In article <94223.082735FORSDYKE at QUCDN.QueensU.CA> <FORSDYKE at QUCDN.QueensU.CA> writes:
>In
>transgenics with cell-mediated immunity, there would be a possibility that the
>expressed protein would educate the T cells during foetal development, so that
>there would be no specifically programmed T cells capable of reacting against
>cells inwhich aggregation of the hyperexpressed protein had occurred. This
This seems like a really circular argument. If the T cells are deleted, then
there would be no autoimmune destruction of the transgene-expressing tissues
due to tolerance. But in this case it does not become clear whether or not
the transgene product is expressed with class I on the cell surface because
of hyperexpression or normal processing of self. You see the point? If T
cells are the gauges of transgene expression and are deleted, then the method
for measuring intracellular self-nonself discrimination is removed.
The experiment to do would be to use 2 mouse strains that are identical
except for one allelic forms of one gene. Hemoglobin would not be a good
choice since it's extracellular. MHC is also a poor choice as it's on the
cell surface, we need an entirely intracellular protein, call it protein X.
In both strains, protein X (a or b allele) has evolved to the "proper"
intracellular concentration as determined by Don's hypothesis. So there would
be no "intracellular nonself." Protein X should also have MHC- binding
motifs. Now transplant an organ from strain a to strain b. If the graft is
rejected by immunological mechanisms (T cell response to the foreign allele),
then it is highly unlikely that intracellular self-nonself discrimination had
anything to do withthe rejection. If the graft is accepted, and, in no
system can an immune response to the foreign allele be demonstrated, then
Don's hypothesis survives a challenge. One problem with this experiment is
the need for costimulation by Target cells of the graft. If tolerance happens
to be due to anergy or ignorance, no conclusion on intracellular
discrimination can be reached.
Of course all the controls have beenleft out of this "gedanken" experiment,
but you get the point.
I am almost certain that someone has though of this and done the experiment.
Shiv
shiv at lenti.med.umn.edu
