Oral Presentations - Federation of Clinical Immunology Societies

S28 Abstracts
F.34 Gleevec: A New Therapeutic for Type I
Diabetes?
Cedric Louvet, Postdoctoral Research Fellow, Diabetes
Center at University of California, San Francisco, San
Francisco, CA, Gregory L. Szot, Islet Transplant Facility
Manager, Diabetes Center, San Francisco, CA, Jiena Lang,
Staff Research Associate, Diabetes Center at University of
California, San Francisco, San Francisco, CA, Jeffrey A.
Bluestone, Diabetes Center Director, Diabetes Center at
University of California, San Francisco, San Francisco, CA,
Michael R. Lee, Staff Research Assistant, Diabetes Center at
University of California, San Francisco, San Francisco, CA
Gleevec (Imatinib, formerly STI571) is the first FDA-approved
drug to directly turn off a specific protein known to cause a
cancer. Although targeted to the Bcr-Abl kinase, Gleevec has
been shown to modestly affect related kinases including PDGF,
c-fms and c-kit potentially involved in various cell types critical
to the development and progression of autoimmune diseases.
Based on these fundamental properties, we embarked on a
study to determine the clinical effects of Gleevec in T1D in NOD
mice.
NOD mice were treated by gavage daily with 1.5 mg/
mouse of commercially available Gleevec suspended in
peanut oil. Pre-diabetic mice treated with Gleevec, but not
with peanut oil only, were protected from spontaneous
diabetes. More importantly, when Gleevec treatment was
initiated at the time of disease onset (blood sugars between
250 and 350 mg/dl), the majority of mice went into remission
and b10% relapsed during the course of the therapy. When
therapy was discontinued at 2 weeks, the majority of the
mice became hyperglycemic within 1–2 weeks. However,
longer therapy (8–10 weeks) resulted in long-term normoglycemia
in a majority of treated animals even after drug
cessation suggesting that Gleevec does not have to be given
continuously to promote long-lasting protection. The possibility
that short-term therapy with Gleevec can lead to longterm
effects makes it a very attractive potential therapeutic
for the treatment of patients with new onset T1D as well as
potentially patients undergoing an islet transplant.
doi:10.1016/j.clim.2007.03.249
F.38 Characterization of Peptide Agonists and
Antagonists for the Interaction of CD200 with
CD200R1 and Their Efficacy in Modulation of
LPS-induced TNFα Production and Mortality In Vivo
Reginald Gorczynski, Professor, University Health Network,
Toronto, ON, Canada, Ivo Boudakov, PDF, University Health
Network, Toronto, ON, Canada, Ismat Khatri, PDF,
University Health Network, Toronto, ON, Canada
After engagement of the Ig-supergene family members
CD200R1 and CD200, immunosuppressive and/or antiinflammatory
signals augment allograft survival and
decrease production of inflammatory cytokines. The primary
domains of both CD200 and CD200R1 implicated in
these interactions are found in the NH2-terminal region of
each molecule. We investigated the capacity of 10–15 mer
synthetic peptides defining the three complementaritydetermining
(CDR1–3) regions of mouse CD200 to reproduce
the function of full-length CD200, or antagonize that
function, assaying the suppression of LPS-induced TNFα
production (in vivo/in); suppression of MLC responses in
vitro; and LPS-induced mortality (d7) in vivo. Peptides
located in the CDR2 region, but not CDR1 or CDR3 were
potent agonists in vitro and in vivo, recapitulating the
effects seen with the full-length molecule (CD200Fc). These
small molecular weight agonists of CD200 might have
efficacy in vivo in models of sepsis (and TNFα production).
In a further analysis we explored the ability of the same
peptides to block the suppressive and anti-inflammatory
effect of the full-length CD200Fc which was seen in MLCs
and after LPS administration both in vitro and in vivo. In
these studies peptides located in the CDR1 and CDR3
regions of the NH2-terminal of CD200 were found to be
antagonists of the biological effects of CD200. Our data
confirm that discrete small molecular weight agonists and
antagonists can be defined for the interactions of CD200
and the CD200R1 receptor. Since these interactions result in
regulation of both acquired immune responses, and
inflammatory responses, these peptides may have clinical
utility.
doi:10.1016/j.clim.2007.03.250
F.39 Calculating the Number of Ordered Mutations
Necessary to Cause a Specific Cancer in a Specific
Risk Group and the Fraction of the Group that is
Immune to the Cancer
Ivan Kramer, Associate Professor, UMBC, Canada Physics,
Catonsville, MD
The series of ordered mutations that cause a cell to
become cancerous is modeled so that the fraction of a risk
group (e.g., white men) that has developed a specific cancer
(e.g., melanoma) at any age can be computed. The saturated
model constructed here allows the possibility that a fraction
of a risk group may be immune to developing a specific
cancer but is otherwise isomorphic to the physical model
describing an ordered chain of radioactive nuclear decays.
The model’s cancer incidence function depends on only
three independent parameters: the number of mutations
necessary for a cell to become cancerous, the fraction of the
group that is immune to developing the cancer, and the time
required for 50% of the group to experience an average
mutation (defined as the mutation half-life). These three
parameters are determined by fitting the model’s cancer
incidence function to the cancer incidence data. For
example, the modeling predicts that all white males in the
USA are vulnerable to developing melanoma, five ordered
mutations are required to develop it, and the mutation halflife
is 33.5 years. By contrast, the modeling also predicts that
80.7% of white females in the USA are immune to developing
melanoma, three ordered mutations are required to develop
it, and the mutation half-life is 54.7 years. Thus, different
risk groups can develop the same cancer through different
pathways. The mechanism underlying female immunity to
melanoma should become a research priority. Stimulating