Course of Crohn's Disease After Allogeneic Marrow Transplantation. Lopez-Cubero SO, Sullivan KM, McDonald GB.Gastroenterology 1998;114:433-40.
Summary: The purpose of the study was to determine whether the course of Crohn's disease (CD) was altered by hematopoietic cell transplants from healthy allogenic donors. Between 1982 and 1992, six patients with CD and leukemia underwent allogeneic marrow transplantation. Five patients had active CD before transplantation, and three had clinical evidence of sclerosing cholangitis. Four marrow donors were HLA-identical siblings, one related donor was mismatched at the DR locus, and one unrelated donor was HLA-matched.
One patient died of septicemia 97 days after transplantation and five patients were observed for 4.5, 5.8, 8.4, 9.9, and 15.3 years after transplantation. One of the five patients, with mixed donor-host hematopoietic chimerism, had a relapse of CD 1.5 years after transplantation. The investigators suggest that host immune dysregulation plays a role in the perpetuation of CD that can be corrected by allogeneic hematopoietic cell transplantation.
Comment: The cause of CD is unknown. Currently, three pathogenetic theories are under consideration: genetic basis, transmissible environmental-infectious agents, and immunologic dysregulation. These causes are not mutually exclusive. Epidemiologic studies as well as the familial pattern of inheritance and twin studies suggest a genetic basis. Genes of the major histocompatibility complex contribute to susceptibility to CD (Lancet 1996;347:1212-7
). Other susceptibility loci for CD have been detected on several chromosomes (Nat Genet 1996;14:199-203
). No specific bacterial or viral infectious agents were shown to cause CD. However, Pirzer et al. (Lancet 1991;338:1238-9
) reported that the physiologic unresponsiveness of T lymphocytes to luminal antigens is abrogated in CD. Environmental bacterial antigens, to which the normal host has tolerance, may therefore cause response by T cells and trigger a chronic intestinal inflammatory reaction in patients susceptible to CD (Clin Exp Immunol 1995;102:448-55
). A cross-reactivity with self antigens may follow or a reaction to bacterial superantigens may occur. Nevertheless, the initiating, probably silent, event of CD remains unknown.
Of the six patients with CD that Lopez-Cubero et al. observed after allogeneic marrow transplantation, three died: Patient 3 committed suicide 5.8 years after transplantation; patient 5 died of myocardial infarction 4.5 years after transplantation; and patient 6 died of septic shock 97 days after transplantation. Only one patient, the one who died of myocardial infarction, had a colonoscopy after the transplantation, on day 1400. It showed a normal mucosa. Thus, although the patients who survived had no signs or symptoms of CD, there is no information about the histology of their colonic mucosa. It is therefore not certain that these patients had complete histologic remission of CD.
Immunosuppression is the cornerstone of treatment of inflammatory bowel disease (Ann Allergy 1994;72:135-41
). The patients reported received immunosuppression during the conditioning as well as 6 months' prophylaxis after the transplantation. Those in whom graft versus host disease developed received immunosuppression treatment for longer periods. It can be argued that the amelioration in the course of CD was a result of the immunosuppression treatment. This argument is supported by the reports of a patient with myasthenia gravis who had an improvement of CD after thymectomy (Gut 1994;35:278-9
) and a patient with CD who had a complete remission in association with immunodeficiency caused by human immunodeficiency virus infection (Gastroenterology 1988;95:1667-9
Although the authors of the present report postulate that the disease disappeared and the genetically determined abnormality responsible for CD was corrected after the marrow transplantation, all treatment for CD must be viewed as palliative until its true cause is known (Immunology 1996;89:475-82
). Considering the low mortality of CD it may only rarely, if ever, be justified, to consider a marrow transplant for the treatment of CD.
Christian P. Braegger
University Children's Hospital; Zurich, Switzerland