Scientific Abstract

Proposal No.  IBD-0153R2
Principal Investigator:  David L. Suskind, M.D.
Applicant Organization:  Children's Hospital and Regional Medical Center (Seattle, Washington, U.S.A.)
Project Title:  Maternal microchimerism in inflammatory bowel disease
Period of Award:  October 1, 2005 – September 30, 2007

Inflammatory bowel disease (IBD) shares many immunologic and clinical characteristics with graft versus host disease (GVHD), a disease caused by the transfer of allogeneic cells during bone marrow transplantation.  Both present with a protean array of gastrointestinal symptoms: abdominal pain, weight loss, nausea, vomiting and diarrhea.  In each, CD4+ T lymphocytes appear central in the development of enteropathy.  CD4+ T cells recognize major histocompatibility complex (MHC) class II.  MHC class II expression is increased in both.  In addition, an adoptive transfer model in which allogeneic cells are transferred to a host animal has been shown to cause an IBD-like illness.

Since maternal cells are known to enter the fetal circulation in a high proportion of pregnancies, it is possible that engraftment of maternal cells can lead to disease.  We hypothesize that maternal engraftment in the fetus results in immune sequela that can lead to IBD.

We will address this hypothesis in two parts:

1)      A prospective case control study involving assessment of HLA markers in persons with IBD and their mothers.  Patients will be divided into Crohn’s, ulcerative colitis and control groups.  HLA type of patients and their mothers will be determined, then using kinetic Polymerase Chain Reaction (kPCR), the presence and extent of maternal microchimerism in the tissues and blood samples from patients will be determined.

2)      The cellular immune response of patients (Crohn’s, ulcerative colitis and control group) towards maternal leukocytes will be analyzed to test if microchimerism is associated with an altered immune response to maternal alloantigen in patients with IBD.  T-cell and NK-cell responses to maternal and third-party antigens will be measured to determine if IBD correlates with either a reduced or increased response to maternal cells.  Cellular responses will be analyzed in vitro by measuring cellular proliferation, cytokine production and cytotoxicity.