Safely Destroying Blood Stem Cells to Enable Immune System Restoration

Destroying and recreating the immune system is a potentially very effective way to treat autoimmune conditions, as the basis of that condition lies in the broken configuration and memory of existing immune cells. The aging immune system has similar problems in its population and cell behaviors, problems that might be removed by replacing all immune cells wholesale. Present strategies to destroy the immune system require harsh chemotherapy, however, which makes it hard to justify on a cost-benefit basis for anything except the most harmful of conditions. Undergoing chemotherapy of this nature has a high mortality rate, and long-term harm to the survivors is on a par or worse than life-long smoking. Chemotherapy will be replaced in the years ahead, however. The research noted here is one step towards selective removal of all immune cells without harmful side-effects, a capability that will open the door to a range of ways to safely rejuvenate an age-damaged immune system and bring an end to autoimmunity:

Blood stem cell transplantation, widely known as bone marrow transplantation, is a powerful technique that potentially can provide a lifelong cure for a variety of diseases. But the procedure is so toxic that it is currently used to treat only the most critical cases. Now, researchers have come up with a way of conducting the therapy that, in mice, dramatically lowers its toxicity. If the method eventually proves safe and effective for humans, it potentially could be used to cure autoimmune diseases like lupus, juvenile diabetes and multiple sclerosis; fix congenital metabolic disorders like "bubble boy" disease; and treat many more kinds of cancer, as well as make organ transplants safer and more successful.

To successfully transplant blood stem cells, a patient's own population of blood stem cells must be killed. Currently, this is done using chemotherapy or radiotherapy, treatments that are toxic enough to damage a variety of organs and even result in death. To avoid these terrible side effects, the researchers composed a symphony of biological instruments that clear the way for blood stem cell transplantation without the use of chemotherapy or radiotherapy. The scientists started with an antibody against a cell surface protein called c-kit, which is a primary marker of blood stem cells. Attaching the antibody to c-kit resulted in depletion of blood stem cells in immune-deficient mice. However, this antibody alone would not be effective in immune-competent recipients, who represent a majority of potential bone marrow transplant recipients. The researchers sought to enhance the effectiveness by combining it with antibodies or with biologic agents that block another cell surface protein called CD47. Blocking CD47 liberated macrophages to "eat" target cells covered with c-kit antibody.

With the CD47 marker blocked and the antibody attached to c-kit proteins, the immune system effectively depleted the animals' blood-forming stem cells, clearing the way for transplanted blood stem cells from a donor to take up residence in the bone marrow and generate a whole new blood and immune system. The success of these techniques in mice raises hopes that similar techniques will succeed in human patients. "If it works in humans like it did in mice, we would expect that the risk of death from blood stem cell transplant would drop from 20 percent to effectively zero. If and when this is accomplished, it will be a whole new era in disease treatment and regenerative medicine."