tems have been used to identify carbohydrate mole- 
cules that allow specific immune cells to leave the 
blood circulation and thus promote their participa- 
tion in the inflammation process. More recently, Dr. 
Low^e and his colleagues have used these genes to 
construct such carbohydrates and have found that 
these molecules function as anti-inflammatory com- 
pounds in animal models of inflammation. The 
genes are also in use in studies designed to answer 
other questions about the regulation and func- 
tion (s) of carbohydrate molecules in mammalian 
organisms. 
Associate Investigator Stephen V. Desiderio, M.D., 
Ph.D. (Johns Hopkins University) and his col- 
leagues continue to study development and activa- 
tion of the immune system. Production of antibod- 
ies depends on a series of DNA rearrangements that 
occur in developing immune cells. These rearrange- 
ments are triggered by the RAG-1 and RAG-2 pro- 
teins. The laboratory has pinpointed specific chemi- 
cal modifications that regulate the activity of RAG-2 
and its level in the cell. These observations suggest 
that DNA rearrangement and control of cell divi- 
sion may be coupled in developing immune cells. 
Dr. Desiderio also continues to study how an im- 
mune response is triggered. Having identified novel 
signal-transducing proteins expressed in immune 
cells, his laboratory has begun to define other mole- 
cules that interact specifically with these proteins, 
with the ultimate goal of linking events at the cell 
surface to responses that occur in the nucleus. 
Associate Investigator Thomas R. Kadesch, Ph.D. 
(University of Pennsylvania) and his colleagues 
have continued to work on the immunoglobulin 
heavy-chain enhancer in B cells and have begun to 
address transcriptional control mechanisms in other 
hematopoietic cell types. The laboratory has contin- 
ued to characterize a candidate-repressor protein, 
Zeb, and to explore the role of another inhibitor, Id, 
in the context of B cell development. Id also appears 
to play a role in the development of myeloid cells. 
Thus B cells and myeloid cells employ a common 
family of transcription factors to control their devel- 
opmental maturation and the expression of their 
genes. 
The activity of antibody genes in B cells has been 
proposed to be regulated by a B cell-specific activa- 
tor protein, Oct- 2. The laboratory of Assistant Inves- 
tigator Harinder Singh, Ph.D. (University of Chi- 
cago) has used a gene-targeting procedure to reduce 
severely the levels of Oct-2 in a B cell. Surprisingly, 
the activity of antibody genes was unaffected in the 
mutant cells. This result strongly suggests that B 
cells can use a diff^erent pathway involving the non- 
cell-type-specific, but related, activator protein 
Oct-1 to regulate the activity of B cell-specific im- 
munoglobulin genes. The Oct-2 mutant cells are, 
however, defective in activating transcription of 
certain constructed genes. This result suggests that 
Oct-2 is critically required to regulate the activity of 
B cell genes that have yet to be identified. 
Histocompatibility molecules are responsible for 
transplant rejection and the binding and presenta- 
tion of viral, bacterial, and tumor antigens to the 
immune system. To bind a large number of these 
antigens and insure the survival of the species it is 
beneficial that many varieties of the histocompatibil- 
ity molecules be found in the population. The mi- 
crorecombination process, which generates variety 
by reassorting genetic information among histocom- 
patibility and related genes in germ cells, has been 
previously studied by isolating mutant mice that dif- 
fered from their parents in histocompatibility genes. 
However, to study this process. Assistant Investiga- 
tor Jan Geliebter, Ph.D. (Rockefeller University) 
and his colleagues are using a reporter construct 
that turns microrecombinant cells blue under spe- 
cific conditions, and they are introducing this con- 
struct into mammalian cells in culture and trans- 
genic mice. 
The parasites that cause the major tropical dis- 
eases of the world possess sophisticated molecular 
mechanisms for evading the immune response 
mounted against them. The laboratory of Investiga- 
tor John E. Donelson, Ph.D. (University of Iowa) 
seeks to understand these mechanisms and devise 
strategies for combating them. African trypano- 
somes, for example, evade the immune response by 
periodically switching the major protein on their 
surface. The molecular events associated with this 
switch are being investigated. Leishmania para- 
sites, on the other hand, possess on their surface 
three forms of a protease that enable them to pene- 
trate and survive within macrophages. The differen- 
tial expression and biological functions of these 
three forms are being examined. 
Investigator Mario R. Capecchi, Ph.D. (University 
of Utah) and his colleagues have developed technol- 
ogy that allows an investigator to mutate specifically 
any gene in the mouse. This technology was used by 
the group to disrupt genes believed to have impor- 
tant roles in establishing positional information 
along the anterior-posterior axis of the early mam- 
malian embryo. Where should the heart develop? 
Where should specific nerves develop? How is the 
shape of the face determined? Disruption of some of 
these genes resulted in mice with heart defects, loss 
of specific cranial nerves, or craniofacial abnormali- 
ties. When this approach is used to study mam- 
malian development, a correlation is established 
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