use of appropriate mouse mutants that either lack or 
suffer depleted populations of thymus-dependent T 
cells (nu/nu), NK cells (bg/bg), mast cells (W/ 
W), B cells (B less), or B and T cells (SCID), Dr. 
Leder and his colleagues showed that these inflam- 
matory cell types are not required for the antitumor 
response. 
Furthermore, by noting that regressing tumors 
contain relatively large numbers of eosinophils (a 
cell type associated with parasitic infection and al- 
lergic responses ) , they took advantage of a monoclo- 
nal antibody targeted to eliminate eosinophils and 
other granulocytes. Treatment with this neutralizing 
antiserum greatly reduced eosinophils at the tumor 
site and strongly suppressed the antitumor effect. 
Thus they established a role for eosinophils in the 
antitumor response and identified a plausible ave- 
nue for therapy in human malignancy. 
Growth/Differentiation Factors 
as Oncogenic Agents 
The 07icogene int-2 and other members of the 
fibroblast growth factor (FGF) gene family. Int-2 
is the product of a gene \cry closely related to the 
FGF family of genes, some of which play an impor- 
tant role in cell growth and differentiation, int-2 
itself is normally expressed only during embryonic 
development and has been shown by others to be 
essential for the formation of the embryonic otic 
cup. In adult mice it has been found, again by 
others, to be perturbed and expressed as a result of 
viral insertional mutagenesis in certain mammary 
carcinomas. Using transgenic mice. Dr. Leder and 
his colleagues showed that the dysregulated int-2 
gene induces mammary hyperplasia and, ultimately, 
mammary carcinoma in female transgenic mice and 
benign prostatic hypertrophy in male mice. In an 
experiment with obvious clinical implications, the 
prostatic effect was shown to be androgen depen- 
dent and hormonally responsive. 
Further detailed studies involving the transplanta- 
tion of hypertrophic mammary epithelium to the 
mammary glands of wild-type recipient mice and 
similar reciprocal experiments showed that the ef- 
fect of int-2 was only active over a very short dis- 
tance, several microns at most. This experiment 
strongly suggests that int-2 induces mammary hy- 
perplasia via a cell-autonomous, autocrine effect, an 
interpretation consistent with int-2's apparent ac- 
tion in the developing central nervous system. 
In separate studies involving transgenic mice and 
in collaboration with Dr. Harold Varmus's group, it 
was demonstrated that int-2 cooperates with the on- 
cogene Wnt-1 (a secreted glycoprotein that also 
induces mammary hyperplasia and carcinoma in 
transgenic mice) to accelerate the incidence of 
mammary carcinoma in mice carrying both onco- 
genic transgenes. Inasmuch as int-2 is a member of 
the FGF family of genes that has been virtually im- 
possible to obtain in soluble form, Dr. Leder's group 
has continued its studies of the molecular interac- 
tions of the closely related gene bFGF (bzsic FGF) as 
a surrogate for int-2. This work has defined the hepa- 
rin requirement for the interaction between bFGF 
and its receptor and points to a role for heparin in 
regulating the short-range release of such growth 
factors from the extracellular matrix. 
Developmental Anomalies in Transgenic Mice 
The role of formins in embryonic development. 
Dr. Leder and his group have defined a set of pro- 
teins, the formins, on the basis of their involvement 
in the embryonic formation of the mouse limb and 
kidney. Using the integration of a transgene that cre- 
ated an allele of the limb deformity {Id) mutation, 
the Leder group defined the locus as one that gives 
rise to a variety of alternatively spliced mRNAs, each 
capable of encoding a different isoform of the 
formin set. Recently they have characterized a new 
isoform that differs from those previously character- 
ized, in that it encodes a highly acidic amino- 
terminal exon. 
This isoform is expressed in the mesenchyme and 
apical ectodermal ridge of the developing embry- 
onic limb bud, as well as the developing central 
nervous system and several adult tissues. The fact 
that the phenotypes of the Id alleles are restricted to 
the limbs and kidneys suggests that they represent 
only partial loss-of-function mutations, a view con- 
sistent with the observation that all the structurally 
characterized alleles of Id involve deletions of the 
same small carboxyl-terminal portion of the formin 
isoforms. 
B less, a novel immunodeficient transgenic mu- 
tation that abrogates B cell formation. Several nat- 
urally occurring mutant mice have been defined in 
which there is interference with the development of 
the immune system. The best characterized and 
most useful of these are the nude mice (thymus- 
dependent T cell) and SCID mice (T and B cell- 
deficient). Both have been used for a variety of 
experimental purposes, many involving transplan- 
tation studies. 
In the course of experiments designed to under- 
stand expression of the human X immunoglobulin 
light-chain gene. Dr. Leder and his colleagues cre- 
ated a transgenic mouse bearing this human gene. 
The mouse is dramatically deficient in B cells and, 
as a consequence, profoundly immunodeficient. 
The molecular basis for this effect, which is sup- 
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