) show relatively mild phenotypes. To explore the possibility that the isoenzymes have partly overlapping functions, single and double knockout mice were examined. The absence of EC-SOD was found to be without effect on the lifespan of mice, and the reduced lifespan of CuZn-SOD knockouts was not further shortened by EC-SOD deficiency. The urinary excretion of isoprostanes was increased in CuZn-SOD knockout mice, and plasma thiobarbituric acid-reactive substances levels were elevated in EC-SOD knockout mice. These oxidant stress markers showed potentiated increases in the absence of both isoenzymes. Other alterations were mainly found in CuZn-SOD knockout mice, such as halved glutathione peroxidase activity in the tissues examined and increased glutathione and iron in the liver. There were no changes in tissue content of the alternative superoxide scavenger ascorbate, but there was a 25% reduction in ascorbate in blood plasma in mice lacking CuZn-SOD. No increase was found in the urinary excretion of the terminal metabolites of NO, nitrite, and nitrate in any of the genotypes. In conclusion, apart from the increases in the global urinary and plasma oxidant stress markers, our phenotype studies revealed no other evidence that the copper-and zinc-containing SOD isoenzymes have overlapping roles.
Targeting cancer through the use of effector T cells bearing chimeric antigen receptors (CARs) leads to elimination of tumors in animals and patients, but recognition of normal cells or excessive activation can result in significant toxicity and even death. CAR T cells based on modified NKG2D receptors are effective against many types of tumors, and their efficacy is mediated through direct cytotoxicity and cytokine production. Under certain conditions, their ligands can be expressed on non-tumor cells, so a better understanding of the potential off tumor activity of these NKG2D CAR T cells is needed. Injection of very high numbers of activated T cells expressing CARs based on murine NKG2D or DNAM1 resulted in increased serum cytokines (IFNγ, IL-6, MCP-1) and acute toxicity similar to cytokine release syndrome. Acute toxicity required two key effector molecules in CAR T cells – perforin and GM-CSF. Host immune cells also contributed to this toxicity, and mice with severe immune cell defects remained healthy at the highest CAR T cell dose. These data demonstrate that specific CAR T cell effector mechanisms and the host immune system are required for this cytokine release-like syndrome in murine models.
Chimeric antigen receptors (CARs) are genetically engineered proteins that combine an extracellular antigen-specific recognition domain with one or several intracellular T-cell signaling domains. When expressed in T cells, these CARs specifically trigger T-cell activation upon antigen recognition. While the clinical proof of principle of CAR T-cell therapy has been established in hematological cancers, CAR T cells are only at the early stages of being explored to tackle solid cancers. This special report discusses the concept of exploiting natural killer cell receptors as an approach that could broaden the specificity of CAR T cells and potentially enhance the efficacy of this therapy against solid tumors. New data demonstrating feasibility of this approach in humans and supporting the ongoing clinical trial are also presented.
The process resulted in production of required cell doses for the first-in-human phase I NKG2D CAR T clinical trial and provides a robust, flexible base for further optimization of NKG2D CAR T-cell manufacturing.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with unclear etiology and few treatment options. Engineering of human cells for therapy has great potential to provide a means to create long-lived therapeutics that can respond to local signals within tissues. One challenge for development of human cell therapeutics is to have disease models that do not reject transplanted human cells. G93A mutant superoxide dismutase-1 (mSOD1) transgenic mouse model is a robust disease model for ALS, with development of local inflammation, activation of microglia and astrocytes, motor neuron death, and development of paralysis. To create a mouse model for ALS that permits the transplantation of human T cells without immune-mediate rejection, we bred the G93A transgene onto the NOD-SCID-IL-2Rγ-deficient (NSG) mouse model to create mSOD1-NSG mice. We report that mSOD1-NSG mice develop a progressive ALS-like disease with microgliosis, astrogliosis, and paralysis development with an average onset at 11 weeks and end-stage at 14 weeks. Transplanted human T regulatory cells survive in these mice for at least 60 days. This mSOD1-NSG mouse model for ALS can be used to test human T cell-based therapeutics, and it may be helpful to test any human cell-based therapy for ALS.
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