Gastro-intestinal toxicity related to haemopoietic stem cell transplantation with a special focus on the intestinal barrier function

Abstract

The myeloablative, cytotoxic therapy (conditioning treatment) prior to haemopoietic stem cell transplantation (HSCT) has the combined purpose of eliminating leukaemic or cancer cells located in the bone marrow or elsewhere in the body and, in the allogeneic setting, of suppressing the immune response of the recipient to prevent marrow rejection. The unwanted effect is the inevitable elimination of normal, haemopoietic stem cells, a lethal effect which is circumvented by the following administration of haemopoietic stem cells from the patient (autologous HSCT) or from a related or an unrelated donor (allogeneic HSCT). However, normal tissues with a high cell-turnover rate, primarily the gastro-intestinal (GI) tract, will likewise be affected. Besides causing significant GI symptoms, this injury includes a disruption of the intestinal barrier, facilitating the permeation of bacteria and endotoxin through the bowel wall, with subsequent septicaemia and release of cytokines, known to be important mediators of graft-versus-host disease (GVHD), the primary complication of allogeneic HSCT. Accordingly, murine HSCT-models have suggested that after intensification of the conditioning treatment, GVHD has been amplified as a result of aggravated GI toxicity.Using a 51Cr-EDTA resorption test, the present study investigates the intestinal-barrier function in HSCT patients receiving myeloablative or reduced intensity conditioning (RIC). It also investigates whether the strengthening of the GI immune system by the oral administration of an immunoglobulin preparation would modify intestinal barrier integrity during autologous HSCT. Finally, on the basis of the observation that the impairment of intestinal barrier integrity by non-steroidal anti-inflammatory drugs (NSAID) is due to an early disturbance of energy metabolism in enterocytes, the existence of a similar mechanism in chemotherapy was searched for. Using high-performance liquid chromatography (HPLC) technique and 51Cr-EDTA resorption, the purine-nucleotide content in enterocytes and intestinal permeability was determined in rats after chemotherapy.It was found that the intestinal barrier was disrupted preceding clinical symptoms with myeloablative conditioning, but preserved with RIC. The oral administration of an immunoglobulin preparation revealed ameliorated intestinal barrier integrity during autologous HSCT. In rats, an early-detectable disruption of the intestinal barrier was found which parallels a decrease in purine-nucleotide content in enterocytes, reflecting a metabolic disturbance.A hypothesis may be formed containing an early intestinal-barrier disruption with chemotherapy, initiated by a metabolic disturbance in enterocytes. Since murine data revealed aggravated GVHD with increased intestinal injury, the preserved intestinal integrity with RIC should have the potential of reducing GVHD severity. These observations suggest that the intestinal barrier function has a central role to play in the intestinal damage induced by cytotoxic therapy as well as in GVHD.