Hematopoietic stem cell transplant (HSCT) is, in essence, a way to replace a person's immune system. These stem cells give rise to all of the immune cells in the body. There are numerous reasons why HSCT is a traumatic procedure, with a comparatively high risk of death, and thus only widely used for very severe diseases. One of them is the struggle to rebuild the immune system rapidly enough for the patient not to succumb to infection; this is particularly challenging in old patients, where the thymus is much diminished and the pace of T cell creation is slowed in comparison to youth. The thymus is where thymocytes produced by hematopoietic stem cells go to mature into T cells, and the rate of production depends on the amount of active thymic tissue that remains. Another issue is the need for aggressive chemotherapy to clear out the existing population of hematopoietic stem cells prior to transplantation, which in and of itself bears risk, particularly to older, frail individuals.
Nonetheless, swapping out the existing immune system for a new one is has many potential uses, far more than are presently actively addressed by the medical community. It is a way to control autoimmunity, suppressing that condition for years, based on results from trials against type 1 diabetes. Of greater interest to our community, rebuilding the damaged immune system of an older person via HSCT should be capable of reversing many of the issues associated with immune aging. (Though it really should be combined with some way of restoring the thymus to greater levels of T cell production). If there was a way to make HSCT safer, to remove the risk and side-effects, then many more people could undergo the procedure whenever issues of aging or autoimmunity made it beneficial.
An antibody-based treatment can gently and effectively eliminate diseased blood-forming stem cells in the bone marrow to prepare for the transplantation of healthy stem cells. The researchers believe the treatment could circumvent the need to use harsh, potentially life-threatening chemotherapy or radiation to prepare people for transplant, vastly expanding the number of people who could benefit from the procedure.
The study is one of two indicating that an antibody targeting a protein called CD117 on the surface of blood-forming, or hematopoietic, stem cells can efficiently and safely eliminate the cells in mice and non-human primates. CD117 is a protein found on the surface of the stem cells. It regulates their growth and activity; the antibody, called SR1, binds to the protein and prevents its function. The results of these studies set the stage for a clinical trial of the antibody in children with an immune disorder called severe combined immunodeficiency.
Often the best chance for a cure for this and other diseases originating in the bone marrow is to eliminate the patient's own defective hematopoietic stem cells and replace them with healthy stem cells from a closely matched donor. But in order to do so, the patient must be able to withstand the pre-treatment, known as conditioning. Most conditioning regimens consist of a combination of chemotherapy and radiation in doses high enough to kill stem cells in the marrow. The researchers studied a mouse model of a class of human diseases called myelodysplastic syndromes, or MDS. People with MDS are unable to make mature, properly functioning blood cells and the only cure is a stem cell transplant. The disease primarily affects older adults, who are more likely than younger people to have additional, complicating medical factors and who are less likely to withstand the conditioning regimen.
The anti-CD117 antibody SR1 recognizes CD117 on the surface of hematopoietic stem cells isolated from either healthy donors or from patients with MDS. The researchers found that the antibody blocked the growth of both healthy and diseased stem cells in a laboratory setting. Then, the researchers investigated the effect of SR1 treatment on mice that were engineered to have a hybrid blood systems consisting of both human and mouse hematopoietic stem cells. They found in the mice that SR1 quickly and efficiently eliminated both healthy human hematopoietic stem cells and cells isolated from low-risk MDS patients. In those animals with diseased human stem cells, SR1 pre-treatment significantly improved the ability of healthy hematopoietic stem cells to engraft after transplantation.