targeting to the lesion and the initiation of the au- 
toimmune process. 
The polypeptide a- and p-chains of the TCR pro- 
vide critical contact points with MHC and antigen 
and form the basis of T cell recognition. Assembly 
of the functional a- and ^chain genes occurs dur- 
ing T cell development in the thymus by a process 
of recombination of germline DNA segments. Once 
a functional receptor is produced, further T cell 
gene rearrangements cease, a phenomenon re- 
ferred to as allelic exclusion. Support for this 
model has been provided by studies conducted by 
Dr. Seidman and others, who have shown that 
transgenic mice bearing a functionally rearranged 
(i-chain gene into the germline of mice prevent ex- 
pression of the endogenous P-chain gene reper- 
toire. 
To examine the role of the endogenous T cell re- 
ceptor repertoire on the development of insulitis 
and the production of autoantibodies in the NOD 
mouse. Dr. Seidman and his co-workers bred a 
functional P-chain transgene into the NOD mouse. 
During earlier studies a functional p-chain gene 
from the DO. 11 hybridoma was introduced into 
B6xSJL mice. These transgenic mice were mated to 
NOD animals and four backcross generations were 
produced (transgene-bearing mice were selected 
for further mating in each generation). As expected, 
PUBLICATIONS 
the transgene is fully functional in the backcross 
mice. Nearly all of the T cells in these animals bear 
the vps determinants encoded by the transgene. 
Furthermore, the transgene produces allelic exclu- 
sion of other vps from the surface of T cells in both 
the thymus and spleen. 
Surprisingly, the transgene has no detectable ef- 
fect on the development of autoimmunity in the 
NOD mouse. Autoantibodies against insulin pre- 
cede the development of overt type I diabetes in 
humans and NOD mice, and the magnitude of the 
titers correlates with the progression to diabetes. 
The transgene did not significantly affect either 
incidence or titer of insulin autoantibodies; 4/15 
(27%) of the transgene-positive mice compared 
with 4/21 (19%) of the transgene-negative mice ex- 
pressed insulin autoantibodies similar to what is 
seen with NOD mice. Furthermore, the frequency 
of insulitis among transgene-bearing mice and non- 
transgene-bearing littermates was not significantly 
different (3/12 vs. 4/24), despite the fact that the 
transgene-bearing T cells were found in large num- 
bers in the insulitis lesions of transgenic mice. 
These studies question the role of TCR specificity in 
the development of autoimmune diabetes. 
Dr. Seidman is also Professor of Genetics at Har- 
vard Medical School. 
Articles 
Bloch, D.B., Bloch, K.D., lannuzzi, M., Collins, F.S., Neer, E.J., Seidman, J.G., and Morton, C.C. 1988. The 
gene for the subunit of human guanine nucleotide binding protein maps near the cystic fibrosis locus. 
Am J Hum Genet 42:884-888. 
Duby, A.D., Weiner, H.L., Benjamin, D.S., Seidman, J.G. , and Hafler, D.A. 1989. Sequestration of virus-specific 
T cells in the cerebrospinal fluid of a patient with varicella zoster viral meningoencephalitis. / Neu- 
roimmunol 22:63-68. 
Fenton, R.G., Marrack, E, Kappler, J.W, Kanagawa, O., and Seidman, J. G. 1988. Isotypic exclusion of-y5 T cell 
receptors in transgenic mice bearing a rearranged (3-chain gene. Science 241:1089-1092. 
Fox, YL., Strauss, WM., and Seidman, J.G. 1989. Isolation and restriction map of the V-J interval of the 
human T cell receptor 7 chain locus. Genomics 4:445-448. 
Hafler, D.A., Duby A.D., Lee, S.J., Benjamin, D., Seidman, J.G. , and Weiner, H.L. 1988. Oligoclonal T lympho- 
cytes in the cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 167:1313-1322. 
Handler, J.D., Schimmer, B.R, Flynn, T.R., Szyf, M. , Seidman, J.G. , and Parker, K.L. 1988. An enhancer element 
and a functional cyclic AMP-dependent protein kinase are required for expression of adrenocortical 21- 
hydroxylase. J Biol Chem 263:13068-13073. 
Hochstenbach, F, Parker, C, McLean, J., Gieselmann, V, Band, H., Bank, I., Chess, L, Spits, H., Strominger, 
J.L., Seidman, J.G., and Brenner, M.B. 1988. Characterization of a third form of the human T cell receptor 
gamma/delta. J Exp Med 168:761-776. 
Continued 
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