Project: Research project

Project Details


DESCRIPTION (adapted from applicant's abstract): Investigators have
previously shown that the insulin gene (INS) is naturally transcribed in the
human thymus and that thymic INS transcription correlates with proinsulin
synthesis. Proinsulin shares most immunodominant epitopes with insulin, a
major target autoantigen in Type I diabetes. They also found that INS
transcription levels in the thymus correlate with allelic variation at the
IDDM2 susceptibility locus for Type 1 diabetes, a polymorphic VNTR
minisatellite that influences INS steady state transcription. These
findings provide a plausible mechanistic explanation for diabetes
susceptibility/resistance associated with the IDDM2 locus. In fact,
genetically determined differences in proinsulin expression in the thymus
may influence the selection of insulin-specific T-lymphocytes and in turn
the development of autoimmune responses against insulin. This hypothesis is
supported by the association of higher INS mRNA levels with VNTRs conferring
dominant protection from diabetes. Moreover, non-obese diabetic (NOD)
transgenic mice expressing proinsulin in the thymus do not develop diabetes,
suggesting that increased proinsulin levels in the thymus may be sufficient
to prevent the disease. Thus, previous work and data from literature
suggest the hypothesis that thymic expression of peripheral antigens such as
proinsulin may be crucial for the development of self-tolerance. In the
mouse thymus, an uncharacterized subset of cells is responsible for the
expression of peripheral antigens and reportedly mediates tolerogenic
signals essential for the development of tolerance. The investigator
hypothesizes that the human thymus may also contain specialized cells
expressing peripheral antigens, and proposes to investigate whether cells
expressing proinsulin can be demonstrated in the human thymus. Preliminary
data indicating that proinsulin-expressing cells can be detected in thymus
and peripheral lymphoid organs supports the hypothesis. The plan is to
characterize the phenotype of proinsulin-expressing cells, both in the
thymus and peripheral lymphoid organs, and to investigate whether proinsulin
expression in peripheral lymphoid organs is also under the influence of the
INS-VNTR/IDDM2 locus. The characterization of proinsulin expression by
specialized immune cells possibly mediating tolerogenic effects may be
useful to better understand the pathogenesis of Type 1 diabetes and perhaps
develop novel preventive strategies based on autologous, antigen-specific,
tolerogenic cells.
Effective start/end date9/29/988/31/02


  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases: $192,939.00
  • National Institute of Allergy and Infectious Diseases


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