Diabetes Research
Laboratory
Laboratory
Head
Associate
Professor Robyn Slattery
Research Fellow
Dr. James de Jersey
Research Assistants
Liliana Serwecinska
Simon Teteris
PhD Students
Dr. Fiona Chan
Sarah Snelgrove
Honours
Student
Karen
Yuen
RESEARCH:
Type
1 diabetes (T1D) in both humans and NOD mice results from T cell mediated
autoimmune destruction of insulin producing pancreatic ß cells. Linkage
studies have shown that T1D in NOD mice is a polygenic disease involving more
than 19 chromosomal susceptibility regions. Our research group is interested
in studying three of these susceptibility regions Idd1 (the MHC) Idd2 (the
insulin promoter) and Idd13 (recently identified by our group as ß2M).
Idd1
Our group utilizes the cre/lox recombination system in NOD mice to understand
the role of the MHC genes in diabetes. This system allows us to remove
MHC genes from specific tissues while leaving these genes expressed normally
in other tissues. We have thus far created a panel of cre NOD mice that
allow us to delete MHC expression from either the target beta cells, or
different subpopulations of the immune system.
Idd2
Recently our group identified some unique mutations in the human insulin
promoter that control the expression of insulin to different cell types.
This is being investigated for its role in predisposing to type 1 diabetes.
Idd13
Despite extensive investigation, the identification of individual
susceptibility genes either within or outside the major histocompatibility
(MHC) region has proven problematic due to the limitations of linkage
analysis. We recently provided the first unequivocal identification of a
single diabetes susceptibility gene, which lies outside the MHC region. Using
allelic reconstitution by transgenic rescue we showed that NOD mice
expressing the ß2Ma allele developed diabetes whereas NOD mice
expressing the ß2Mb allele were protected. The murine ß2Ma allele
differs from the ß2Mb allele only at a single amino acid. The
mechanism of susceptibility and resistance conferred by ß2M has not been
elucidated. In particular, it is not known how such a small change in ß2M
could confer such a dramatic alteration in the immune response to islet
tissue. It is not known which cell types impart ß2M mediated resistance
and susceptibility to T1D. Utilizing the ß2Ma (susceptible) and
ß2Mb (resistant) transgenic mice it will be possible to dissect out the
role of different cell populations in the thymus, and in the periphery, which
confer ß2M isoform mediated protection and susceptibility. Likewise,
utilizing the tissue specific knock-out NOD mice which have specific
deletions of ß2M in both the insulin producing beta cells (HIPcre) and in the
antigen presenting cells of the thymus and the periphery (PIEcre) it will be
possible to assess the role of tissue specific expression of ß2M in
conferring susceptibility.
Relevance to type 1 diabetics
Our understanding of the role of ß2M and MHC in directing the autoimmune
response is crucial to an understanding of how to regulate the disease in
predisposed individuals. Early identification of patients, through
genetic markers such as those we have identified in Idd2, will give us a
therapeutic window before the onset of diabetes in which to immunomodulate
at-risk individuals.
FUNDING:
Juvenile Diabetes Research
Foundation (JDRF)
Monash University N ear Miss Grant
PAPERS:
de
Jersey J, Snelgrove SL, Palmer SE, Teteris SA, Mullbacher A, Miller JF,
Slattery RM. Beta cells cannot directly prime diabetogenic CD8 T cells in
nonobese diabetic mice. Proc Natl Acad Sci U S A. 2007;104(4):1295-300.
Serreze
DV, Holl TM, Marron MP, Graser RT, Johnson EA, Choisy-Rossi C, Slattery RM,
Lieberman SM, DiLorenzo TP. MHC class II molecules play a role in the
selection of autoreactive class I-restricted CD8 T cells that are essential contributors
to type 1 diabetes development in nonobese diabetic mice. J Immunol. 2004;172(2):871-9.
Hamilton-Williams EE,
Palmer SE, Charlton B and Slattery RM. Beta cell MHC class I is a late
requirement for diabetes. Proc Natl Acad Sci USA.
2003; 100: 6688-6693.
Silva D, Petrovsky N, Socha L, Slattery
R, Gatenby P and Charlton B. Mechanisms of accelerated immune-mediated
diabetes resulting from islet beta-cell expression of a FAS ligand transgene.
J Immunol. 2003; 170: 4996-5002.
Hamilton-Williams EE, Serreze DV,
Charlton B, Johnson EA, Marron MP, Mullbacher A and Slattery RM.
Beta2-microglobulin identified as a diabetes susceptibility gene in NOD mice.
Proc Natl Acad Sci USA.
2001; 98: 11533-11538.
Charlton B, DaZhang M and Slattery RM. B
lymphocytes not required for progression from insulitis to diabetes in
NOD mice. Immunol Cell Biol. 2001; 6: 597-601.
Charlton B, Fathman CG and Slattery RM.
Th1 unresponsiveness can be infectious for unrelated antigens. Immunol
Cell Biol. 1998; 76: 173-178.
Hogan SP, Foster PS, Charlton B and
Slattery RM. Prevention of Th2-mediated murine allergic airways disease by
soluble antigen administration in the neonate. Proc Natl Acad Sci USA.
1998; 95: 2441-2445.
Pritchard CA, Bolin L, Slattery R, Murray R and
McMahon M. Post-natal lethality and neurological and gastrointestinal defects
in mice with targeted disruption of the A-Raf protein kinase gene. Curr
Biol. 1996; 6: 614-617.
Slattery RM and Miller JFAP. Influence
of T lymphocytes and major histocompatibility complex class II genes on
diabetes susceptibility in the NOD mouse. Curr Top Microbiol. 1996;
206: 51-66.
Slattery RM, Miller JFAP, Heath WR and
Charlton B. Failure of a protective major histocompatibility complex class II
molecule to delete auto reactive T cells in autoimmune diabetes. Proc
Natl Acad Sci USA.
1993; 90: 10808-10810.
Georgiou HM, Slattery RM and Charlton B.
Marrow bone transplantation prevents autoimmune diabetes in non obese
diabetic mice. Transplant Proc. 1993; 25: 2896-2897.
Charlton B, Guymer RH, Slattery RM and
Mandel TE. Intercellular adhesion molecule (ICAM-1) inhibition can induce
tolerance in vivo. Immunol Cell Biol. 1991; 69: 89-93.
Slattery RM, Kjer-Nielson L, Allison J,
Charlton B, Mandel TE and Miller JFAP. Prevention of diabetes in non-obese
diabetic I-Ak transgenic mice. Nature. 1990; 345: 724-726.
Charlton B, Bacelli A, Slattery RM and
Mandel TE. Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for
suppression in spontaneous autoimmune diabetes mellitus. Diabetes.
1990; 38: 441-447.
For more information on any of the work
being carried out in this laboratory please contact Associate Professor Robyn
Slattery
Email: robyn.slattery@med.monash.edu.au
Phone: (03) 9903 0075
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