III. PROGRAM IN IMMUNOLOGY 
The Program in Immunology, one of the original 
disciplinary areas of the Institute, is represented at 
the University of Michigan, the University of Ala- 
bama at Birmingham, the Massachusetts Institute of 
Technology, Texas Southwestern Medical Center at 
Dallas, the National Jewish Center for Immunology 
and Respiratory Medicine at Denver, Duke Univer- 
sity Medical Center, Baylor College of Medicine, the 
University of California at Los Angeles and at San 
Francisco, Yale University, Columbia University Col- 
lege of Physicians and Surgeons, Stanford Univer- 
sity, the California Institute of Technology, the Uni- 
versity of Washington, and Washington University in 
St. Louis. Among the topics being studied by inves- 
tigators in this program are the development of the 
immune system and the mechanisms for generating 
immunological diversity, the structure and function 
of immunoglobulins and the T cell antigen recep- 
tors, regulation of the immune response, effector 
mechanisms in the immune response, and immu- 
nopathology. 
Investigator Max D. Cooper, M.D. (University of 
Alabama at Birmingham) is interested in the normal 
and abnormal development of immunocompetent 
T and B cells in vertebrates. This laboratory has 
identified a third type of T cell in birds. Comparison 
of the antigen receptors on this recently discovered 
T cell with those recognized previously suggests 
the existence of T cell receptor subclasses, the 
genes for which are programmed for sequential re- 
arrangement and expression. Also in birds, a thy- 
mus-independent line of lymphocytes has been 
identified that expresses certain T cell products but 
not the classical antigen receptors. 
The research of Assistant Investigator Craig B. 
Thompson, M.D. (University of Michigan) and his 
colleagues is focused on characterizing the molecu- 
lar events associated with the regulation of lym- 
phoid development and proliferation. They report 
progress in determining how genetic diversity is 
created in the immunoglobulin genes of developing 
chicken B cells. This work provides insights into 
how genetic heterogeneity arises through the pro- 
cess of gene conversion. In addition. Dr. Thomp- 
son's laboratory continues to examine gene regula- 
tion during T cell proliferation. The laboratory has 
demonstrated a specific role for the regulation of 
mRNA stability in the regulation of lymphokine 
gene expression. Studies concerning the regulation 
of mRNA stability are under way. 
Molecular genetic events involved in the ability of 
animals to produce antibodies have been examined 
by the laboratory of Investigator Frederick W Alt, 
Ph.D. (Columbia University). Antibody genes are 
encoded in pieces in the germline; these genes 
must be assembled during development of anti- 
body-producing cells. This laboratory has eluci- 
dated aspects of the mechanism and control of this 
gene assembly process that have provided funda- 
mental insights into the way mice and humans gen- 
erate a specific antibody repertoire and also the na- 
ture of genetic defects that impair this process. 
They have now applied new technologies to alter 
the genetic constitution of mice to create model 
systems and elucidate the molecular and physiolog- 
ical mechanisms regulating the development of 
antibody-producing cells and the generation of the 
immune response. 
The research of Assistant Investigator Rudolf 
Grosschedl, Ph.D. (University of California at San 
Francisco) and his colleagues is focused on the 
mechanisms that allow immunoglobulin (Ig) |jl and 
K genes to be expressed only in one cell type and in 
a temporally ordered manner. By transfer of wild- 
type and mutated genes into the mouse germline, 
specific factor-binding sites in the enhancer and 
promoter were shown to be important for |x gene 
expression in lymphocytes. The temporal regula- 
tion of Ig gene expression was found to be medi- 
ated, at least in part, by the enhancer. This genetic 
element was also found to be a determinant for the 
stable propagation of the pattern of Ig gene expres- 
sion from mother to daughter cells. Finally, cDNA 
clones representing novel lymphocyte-specific 
genes were isolated and partially characterized. 
In addition to their role in the body's defense 
against invading organisms such as viruses and bac- 
teria, T cells are also thought to mediate the devel- 
opment of certain autoimmune diseases and to par- 
ticipate in tissue or organ transplant rejection. 
Thus T cells must be able to recognize foreign in- 
vaders. However, these cells should not recognize 
and respond to the host animal itself, since such an 
event can lead to a number of autoimmune dis- 
eases. The laboratory of Investigator Philippa 
Marrack, Ph.D. (National Jewish Center for Immu- 
nology and Respiratory Medicine, Denver) is inter- 
ested in the events that lead to the state where T 
cells can recognize foreign material, but not self It 
has been found that events critical to this distinc- 
tion usually occur in the thymus, the organ in 
which T cells develop. During T cell development 
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