Chris, I shoot the Nikon D3S in addition to the S2 and I know several of the other S2 owners are Nikon shooters as well... I hope they will chime in with their experiences. To address your first issue... the S2 is well suited for hand held shooting in large part due to the ergos of the camera. If you are accustomed to shooting hand held with a pro Nikon body you will have no problem doing the same with the S2. Second question depends on what you mean by high ISO. The Nikon D3S is, IMHO, king of the hill for high ISO shooting and the S2 is not even in the same ballpark. If you've got decent light, ISO 640 will give good results... but if you're looking for ISO 6400, stick with Nikon
I think the best Nikon glass is excellent, especially the zooms. But the Leica glass is simply superb. The images from the S2 are a quantum leap better than anything I get from my D3S and I personally know at least one D3X (and S2) shooter who would say the same. Take one for a test drive and I think you will see the difference immediately...
One caveat worth mentioning. If you're planning on getting several of the Leica lenses you may need to wait a while. They have been increasingly difficult (if not impossible) to get quickly.