Combination Immunosuppressive Therapy Works Better for Stem Cell Treaments in Amyotrophic Sclerosis Patients

A research team from the University of California, San Diego has successfully grafted human spinal stems into the spinal cords of rats that have a rodent version of the neurodegenerative disease amyotrophic sclerosis (ALS). ALS is also known as Lou Gehrig’s Disease, which is progressive, degenerative, lethal, neuromuscular disease. In this study, the research group tested four different protocols that suppress the immune response to ensure that the transplanted cells were not attacked and rejected by the host animal’s immune system. The goal of this study was to determine which protocol improved the long-term therapeutic effects of the transplanted cells. This study demonstrated that a combined, systematically-delivered immunosuppression regimen of two drugs significantly improved the survival of the human spinal stem cells. Their results are published in the current issue of Cell Transplantation (20:8).

Michael P. Hefferan from the University of California, San Diego Neurodegeneration Laboratory and a corresponding author on the paper said, “There are no therapeutic strategies that successfully modify ALS progression or outcome. “Cell-based transplantation therapies have emerged as potential treatments for several neurological disorders, including ALS. However, cell graft survival seems to greatly depend on an accompanying immunosuppression regimen, yet there are differential responses to identical immunosuppressive therapies.”

The precise reason for this differential response is presently unclear, but the authors of this study suggested several mechanisms, including distinct types of acute and inflammatory responses, might be the primary reason for different efficacies of the same treatment. To address this possibility, the authors tried to optimize an immunosuppressive protocol for transplanting human spinal cord cells into rats that were genetically preprogrammed to develop ALS (ALS G93A rats). Two drugs, tacrolimus (FK506) and mycophenolate, were used to suppress the immune response against the transplanted spinal stem cells. These drugs were either used alone or in combination with each other.

Human spinal stem cells were transplanted before the ALS G93A rats started to show any ALS symptoms (presymptomatic). ALS G93A rats have a mutant superoxide dismutase gene. Superoxide dismutase is an enzyme found in every cell of our bodies and it detoxifies “superoxide radicals.” Superoxide radicals are oxygen molecules with an extra electron (O2-). Superoxide radicals form as a consequence of the chemical reactions cells use to make energy. Fortunately, our cells have enzymes, like superoxide dismutase, to convert superoxide radicals to hydrogen peroxide (H2O2). Hydrogen peroxide is degraded by the enzyme catalase to water and molecular oxygen. Without a functional superoxide dismutase enzyme, these rats sustain extensive cellular damage in their central nervous system, and, consequently, their motor neurons (those neurons responsible for voluntary movement) begin to die off.

Dr. Hefferan explained: “Although FK506 has been used successfully as monotherapy in our previous studies of spinal ischemia, it failed in the present study on ALS. In contrast to ALS, where spinal inflammation continues and likely worsens until endstage, the traumatically-injured spinal cord is typically characterized by an acute inflammatory phase followed by a progressive loss of most inflammatory markers.”

In this research project, those animals that received the combined immunosuppression of both FK506 and mycophenolate did better than those that received either drug alone and much better than those that received no immunosuppressive therapy. In all likelihood, the combination of the two drugs works better because of the longer drug half-life of mycophenolate rather than from its action. The addition of mycophenolate seems to supplement inhibition of T-cell formation, which leads to a robust survival of the grafted stem cells when analyzed three weeks after transplantation. This suggests that the extensive inflammation in the spinal cords of ALS patients requires extensive immunosuppressive therapies for transplanted stem cells to survive and provide regenerative effects.

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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      Thanks for reading and visiting my blog site. Without more details it is very difficult to know what you mean by “leaps in logic.” It is also equally uncertain to me what you mean by “fill in those breaks.” The article upon which you commented is about immunosuppressive therapies used in combination with stem cell treatments for amyotrophic sclerosis. Since this disease results from intracellular oxidative damage to motor neurons that ultimately results in their death, stem cell treatments might replace the lost neurons or prevent them from dying. Likewise, because the immune response can sometimes hasten the death of damaged cells and exacerbate neurodegeneration, suppressing the immune response might very well delay cell death, allow allogeneic stem cells to reach their destination and help the patient, and ameliorate the patient’s condition. Animal trials showed that this prediction was largely borne out. Where is the leap in logic? What needs to be filled in? Furthermore this study showed that a specific immunosuppressive protocol worked the best. If you have a problem with the study, please look up the paper and let me know what you think of it. If you do not think that I properly represented the study, then please specifically state why. I appreciate constructive criticism to make this site better. Vague statements are not as helpful. I need more details.

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    1. Jason, Thanks for visiting my site. I hope you find lots of great stuff to read here. If you frequent the site more often, you might also find other things that I have yet to write. Cheers!!!

  56. I do love the manner in which you have presented this particular difficulty and it does indeed present me some fodder for consideration. However, because of what precisely I have witnessed, I simply wish when other feed-back pile on that folks keep on issue and don’t start on a tirade associated with some other news du jour. All the same, thank you for this fantastic point and even though I can not really agree with the idea in totality, I respect your perspective.

    1. Joaquin, I am little confused about your precise meaning. What idea cannot you agree with? What perspective of mine do not respect? Can you give me more specifics because I simple cannot discern your meaning.

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    1. Lanzer86, my policy is that you can use anything here as long as the site is properly acknowledged and everything is site in its proper context. If those wishes are respected then you may use whatever you wish.

  58. Exceptional post but I was wanting to know if you could write a litte more on this subject? I’d be very grateful if you could elaborate a little bit further. Cheers!

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