B CELL REPERTOIRE OF NORMAL AND AUTOIMMUNE MICE

Project: Research project

Project Details

Description

This proposal addresses abnormal development of B cells and B cell
precursors in murine models of systemic lupus erythematosus (SLE). We
hypothesize that NZB and (NZB x NZW)F1 autoimmune mice undergo a
progressive decline in both the number of B cell precursors detected
within the bone marrow and in the mitotic activity of these precursor
cells. This may result from either 1) failure of B cell precursors
respond to developmental signals: 2) failure of the bone marrow stroma to
adequately support B lineage proliferation and development; or 3) abnormal
down-regulation of B lineage precursors via T cells and/or regulatory
Ly1/Mac1 lineage B cells. In order to test this hypothesis, we will: A)
Use vincristine induced metaphase arrest (stathmokinetic) assays to assess
the mitotic activity of B cell precursor cells in both normal and NZ
autoimmune bone marrow as a function of age. B) Define whether the
mechanisms responsible for defective B lymphopoiesis in NZ mice operate at
the precursor cell level or upon the non-lymphoid stroma necessary for the
support of B lineage cell proliferation and differentiation. These
experiments will use in vitro short term and long term bone marrow cell
culture systems to allow differentiation of NZ B lineage cells with normal
bone marrow stroma and vice versa. C) Determine the capacity of NZ bone
marrow stromal cells to secrete cytokines, including IL-7, necessary for
maintenance of pre-B cell growth. These experiments will use bioassays
and also will quantitate ILl-7 mRNA levels in normal vs. NZ stroma. D)
Evaluate the capacity of NZ T cells to secrete excessive quantities of
lymphokines which inhibit proliferation of B lineage precursor cells.
Specific bioassays for both IL-2 and IL-4 will be performed since these
lymphokines may influence B lineage cell development and growth. E)
Assess the capacity of NZ Ly1/Mac1 bearing B cells within the bone marrow
to down-regulate the proliferation and generative capacity of bone marrow
B lineage cells. These experiments will use in vivo model systems in
which NZ Ly1/Mac1 B cells will be expanded in normal recipients (e.g.,
[NZB x BALB/c]F1 or immunodeficient SCID mice). The capacity of normal B
lineage precursor cells to proliferate and develop in the presence of NZ
LY1/Mac1 B cells will then be determined. With this experimental plan, we
will test the above hypothesis and establish the mechanisms by which B
lineage cell development in NZ mice is decreased and the possible role of
this defect in establishment of lymphocyte autoreactivity.
StatusFinished
Effective start/end date12/31/8912/31/93

Funding

  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Allergy and Infectious Diseases

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