sociated with HIV replication. The mechanism of 
NF-KB-mediated activation and the role of the TATA 
box have been defined, and a cDNA clone that en- 
codes a KB-like-binding protein has been identi- 
fied. 
Characterization of the immunoglobulin heavy- 
chain enhancer has continued in the laboratory of 
Assistant Investigator Thomas R. Kadesch, Ph.D. 
(University of Pennsylvania). Two protein-binding 
sites have been identified that, together, recapitu- 
late a negative mode, cell-type-specific regulation. 
One site binds a constitutively active transcription 
factor whose activity is specifically inhibited in non- 
B cells in the presence of the second site. Thus far 
this laboratory has isolated one cDNA encoding a 
protein that binds the first site and three distinct 
cDNAs (encoded by different genes) encoding pro- 
teins that bind the second site. All of the encoded 
proteins function as positive-acting transcription 
factors and possess structural motifs that facilitate 
protein-protein interactions. 
Histocompatibility molecules are responsible for 
the binding and presentation of viral, bacterial, and 
tumor antigens to the immune system and for 
transplant rejection. In order to bind a large num- 
ber of these antigens and ensure the survival of the 
species, it is beneficial that many varieties of the 
histocompatibility molecules be found in the pop- 
ulation. The microrecombination process gener- 
ates variety by reassorting genetic information 
among histocompatibility genes and other related 
genes in germ cells. This has been studied pre- 
viously by isolation of mutant mice that differed 
from their parents in histocompatibility genes. The 
laboratory of Assistant Investigator Jan Geliebter, 
Ph.D. (The Rockefeller University) is investigating 
the microrecombination process by analyzing germ 
cells of normal mice. Since thousands of eggs or 
millions of sperm can be obtained from a single 
mouse, the group can analyze the equivalent of mil- 
lions of mice for microrecombinations. These stud- 
ies should enhance our understanding of the ge- 
netic processes that control the evolution and 
ultimately the function of the mammalian immune 
system. 
The mechanism of tolerance to peripheral anti- 
gens has been examined by the laboratory of Inves- 
tigator Richard A. Flavell, Ph.D. (Yale University). In 
these studies transgenic mice were used in which 
expression of the class II major histocompatability 
complex (MHC) molecule I-E was directed to the P 
islet cells of the pancreas (using the insulin pro- 
moter) and to the acinar tissue of the pancreas 
(using the elastase promoter). Mice carrying this 
peripherally expressed MHC are tolerant to the an- 
tigen, but the tolerance does not appear to result 
from clonal deletion of T cells that may be reserved 
for tolerance to MHC molecules that are expressed 
in the thymus. Instead, at least in the case of the in- 
sulin transgenic mice, these initial data suggest that 
tolerance results from a clonal paralysis of I-E-reac- 
tive T cells. In contrast to those cells from normal 
mice, I-E-reactive cells from the transgenic mice ap- 
pear to be incapable of activation by exposure to 
antigen. These results suggest that the mechanism 
of tolerance to peripheral antigens may, at least in 
part, result from nondeletion mechanisms. 
Assistant Investigator Stephen V Desiderio, M.D., 
Ph.D. (The Johns Hopkins University) and his col- 
leagues continue their work on the development of 
the immune system. One area of study is the assem- 
bly of antibody genes. This recombination reaction 
has been examined in detail, and a novel pathway 
for antibody gene rearrangement has been identi- 
fied that has important implications for the mecha- 
nism of rearrangement and may serve to increase 
the diversity of the immune response. A conserved 
DNA sequence element, which accompanies all an- 
tibody genes, is required for efficient rearrange- 
ment and is the recognition site for a specific DNA- 
binding protein that has been purified to 
homogeneity and may represent a component of 
the recombination machinery The laboratory also 
is examining transduction of growth and differenti- 
ation signals in cells of the immune system. They 
have found and characterized a novel gene that en- 
codes a specific type of signal-transducing protein, 
similar in structure to a number of known 
oncogenes. The structure and restricted pattern of 
expression of this gene suggest that its product 
transduces a signal for growth and/or differentia- 
tion of antibody-producing cells. 
The primary research focus of the laboratory of 
Assistant Investigator John B. Lowe, M.D. (Univer- 
sity of Michigan) has been to investigate mamma- 
lian genes that determine the expression of cell sur- 
face carbohydrate molecules. These efforts have 
exploited experimental systems developed in Dr. 
Lowe's laboratory to isolate these genes without 
first purifying the proteins they encode. Three dis- 
tinct glycosyltransferase genes have been isolated. 
These include the human genes that determine ex- 
pression of the H and Lewis blood groups. Studies 
designed to answer questions about the functions 
of these genes during the early development of 
mammalian organisms are under way. 
Continued 
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