The Tumor Necrosis Factor Receptor Superfamily (TNFR) is responsible in regulating a myriad of physiological function including the regulation of the immune system. Among the members include CD137 (4-1BB), an inducible costimulatory receptor known for its potent activation, proliferation, and survival effects on T cells. Stimulation of NK cells with agonistic α-CD137 antibodies are known to increase IFN-γ production and proliferation in NK cells as well as increase efficacy of anti-tumor responses. However, NK cell death has also been seen in certain circumstances, although the mechanism remains to be determined. In vitro stimulation of NK cells revealed that α-CD137 induced NK cell death occurs through both TNFR1 and TNFR2, although the action of TNF-α and TNF-ß remain uncertain. Death was independent of other cytotoxic mechanisms such as granzyme/perforin, Fas-Fas ligand, and TRAIL. During MCMV infection, α-CD137 induces NK cell death during the early phase of infection reducing viral resistance. This causes increased viral proliferation which drives NK cell proliferation, likely through Ly49H-m157 interactions, to high levels by day 4 of infection. The use of α-CD137 as a tumor therapeutic is promising with several applications undergoing clinical trials. However, my results raise concern of other effects including the depletion of NK cells. This may cause a temporary impairment in immune function against pathogenic infections and a compensatory reaction of NK cell proliferation, both of which may cause damage to the host. However, with proper co-stimulation or co-treatments, this impairment may be overcome and prevent adverse effects in patients.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/36710 |
| Date | January 2017 |
| Creators | Hahm, Dahn |
| Contributors | Lee, Seunghwan |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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