A point of confusion regarding “stem cell therapy” for multiple sclerosis comes from two very different types of approaches that both use stem cells. The first approach is the use of stem cells WITHOUT depleting the recipient immune system, the second approach involves administration of stem cells AFTER depleting of the immune system.
The first approach usually involves mesenchymal stem cells, such as found in the patient’s own fat, but has also been performed with cord blood. The rationale for using stem cells in the absence of immune suppression is that the stem cells may help to regenerate the injured tissue, and also that they may suppress the autoreactive immune response. Another interesting feature of mesenchymal stem cells is that they specifically “react” to their environment. In other words, mesenchymal stem cells produce a certain level of antiinflammatory compounds when they are grown in tissue culture by themselves, however, when they are treated with compounds that cause inflammation, such as TNF-alpha, then they markedly upregulate their production of antiinflammatory agents such as IL-10, and also start producing more growth factors such as IGF-1. This is believed to be because the mesenchymal stem cell normally acts as a “repair cell”. That is, when there is tissue injury in the body, the mesenchymal stem cells naturally migrate to the injury (by virtue of proteins called chemokines) and then play a fundamental role in the healing process.
The second approach to treatment of multiple sclerosis by stem cells focuses on “reprogramming” the immune system. Stem cells used for this are the stem cells that make blood, called “hematopoietic” stem cells. In other words, we know that in multiple sclerosis there are numerous T cells that are attacking the body, and specifically the myelin sheath of the central nervous system. These “bad” T cells have not only been identified but vaccines have been made with them. Well instead of selectively killing some specific T cells, or only killing the activated T cells (like daclizumab does), the process of using stem cells with immune depletion involves first killing ALL immune cells, and secondly restoration of the immune cells by administering the patient’s own purified hematopoietic (blood making) stem cells. By readministering the patient’s own stem cells in absence of T cells, the body is left to make its own T cells again from scratch. Theoretically this is very appealing. Practically there are a couple of problems. First of all, the period of time from when the patient’s immune system is destroyed artificially (usually by chemotherapy and/or irradiation), to when the administered stem cells make new immune cells, leaves the patient exposed to many bacteria and viruses. Secondly, there is a phenomena called “homeostatic expansion” in immunology. This is explained in this video. Essentially, when a small number of immune cells are placed in a host that lacks immune cells, the few immune cells start to multiple aggressively and lose ability to be regulated by normal mechanisms that stop the body from attacking itself. In autologous transplantation with immune depletion, purified stem cells are reintroduced to the patient, so this should not be a problem, however, even a small amount of T cell contamination could potentially cause exacerbated disease. The third danger with this approach is that when the stem cells are given to the patient that is lacking an immune system, the new T cells need to be made in the same way that the T cells were made from stem cells when the patient was young. See, T cells only get made before you are born, primarily because of bone marrow hematopoietic stem cells migrating to the thymus and making new T cells in the thymus. After puberty the thymus becomes much smaller and loses a lot of its functional ability. This is because almost no new T cells are made after puberty. So when you destroy the immune system and “ask” the hematopoietic stem cell to regenerate a brand new population of T cells, these T cells are made in a thymus that is severely atrophied. Therefore the new T cells may have many potential abnormalities.
The two stem cell approaches (without destruction of the recipient immune response and with it) are discussed in a recent publication (Muraro et al. Immuno-Therapeutic Potential of Haematopoietic and Mesenchymal Stem Cell Transplantation in MS. Results Prob Cell Differ 2009 Jan 23).
The authors review how hematopoietic stem cell transplantation (involving immune destruction) has been used for more than 40 years for treatments of leukemias, and is now expanding into the area of autoimmune diseases, not only multiple sclerosis, but also rheumatoid arthritis and type 1 diabetes. According to the paper, the highest number of hematopoietic stem cell transplants for autoimmunity has actually been performed in multiple sclerosis.
In multiple sclerosis, hematopoietic stem cell transplants appear to stop acute inflammation in the central nervous system and prevent relapses. Unfortunately, limited to no effect is seen in patients with secondary progressive multiple sclerosis.
The article then goes on to talk about non-immune depleting transplants, specifically focusing on mesenchymal stem cells. It states that the original idea with using mesenchymal stem cells was that they can differentiate into myelin producing oligodendrocytes and neurons, but now most people believe that the mechanism of action of these cells is primarily mediated by modulation of the immune system.
Currently clinical trials are being conducted using mesenchymal stem cells that have been culture-expanded and hematopoietic stem cells with destruction of the immune system before placement. It will be interesting to see which ones have better effects. Of course the period of immune destruction before administration of the hematopoietic stem cells has the potential to cause numerous adverse effects. Therefore, places like StemNow.com exclusively offer therapies that do not involve destruction of the immune system before stem cell administration.