ANTIGEN PRESENTATION IN ACQUIRED TOLERANCE

  • Parker, David, (PI)

Project: Research project

Project Details

Description

This proposal examines mechanisms of acquired tolerance to protein antigens
with a focus on the antigen presenting cell. The experiments will test the
hypothesis that small B cells present antigen to primary helper T cells and
turn them off instead of on, because small B cells lack certain accessory
signals required by a potentially responsive T cell. This hypothesis
offers a satisfactory explanation for the phenomenon of low zone tolerance,
in which antigen is introduced in a form which is presented only by
antigen-specific small B lymphocytes, bypassing other kinds of APC that are
required for a positive response by primary T cells. It may also explain
high zone tolerance, since at high antigen concentrations, small B cells
can process and present antigens nonspecifically, and they outnumber other
class II positive cells. Small B cells may play a role in self tolerance
to soluble proteins including immunoglobulins and in transplantation
tolerance induced and maintained by allogeneic lymphocytes. Acquired
tolerance has obvious potential applications in transplantation, the
treatment and prevention of autoimmune disease and chronic infections, and
the effective use of the novel therapeutic proteins that can be produced by
recombinant DNA techniques. To test the hypothesis: 1. small B cells will be pulsed with antigen in
vivo using soluble antigen targeted specifically to membrane IgD, and 2.
small B cells from a transgenic mouse expressing a foreign protein antigen
will be transfused into syngeneic, non-transgenic mice. In each case, mice
will be challenged with antigen in adjuvant and various CD4+ T cell
responses will be measured. 3. Class II MHC restriction of helper T cell
recognition will be exploited to study the effects of SCID mice (which lack
functional B and T lymphocytes) reconstituted with F1 T cells and B cells
of a different MHC haplotype from the SCID host. 4. The mechanism of
inactivation of CD4+ T cells by B cells actin as APC will be studied in
vivo and in vitro using T cells from transgenic mice in which virtually all
of the T cells are specific for a particular protein antigen.
StatusFinished
Effective start/end date1/1/9112/31/06

Funding

  • National Institutes of Health: $264,250.00
  • National Institutes of Health: $189,036.00
  • National Institutes of Health: $264,250.00
  • National Institutes of Health
  • National Institutes of Health: $149,481.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $183,529.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $148,293.00
  • National Institutes of Health: $188,060.00
  • National Institutes of Health: $194,709.00
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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