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Preventing intestinal damage during stem cell transplantation

Researchers may perhaps have found a way to prevent intestinal damage during stem cell transplantation. Donor stem cells can cause life-threatening damage to the intestinal membrane in children. 'By administering ruxolitinib early during treatment, we might be able to protect the intestinal mucosa,' says Caroline Lindemans, stem cell transplant specialist at the Princess Máxima Center for Pediatric Oncology in Utrecht, the Netherlands.

Stem cell transplantation may be necessary in the treatment of leukemia and other hematologic disorders. Stem cells are unspecialized cells from which all types of cells arise. The stem cells that make blood cells are found in the bone marrow. Every now and then something goes wrong in the stem cells and that can lead to disorders such as leukemia, in which case the diseased stem cells need to be replaced with healthy donor cells.

Immune system
Because donor cells do not originate from the patient's own body, the immune system can respond to and attack the donor stem cells. As a preventative measure, the patient's immune system is suppressed before and after the stem cells are transplanted. The donor's bone marrow also contains immune cells, called T cells. These T cells can regard the last leukemia cells as being 'foreign cells' and consequently attack those cells. However, they can attack the child's other body cells as well. This is called graft-versus-host disease, which often causes intestinal damage and is a life-threatening complication.

Intestinal damage
Caroline Lindemans, stem cell transplant specialist at the Princess Máxima Center, investigated how T cells damage intestinal mucosa. 'The T cells in the donor bone marrow secrete a substance that damages and even destroys intestinal stem cells, causing long-term damage to the intestine. In the event, we prescribe more suppressants such as Prednisone. But the treatments we currently provide to inhibit T cells are not as effective as we would wish. Too many children still die from graft-versus-host disease.'

'The death of a child from graft-versus-host disease is dreadful,' says Caroline Lindemans. 'The intestinal damage causes severe diarrhea, undermining the child's condition to an ever worsening degree,' says Lindemans. 'And for parents it is incomprehensible that, after finally getting their child's cancer under control, they can be hit by yet "another disaster". Those are the most dire cases.'

Previous research has already shown that ruxolitinib can inhibit T cells. It is therefore used to treat severe graft-versus-host disease when nothing else seems to work. 'But we believed ruxolitinib could also inhibit the effect of the harmful substance on the intestinal tissue,' Lindemans explains. Lindemans and her colleagues envisioned a new use for the drug: 'Instead of focusing on inhibiting the attacking immune system, treatment can be aimed at protecting the tissue that is under attack.' In the laboratory it was found that the intestinal mucosa was protected if ruxolitinib was administered sooner, namely 'Before the intestinal cells are damaged,' Lindemans explains.

Lindemans and her colleagues published their findings in the specialist journal Science Immunology. The research was conducted within Child Health and regenerative Medicine at UMC Utrecht and at the Memorial Sloan Kettering Cancer Center. 'We must now investigate whether this approach also works on children with graft-versus-host disease,' says Lindemans. 'We hope to start a clinical trial to find out.'

Links: https://immunology.sciencemag.org/content/4/42/eaay8556?utm_campaign=toc_imm_2019-12-06&et_rid=495965004&et_cid=3113159