II. Immune Function and Dysfunction in Transgenic 
Mice Expressing Human CD4 and HLA-DQ Genes. 
This year Dr. Flavell's laboratory initiated studies 
that attempt to examine aspects of the functioning 
of the human immune system in the mouse. If 
these human molecules will function in a murine 
environment, it should be possible to study their 
functioning within an immune system in vivo and 
to analyze certain aspects of pathology related to 
the human immune system. In an initial attempt, 
transgenic mice expressing the human CD4 gene 
and the HLA-DQ 3.2 gene have been generated, in 
collaboration with Dr. Dimitris Kioussis (National 
Institute for Medical Research, Mill Hill, London, 
England). The human CD2 promoter/enhancer, 
which, unlike the CD4 promoter, has been shown 
to function in transgenic mice, was used to express 
CD4. The CD4 gene seems to be expressed in thy- 
mocytes and peripheral T cells, as well as in B cells 
(since it has recently been shown that murine CD2 
is expressed in B cells, the latter result is expected). 
HLA-DQ appears to be expressed in the same sites 
and at about the same level as the normal murine 
class II genes. Current studies are directed at deter- 
PUBLICATIONS 
mining whether these human elements function in 
the setting of the murine immune system and in 
using these mice as models for acquired immune 
deficiency syndrome (AIDS) pathogenesis. 
III. Regulation of MHC Gene Expression. 
Dr. Flavell's laboratory is also studying the regu- 
lation of MHC class I and class II gene expression. 
Work in collaboration with the laboratory of Dr. 
Phillip A. Sharp (Massachusetts Institute of Tech- 
nology) has shown that transcriptional activation of 
class I genes is explained at least in part by the 
binding of a DNA-binding factor (IBP-1) to an inter- 
feron response element in the promoter region of 
the class I gene (using in this case the gene). 
During this year they have shown this factor to be a 
molecule of —59 kDa and further defined the DNA 
regions to which it binds. Current efforts are di- 
rected at cloning the gene that encodes this protein 
and understanding the ways in which it mediates 
the interferon signal. 
Dr. Flavell is also Professor of Immunobiology at 
Yale University School of Medicine. 
Books and Chapters of Books 
Lo, D., Quaife, C, Heber-Katz, E., Burkly L., Markmann, J., Cowing, C, Widera, G., Naji, A., Flavell, R.A., Pal- 
miter, R.D., and Brinster, R.L. 1989. Transgenic mice with specific expression of class II MHC on p cells: 
antigen-presenting function and tolerance induction. In Current Communications in Molecular Biology. 
Cold Spring Harbor, NY: Cold Spring Harbor, pp 163-168. 
Articles 
Blanar, M.A., Baldwin, A.S., Jr., Flavell, R.A., and Sharp, P.A. 1989. A gamma interferon-induced factor that 
binds the interferon response sequence of the MHC class I gene, H-2K''. EMBO J 8:1159-1144. 
Blanar, M.A., Burkly, L.C., and Flavell, R.A. 1989. NF-kB binds within a region required for B-cell-specific ex- 
pression of the major histocompatibility complex class II gene E^'^. Mol Cell Biol 9:844-846. 
Burkly, L.C., Lo, D., Cowing, C, Palmiter, R.D., Brinster, R.L., and Flavell, R.A. 1989. Selective expression of 
class II E^*^ gene in transgenic mice. J Immunol 142:2081-2088. 
Lo, D., Burkly, L.C., Flavell, R.A., Palmiter, R.D. , and Brinster, R.L. 1989. Tolerance in transgenic mice express- 
ing class II major histocompatibility complex on pancreatic acinar cells. J Exp Med 170:87-104. 
Murphy D.B., Lo, D., Rath, S., Brinster, R.L., Flavell, R.A. , Slanetz, A., and Janeway C.A., Jr. 1989. A novel 
MHC class II epitope expressed in thymic medulla but not cortex. Nature 338:765-768. 
Statter, M.B., Fahrner, K.J., Barksdale, E.M., Jr., Parks, D.E., Flavell, R.A. , and Donahoe, R 1989. Correlation of 
fetal kidney and testis congenic graft survival with reduced major histocompatibility complex burden. 
Transplantation 47:651-660. 
Verland, S., Simonsen, M., Gammeltoft, S., Allen, H., Flavell, R.A. , and Olsson, L. 1989. Specific molecular in- 
teraction between the insulin receptor and a D product of MHC class I. J Immunol 143:945-951. 
Continued 
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