Genetic Approaches to Immune Function and Tolerance 
expressed in thymic tissues. Instead, these T cells 
are present but have been inactivated in some 
way, such that they are no longer able to respond 
to the MHC antigen, either in the animal or in 
test-tube experiments. As a result, no destruction 
of the pancreatic tissue occurs. 
To determine whether the above-mentioned 
mechanism applies to the more general situation 
of immune tolerance — namely tolerance to pro- 
tein antigens themselves — we have generated 
transgenic mice that express the T cell receptor 
reactive with a specific antigen, the T antigen of 
SV40 (simian virus 40). We have obtained from 
several collaborators transgenic mice that ex- 
press SV40 T antigen in various peripheral tissues 
in the body, including the jS cells of the pancreas, 
the secretory tissues of the pancreas that produce 
digestive enzymes, and the lens of the eye. In the 
former two cases these experiments are analo- 
gous to our previous studies, except that now we 
are able to study directly tolerance to a protein 
antigen measured by its effects on a monoclonal 
population of T cells obtained by the use of T cell 
receptor transgenic mice. In the case of the lens 
of the eye, antigen is expressed in a compartment 
of the body traditionally believed to be an im- 
munoprivileged site (inaccessible to the immune 
system). Tolerance in this compartment has not 
been previously studied. We have now bred the T 
cell receptor transgenic mice with those mice ex- 
pressing antigens in these respective tissues and 
are studying tolerance mechanisms. 
We have also initiated research to study the re- 
sponse of the immune system to the spirochete 
Borrelia burgdorferi, which causes Lyme dis- 
ease, the notorious inflammatory disease. We 
have produced recombinant proteins for several 
of the outer-surface components of this spiro- 
chete and have immunized mice with these pro- 
teins. A mouse model has been developed by Ste- 
phen Barthold (Yale University) that exhibits 
many of the symptoms of the human disease, in- 
cluding arthritis and inflammation of the tissues 
surrounding the heart. Mice immunized with 
these proteins were challenged by infection with 
the Lyme disease agent. Strikingly, mice immu- 
nized with recombinant outer-surface protein A 
(OspA) were fully protected from infection with 
the spirochete. Both the protection and the immu- 
nity of the mouse to this organism appear to be 
long-lived. These encouraging results suggest 
that, administered appropriately, recombinant 
OspA could serve as a vaccine for protection of 
humans and animals against the Lyme disease 
agent. Vaccination may well be a desired ap- 
proach, since this disease is widespread, causes 
serious chronic symptoms, and frequently goes 
undetected in early stages. We have also charac- 
terized the response of the human immune sys- 
tem to outer-surface proteins of this organism. 
The human immune response to OspA is qualita- 
tively similar to the mouse response, suggesting 
that it should be possible to obtain a protective 
response in humans. Humans, however, respond 
to OspA later in infection than do mice, suggest- 
ing that further work may be necessary before an 
effective human vaccine is obtained. 
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