Abstract
| Grant Number: |
2R01DK053056-05 |
| PI Name: |
BLUMBERG, RICHARD S. |
| PI Email: |
mailto:rblumberg@partners.org |
| PI Title: |
ASSOCIATE PROFESSOR OF MEDICINE |
| Project Title: |
INTESTINAL TRANSCYTOSIS OF IgG IN ADULT LIFE |
Abstract: DESCRIPTION (provided by applicant): The neonatal Fc
receptor for IgG (FcRn) is a major histocompatibility complex (MHC) class
1-related molecule that is responsible for maintaining steady-state levels of
IgG in adult rodents and, possibly, all mammals through its ability to
specifically protect IgG from catabolism. FcRn has also been proven to mediate
the vectorial transport of IgG across the intestinal epithelial cell barrier
in suckling mice and rats and, likely, the placenta in humans. These effects
on the physiology of IgG result from the action of FcRn as an intracellular
trafficking receptor. Expression of FcRn is developmentally regulated in
rodent intestine and for many years FcRn was considered to be absent from
adult tissues. It is now known that FcRn is expressed in the epithelium and
macrophages of the adult human; an observation that challenges the paradigm of
strict developmental expression of FcRn and raises the question as to the role
of FcRn and IgG at mucosal surfaces. One of mucosal immunology's greatest
deficiencies is that significant levels of IgG occur in human secretions with
almost no understanding of either how this molecule arrives or is functional
in mucosal effector sites. This grant addresses the overall hypothesis that
FcRn mediates (by bi-directional transepithelial transport) a steady-state
distribution of IgG across mucosal surfaces of the intestine and lung for the
purpose of functioning in immune surveillance and host defense. Aim 1
investigates the intracellular itinerary taken by FcRn in the transepithelial
transport of IgG and the basic structure-function relationships of FcRn in
this process. It is proposed to: (1) define the steady-state distribution of
FcRn; (2) define whether FcRn transits through the golgi en route from the
apical or basolateral surfaces; (3) define the structural characteristics of
the FcRn cytoplasmic tail that defines FcRn function, and; (4) characterize
the major structural features of FcRn biogenesis and function through
assessment of the major domains of FcRn. Aim 2 examines the presence of
FcRn-dependent transepithelial transport of IgG in vivo in adult life. It is
proposed to test for IgG transport across the mucosal barrier of the
respiratory tract and/or intestine of wild-type mice and rabbits and mice
expressing a human FcRn transgene using either a wild-type Fc or a Fc mutated
in the FcRn binding site linked to a polypeptide hormone as a probe. Aim 3
seeks to define the role of FcRn in immunosurveillance and host defense by
examining whether FcRn can sample antigens from the lumen in an in vitro model
system and whether FcRn can deliver model immune complexes to subjacent
epithelial tissues and elicit an immune response. Aim 4 seeks to determine
whether macrophages contribute to the protection of IgG from catabolism by
examining IgG half-life in op/op mice.
Thesaurus Terms:
antibody receptor, gastrointestinal absorption
/transport, immunoglobulin G, mucosal immunity, protein transport,
transcytosis
age difference, immune complex, intracellular transport,
macrophage, protein structure function
chimeric protein, laboratory mouse,
laboratory rabbit, tissue /cell culture
| Institution: |
BRIGHAM AND WOMEN'S HOSPITAL |
|
75 FRANCIS ST |
|
BOSTON, MA 02115 |
| Fiscal Year: |
2002 |
| Department: |
|
| Project Start: |
01-SEP-1997 |
| Project End: |
31-DEC-2006 |
| ICD: |
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY
DISEASES |
| IRG: |
GMA |
  
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