Genetic Animal Model Core

Personnel

Cox Terhorst, Ph.D. Director
Aimie Julien, B.Sc. Research Assistant
Anuj Kalsy, B.Sc. Research Assistant
Atul Bhan, M.D. Consultant
Barbara Garibaldi, D.V.M. Consultant Veterinarian
Joel Lawitts, Ph.D. Consultant
Steven Niemi D.V.M, Ph.D. Consultant
Robert Sedlacek M.SC. Technical Consultant

Overview

The Genetic Animal Model Core facilitates the use of informative animal models of chronic colitis. The development and study of useful animal models in IBD research has long been appreciated as an important priority. Murine models of intestinal inflammation arising from a number of genetic manipulations offer the most direct means to approach the underlying hypothesis of the CSIBD, i.e., characterization of the effects of genetic factors in altering mucosal barrier function and immune responses that lead to chronic inflammation. These models also allow the opportunity to define the importance of interaction among different genetic loci and the impact of "environmental" factors on phenotypic expression of "IBD." As a result of these developments, this Core places a major emphasis on these valuable research tools, providing economical access to these models by center investigators and promoting further characterization of these models. The utility of these resources are being substantially enhanced by an expanded core scope to include gnotobiotic colony conditions.

Core Access

All requests for use of murine models of IBD are made through the Director, Dr. Terhorst. Investigators must have documented approval from the relevant Animal Use Committees at the BIDMC and MGH prior to initiation of studies using animals made available from the Core. The Director is responsible for establishing priorities in providing mice to investigators; priority is given to investigators supported by CSIBD PFS awards. In general, mice are provided in order of request, noting it is typically possible to simultaneously supply two or more investigators using a model in parallel. The Director can adjust the level of mouse production from different lines in proportion to demand, i.e. lines not actively used are maintained by a minimal breeding program with expanded breeding of lines being actively studied. Similarly, tissues are made available to investigators not requiring intact mice.

Services

The Genetic Animal Model Core provides CSIBD investigators with genetically defined mice for a multitude of studies involving normal and abnormal development of the intestinal mucosa and the role of lymphocytes and professional APCs in the onset of colitis and enteritis. The main objective of this core to facilitate access of CSIBD Investigators to an enlarging variety of murine models, their utilization and the development of new models. The specific services offered to CSIBD investigators include:

  • Murine model production breeding
  • Characterization of murine models (in conjunction with Morpology core)
  • Sample collection from murine models of IBD
  • New murine model development
  • Bone marrow transfers and adoptive T cell transfers
  • Database of studies of experimental colitis in mutant mice
  • Derivation, production and maintenance of gnotobiotic mice

A . Spontaneous Colitis Models

Mouse Strain

Pathology

Effect on Colitis

Described by

IL-2 -/-

Colon/Rectum. Mucosa/sub-mucosa. Crypt abscesses. Epithelial proliferation and crypt elongation. Ulcerations/bleeding. Large increase in CD4 + and CD8 + T cells. High cytotoxic activity in small and large bowel.

Severe

I. Horak

IL-2 -/- x b 2 M -/-

Mild disease. Develop adenocarcinomas

Mild

C. Terhorst*

IL-10 -/-

Disease as described

Severe

K. Rajewsky

TCR a -/-

Crypt abscesses, elongation and branching. Lymphocytic and granulocytic inflammation. Ulcerations and intestinal bleeding

Severe

A. Bhan*

WASP -/-

Crypt abscesses, elongation and branching. Lymphocytic and granulocytic inflammation. Ulcerations and intestinal breeding

Severe

S. Snapper*

ITF -/-

Absence of intestinal trefoil factor

Mild

D. Podolsky*



B. T Cell Transfer Models

Principal Recipients

Development of IBD

Effect on Colitis

Described by

Rag-1 -/- B6 H-2 b

Disease after transfer of wt CD45Rb hi cells

Severe

S. Tonewaga

Rag-2 -/- 129Sv H-2 b

Disease after transfer of wt CD45Rb hi cells

Severe

F. Alt

Rag-2 -/- Balb/c H-2 d

Disease after transfer of wt CD45Rb hi cells

Severe

F. Alt

tg e 26 H-2 b/k

Disease after transfer of wt CD45Rb hi cells

Severe

C. Terhorst*

Secondary Recipients

CD1 -/- x Rag-2 -/-

Less Disease after transfer of wt CD45Rb hi cells

Mild

S Snapper*

MIF x Rag -/-

No Disease after transfer of wt CD45Rb hi cells

None

C. Terhorst*

SLAM -/- x Rag -/-

No Disease after transfer of wt CD45Rb hi cells

None

C. Terhorst*

CD45Rb hi from

CD1 -/-

Ameliorated disease after transfer of CD45Rb hi

Mild

R. Blumberg/

C. Terhorst*

IL-10 -/-

Disease after transfer of CD45Rb hi , but impaired Treg cell functions

Severe

F. Powrie

MIF -/-

Disease after transfer of CD45Rb hi cells

Severe

C. Terhorst*

SLAM -/- B6

Disease after transfer of CD45Rb hi cells

Severe

C. Terhorst*

SLAM -/- Balb/c

Disease after transfer of CD45Rb hi cells

Severe

C. Terhorst*



C. Colitis induced by bone marrow transplantation

Primary Recipients

Pathology

Effect on Colitis

Described by

tg e 26 H-2 b/k

Disease as described

Severe

C. Terhorst*

Secondary Recipients

MIF -/- x tg e 26

No disease.

None

C. Terhorst*

F5 x Rag -/- H-2 b

No disease.

None

C. Terhorst*

tg e 26 H-2 b/k

Disease as described

Severe

C. Terhorst*

Primary Donors

Disease after bone marrow transplant.

CBA

+++

Severe

C. Terhorst*

IFN g -/-

+++

Severe

C. Terhorst*

MIF -/-

+++

Severe

C. Terhorst*

F5 x Rag -/- H-2 b

+++

C. Terhorst*

TCR a -/-

+++

Severe

A. Bhan*



D. Chemically induced colitis in mutant mice

Mouse strain

Pathology

Effect on Colitis

Described by

ITF -/-

DSS +++

Severe

D. Podolsky*

MIF -/-

TNBS

None

C. Terhorst*