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Animal Core C

Animal Core C

Core Director: Stefan Niewiesk, DVM, PhD, The Ohio State University

The
Core will support the use and development of animal models by all projects of
the PPG. The development of humanized mice has been a milestone for the PPG as
it allows for the first time all projects to utilize the same primary animal
model. Thus the humanized mouse becomes an important aspect for the integration
of research between projects and the comparison of data. In addition, the core
will facilitate animal model use by closely interacting with the various PPG
investigators to help with animal use protocols, regulatory questions, and
advice on use of equipment and services. The Core will also manage all aspects
of sample collection and histo-pathological evaluation, including coordinating
histological and immunohistological assessments as needed.

To date, the
Animal Core has developed and utilized four animal models to evaluate specific
stages of infection and tumor development:

Rabbit model of persistent
infection by HTLV-1:
Rabbits can be infected with HTLV-1 by
both the mucosal and intravenous route, making it a unique model for studying
the various modes of transmission of HTLV-1. After the acute phase of
infection, rabbits become persistently infected without the development of
clinical disease. The rabbit model has been used to analyze early virus
replication and the immune responses to this infection. Through the use of
infectious molecular HTLV-1 clones, we have been able to modify the virus for
in vivo studies of the functional properties of HTLV-1 proteins, including p12,
p13, p30, Rex, Env, and Hbz.

Transgenic mouse models of
tumorigenesis:
Although mice cannot be infected with HTLV-1,
transgenic mice over-expressing Tax or Hbz have provided an understanding of
the role of Tax and Hbz-mediated tumorigenesis. These animals have been used to
study the interaction of the tumor cells with the immune system and
microenvironment. In transgenic animals, lymphocytic tumors and bone lesions
develop which are comparable to those seen in patients with ATL.

Transfer of ATL cells into
immune deficient mice:
Immune deficient NOD/SCID
mice receive transfers of ATL cells which lead (depending on the cell lines
used) to localized or multicentric lymphoma/leukemia. This model has proven to
be useful in determining factors important in tumor adhesion and invasion, as
well as for analyzing the interactions of ATL cells with their
microenvironment.

Humanized immune system
(HIS) mouse model of tumorigenesis:

we
have developed mice with a phenotypically normal human immune systesm (HIS
mice) which faithfully reproduce all three key stages of HTLV-1-induced
tumorigenesis in a very compact time frame: 1) persistent infection, 2) chronic
proliferation of CD4 T cells and 3) development of adult T cell
leukemia/lymphoma. We have created humanized mice by reconstituting immune
deficient NSG mice with CD34+ human umbilical cord stem cells (HUSC). This
leads to development of phenotypically normal human lymphocytes. Infection of
these lymphocytes with HTLV-1 results in integration of the virus into the
genome of lymphocytes and activation and proliferation of CD4 T cells.
Subsequently, a CD4+ T cell leukemia and lymphoma develops which leads to bone
destruction through leukemic cells and death of mice. These processes can be seen
with both a wild-type HTLV-1 (from MT-2 cells) as well as after infection with
a molecularly cloned HTLV-1 (ACH). The ability to induce disease in this model
with molecularly cloned HTLV-1 allows for detailed investigation of CD4+ T cell
transformation and tumorigenesis.

Pathology
support will be provided by veterinary anatomic and clinical pathologists that
are diplomates of the American College of Veterinary Pathologists. Expertise in
animal models of lymphoma, leukemogenesis, and bone pathology will enable
appropriate interpretation and evaluation of the mouse and rabbit models in the
research projects and comparison to human lymphoma and leukemia. The quality of
the research will be improved because personnel (such as a board-certified
veterinary pathologist, veterinary pathology resident, and experienced
histotechnologist) that are well trained in animal experimentation and tissue
processing will work with the project leaders to conduct the investigations.

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