Experimental and clinical gnotobiotics: influence of the microflora on graft-versus-host disease after allogeneic bone marrow transplantation

Abstract

One of the major complications of allogeneic bone marrow transplantation (BMT) is graft-versus-host disease (GvHD), which is caused by donor type lymphocytes which react against the recipient's tissues. An important factor which influences GvHD is the recipient's gastrointestinal microflora. This was originally observed in gnotobiotic mice. Infusion of 10(7) H-2 incompatible bone marrow cells into lethally irradiated (9.0 Gy X-rays) conventional mice results in a late onset type GvHD which causes the death of the majority of the recipients during the first two months after BMT. This mortality can be completely prevented if the recipients are germfree mice, or when they are conventional animals which have been subjected to complete or selective gastrointestinal decontamination (GID). In a mouse model, the mechanism responsible for the influence of the microflora on GvHD after allogeneic BMT was investigated. These studies indicate that GvHD can be induced by activated T-lymphocytes from donor origin reacting against bacterial antigens which might be cross-reactive with the recipient's epithelial tissue antigens. Activation of these T-lymphocytes is confined to antigens of certain bacterial species of the recipient which are not present in the indigenous microflora of the donor mice. These bacteria most likely belong to the anaerobic flora of the recipient. The latter hypothesis is strongly supported by the observation in human patients that, in contrast to complete GID, selective decontamination of the gastrointestinal tract did not have any beneficial effect on moderately severe to severe GvHD after transplantation with MHC-matched sibling donor bone marrow grafts.