Genetic Approaches to Immune Function and Tolerance 
experiments the mice were indeed found to be 
tolerant to the MHC antigens. T cells that would 
normally react with this MHC product are not 
eliminated, which is what would be found if the 
class II antigen is expressed in thymic tissues. In- 
stead, these T cells are present but have been in- 
activated 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 mechanisms of peripheral toler- 
ance to protein antigens, rather than MHC, we 
made transgenic mice that express the T cell re- 
ceptor (TCR) reactive with a fragment of the T 
antigen of SV40 (simian virus 40). We have ob- 
tained transgenic mice that express SV40 T anti- 
gen in various peripheral tissues in the body, in- 
cluding the |8-cells of the pancreas and the 
secretory exocrine cells of the pancreas that pro- 
duce digestive enzymes. By crossing the TCR 
transgenics with mice expressing the antigen, we 
can determine the immune status to SV40 T anti- 
gen. Tolerance is found to the SV40 T antigen 
provided that expression has occurred prior to 
the release of T cells from the thymus in the new- 
born animal. This tolerance results in partial elim- 
ination of antigen-specific T cells and clonal 
inactivation of the remainder. If, however, ex- 
pression of antigen is delayed, the T cells 
are not tolerant but instead become activated, 
with resultant autoimmune destruction of the 
pancreas. 
Delayed expression of antigen therefore seems 
to place an individual at risk for autoimmunity. 
However, even in individuals genetically predis- 
posed to become autoimmune, nongenetic fac- 
tors play an important role. One model suggests 
that a precipitating event for autoimmunity can 
be the onset of a local inflammatory response in 
the tissue, for example, as a consequence of in- 
fection. To test this we made transgenic mice that 
express the inflammatory cytokine TNF (tumor 
necrosis factor) on the pancreatic islets, which 
simulates local inflammation. This cytokine ex- 
pression causes a massive infiltration of T and B 
lymphocytes, which mimics the infiltrate seen in 
mouse autoimmune diabetes and causes partial 
destruction of the insulin-producing j8-cells of 
the pancreas. We are currently determining 
whether the inflammatory cells present in the 
TNF transgenic mice are specific for pancreatic 
antigens, as is the case in true IDDM. 
We also study the response of the immune sys- 
tem to the spirochete Borrelia burgdorferi, 
which causes the notorious inflammatory dis- 
ease, Lyme disease. We showed last year that mice 
vaccinated against an outer surface protein of 
Borrelia (OspA) are protected against infection 
by Borrelia burgdorferi. We have now shown 
that protection can also be mediated by a second 
protein (OspB) but not by the flagellar antigen, 
even though a potent antibody response is ob- 
tained to this protein. 
For such a vaccine to work it must be eff'ective 
against most, if not all, strains of the infectious 
agent and be effective against a natural challenge. 
Since the natural vector is the deer tick, we also 
infected laboratory mice with B. burgdorferi by 
placing infected ticks on these mice. Encourag- 
ingly, mice vaccinated with either OspA or OspB 
were protected; furthermore, spirochetes in the 
gut of ticks feeding upon vaccinated mice were 
eliminated, whereas they were unaffected in non- 
vaccinated mice. This shows an additional poten- 
tial benefit of the vaccine, which is to eliminate 
spirochetes from the vector. We are now con- 
sidering strategies for the eradication of the spiro- 
chetes in the wild population of ticks by a related 
approach. 
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