Yes, the tone would be gritty and realistic, but not hopeless. I think the best parts of Twilight: 2000 involve a desire to rebuild and make things better in the aftermath of WWIII. I don't have much desire to roleplay out radiation sickness while slowly dying of starvation. On the other hand, it's not going to be an action movie without consequences either.
The system is still up in the air and I'm trying to decide between 3 alternatives. One, Gurps is the system I'm most familiar with, its sufficiently realistic and lethal when need be. I currently own all the books I would need to run it, which is a plus. Gurps Lite is freely available, which gives everyone a cheap way in. On the down side, it can be intimidating to new players and I'd need to shoe horn in a life path system.
Two, would be the 2.2 version of T2K. It fits the mood I'm going for, has everything we need in it. I would need to buy a few pdfs to get the information I'm looking for, but that's not a big deal. I've never run any version of Twilight, so there's going to be some teething problems and systems hiccoughs. The system is showing its age and kind of inelegant, also there's no free way in...its not like playing around a physical table, so there'd be issues with character creation and playing unless all the players committed to buying the core pdf.
Three (and the most out there idea) would be using 1st Edition Spycraft. Since its based on 3rd Edition D&D, a large number of people would be familiar with the system. I own most of the books we'd need and i can get pdfs of the rest fairly cheaply. The biggest drawback is that its going to feel more like an action movie of Twilight, although the VP/WP mechanic is light years better than escalating HP.
So, I'm still in the process of figuring out which way to go...now that Christmas is over, I'll be able to relax a bit and start thinking about this a bit more. I have decided on going alt-history and having the balloon go up in 1985, still working out the exact details surrounding this timeline though.