Scientific Abstract

Proposal No.  IBD-0004
Principal Investigator:  Robert M. Craig, M.D.
Applicant Organization:  Northwestern University (Chicago, Illinois, U.S.A.)
Project Title:  Immune ablation and hematopoietic peripheral stem cell support in patients with severe Crohn's disease
Period of Award:  March 1, 2002 - February 29, 2004

Crohn's disease (CD) is a chronic illness, immunologically mediated, probably induced by the exposure of the intestine to an antigen or antigens similar to the intestine, to which immunologic tolerance is lost.  The disease has a variable course, requiring symptomatic therapy including immunosuppressive therapy, surgery or both.  The molecular defect causing CD has not been characterized, but probably involves aberrant T cell function.  Although CD often responds to immunosuppressive medication including azathioprine and cyclosporin A (CSA), to anti-inflammatory drugs such as 5-aminosalicylate (5-ASA), or to some antimicrobial agents, including metronidazole, no therapy has been curative.

In patients with severe CD, who have been poorly responsive to corticosteroids, azathioprine, 6-mercaptopurine, 5-ASA, metronidazole, and infliximab, and who are being considered for surgery, we propose a phase I-II study consisting of complete immune ablation and subsequent reconstitution with autologous stem cells depleted of T lymphocytes harvested from the patient prior to immune ablation.  The combination of high dose cyclophosphamide and anti-thymocyte globulin will be followed by rescue with autologous T lymphocyte depleted peripheral stem cells.  This study will use immune suppression to the point of complete immune ablation and subsequent recapitulation of lymphocyte ontogeny by stem cell rescue.  Subsequent disease activity will be followed by:  (1) Crohn's disease activity index (CDAI); (2) Type and amount of therapy for CD; (3) Clinical parameters including blood counts, sedimentation rate, C-reactive protein, anti-saccharomyces boulardii antibody (ASCA); and (4) flow cytometry of peripheral blood lymphocyte subsets.  In addition, the subjects will undergo periodic absorption function testing, colonoscopic examinations, and small intestinal radiographs.

The unique feature of this therapeutic approach is the complete elimination of clones of T-lymphocytes that have caused the disease and the potential for cure.  We anticipate that this study will also form the basis to clarify the role of the immune system and stem cell therapy in CD.