Graduate Thesis Or Dissertation
 

Investigations of T cell costimulation and autoimmunity in mice, and development of flow cytometric methods to assess lymphocyte stimulation in dogs

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  • Proper immune function is indispensable, as failure to mount an immune response against a pathogen can lead to serious complications or even death. T cells act by enhancing the activation of phagocytic cells as well as the activation of B cells. Their widespread influence on an immune response makes optimal T cell activation vital. Maximal T cell proliferation and survival is accomplished by stimulation with antigen, a costimulatory signal, and an adjuvant. However, excessive T cell activation can lead to chronic B cell activation and the production of autoantibodies, a hallmark of autoimmune disease. In this thesis, optimal T cell stimulation was studied using an in vivo adoptive transfer model. Results showed that antigen stimulation of T cells along with ligation of the costimulatory molecule OX40 led to an accumulation of antigen-specific cells. OX40 ligation allowed the antigen specific cells to proceed through more cell cycles than cells stimulated with antigen alone. The addition of the adjuvant lipopolysaceharide (LPS) to this system allowed for increased cell survival. However, the continual presence of an adjuvant may also have injurious effects. This was highlighted with the appearance of "Toxic Oil Syndrome" (TOS) in which an adulterated rapeseed oil, an oil with known adjuvant activity, was sold for human consumption. People developed an autoimmune condition characterized by polyclonal B cell activation and autoantibody production. A genetic predisposition was implicated with TOS and was further investigated in this thesis. Although the A. SW mouse has the genetically susceptible genotype, these mice did not develop TOS following exposure to "toxic oil" indicating that other factors may be important in TOS susceptibility. Extending the techniques used in these studies and applying them to the canine immune system was the final topic investigated in this series of studies. Understanding immune pathways of the mammalian immune system is particularly important for comparative studies when dogs are used as models to investigate human immune system disorders. These studies combined will allow for a better understanding of the balance between an optimal immune response and an imbalance leading to hypersensitivity or immunosuppression, as well as interspecies relationships.
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