In my last blog post, I discussed our plan to transplant our own younger mesenchymal stem cells (MSCs) to our older selves for the purposes of rejuvenation. Interestingly, a clinical trial was recently concluded where young donor (allogeneic) MSCs were transplanted into elderly individuals to treat age-related frailty [1].
This study found that a single dose of 100M young allogeneic MSCs provided benefit in older people. Specifically, aged individuals treated with 100M young allogeneic MSCs showed improvement on a 6-minute walk test, a short physical performance exam, and had improved forced expiratory volume. Also, some proteins associated with inflammation were reduced.
These are encouraging results.
That said, some data from this trial suggests that the use of allogeneic MSCs limited the effectiveness of this treatment.
Dr. Benjamin Buller previously wrote a post on why your own cells matter. In short, allogeneic MSCs do not remain in your body long, and as foreign cells, they have the potential to elicit an adverse immune response. For this reason, allogeneic MSCs are a double-edged sword: they can provide short term benefit intrinsic to MSCs, but they are removed by your immune system in a manner than may have negative effects [2, 3].
This clinical trial had three treatment groups: 1) Placebo, 2) 100M allogeneic MSCs, and 3) 200M allogeneic MSCs. The cells were administered in a single intravenous injection.
Of interest, whereas the 100M cell dose resulted in physical improvement in patients, the higher 200M cell dose did not.
Why would this be?
One possibility is that 200M MSCs is simply too many cells, however, it is within a dose range that is commonly given in MSC therapies. Another possibility is that 200M allogeneic MSCs results in negative effects due to immune rejection.
In this trial, one patient treated with 100M cells had a mild increase in donor-specific antibodies, whereas two patients treated with 200M cells had a moderate increase in donor-specific antibodies. In addition, two other patients treated with 200M cells had a moderate increase in ‘panel reactive antibodies’ (PRA) that were not considered to be donor specific. A high PRA indicates that someone has been exposed to ‘non-self’ proteins and that they have developed antibodies against them. This data suggests a possibility of immune sensitization, but it is not conclusive.
That said, MSCs are often used for their ability to reduce inflammation by immune-suppression. In this trial, patients that received either 100M MSCs or 200M MSCs had a reduction in some inflammation associated proteins (TNF-α), and the presence of some immune cell markers (CD8 and CD25), whereas placebo did not, which suggests some general and beneficial immunomodulation from the donor cells.
What this means, is that allogeneic MSCs may be both stimulating an immune response, because they are foreign, but also suppressing an immune response, because that is what MSCs do. It is difficult to say why the 200M allogeneic MSC dose did not provide physical benefit, but given that 40% of patients in the 200M cell dose had a detected antibody response, it should be considered.
It is also worth mentioning that one problem with immune sensitization, is that it prevents further use of the same cells. Once you have developed anti-bodies to a specific donor, your immune system will efficiently attack tissue from that donor. Thus, using the same donor cells more than once becomes less effective, if not risky.
As with most things biological (and all things immunological), interpretation is complicated. As mentioned, this study is a very small one. Therefore, it is difficult to draw firm conclusions.
It is very promising to find that MSCs have the potential to treat symptoms of aging in humans.
However, the higher dose of young donor MSCs did not provide physical benefit whereas a lower dose did. As some higher dose patients displayed an immune response against them, the use of donor cells is likely limited by immune rejection.
It would be interesting to see the effects if patients were treated with their own young MSCs.
We are going to find out.
1. Tompkins BA, et al. Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Gerontol A Biol Sci Med Sci. 2017, 72(11):1513-1522.
2. Ankrum JA, et al. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014, 32(3): 252–260.
3. Oliveira RL, et al., In Vivo Immunogenic Response to Allogeneic Mesenchymal Stem Cells and the Role of Preactivated Mesenchymal Stem Cells Cotransplanted with Allogeneic Islets. Stem Cells Int. 2017, 9824698.
