Severe neuroimmune complications of adult stem cell therapy – analysis of 2 cases

by Alexey Bersenev on November 18, 2012 · 2 comments

in complications/ safety

I’ve written about severe complications of cell therapy, including stem cells. My main focus was cases of death, related or “possibly related” to cell therapy procedures. There is a lot of emphasis on potential tumor formation in stem cell therapy safety. But, sometimes, other severe complications could be life threatening. Today, I’ll discuss two cases of demyelinating encephalomyelitis as a complication of adult stem cell therapy. Both reports came up recently and were not discussed in mass media and professional communities.

case 1
The case was published in J of Child Neurology. The patient – 17-year-old girl from US with a history of drug-resistant, relapsing multiple sclerosis (MS), underwent “stem cell treatment” (as a tourist) in Costa Rica. This is what she got:

For her stem cell transplantation, a conditioning regimen of immunosuppression was not used. The patient received 4 intrathecal doses of allogenic CD34+ mesenchymal stem cells derived from umbilical cord blood, as well as 2 infusions of autologous adipose-derived stem cells obtained by liposuction.

During the treatment she acutely developed “headache, nausea, vomiting and difficulty with ambulation”. She was urgently transported back to US, and developed “encephalopathy, bilateral papilledema, hearing loss, quadriparesis, and locked-in syndrome”. On MRI – signs of extensive demyelination. She was in critical condition, but gradually recovered after intensive care. She remained ataxic and heavily disabled in long-term outcome.

Please note the following:

During the patient’s posttransplantation illness, her experience was posted online in stem cell patient discussion forums to bring balance to the anecdotes. This posting was subsequently removed by some of the websites.

The authors conclude that acute severe meningoencephalomyelitis in MS patient was related to stem cell treatment. They noted that:

… severe immune reaction observed in this patient was likely secondary to the stem cell treatment and resulted from the interaction between the pre-existing neuroinflammatory milieu related to active multiple sclerosis and the transplanted stem cells.

We don’t know for sure if these cells were freshly isolated or cultured. But since, cultured mesenchymal stromal cells (MSC) don’t express CD34, I can speculate that cells were freshly isolated. Also, allogeneic and autologous cells were mixed (or administered sunsequently). Therefore, we can’t speculate on a role of acquired of inherited (allogeneic) immunogenicity of the cells. The authors indicate that the “antigenic challenge” was a trigger of such reaction, but not biological properties of cells (aka “stemness”).

Based on neuroimaging and pathology, this patient appears to have a diffuse fulminant encephalomyelitis. The challenge is in distinguishing whether this event represents a severe exacerbation of her underlying multiple sclerosis or a superimposed acute disseminated encephalomyelitis.

A limitation of this report is that we are unable to confirm that the inflammatory response is directly related to antigenic challenge by stem cell transplantation, in spite of the temporal association and absence of stem cells in the biopsy.

case 2
The case was published online in J of Clinical Neuroscience. The patient – 27-year-old female with acute transverse myelitis, underwent intrathecal injection autologous bone marrow-derived MSC. The treatment was approved by ethical committee of Cairo University. MSC were isolated from mononuclear cells (gradient centrifugation) by 24-hour adherence. The cells had a typical morphology and were CD34-/CD44+. Cells were injected 3 times in dose 5-6 million/ kg. 6 hours after third injection, patient developed fever and “disturbed level of consciousness”. The patient was diagnosed with optic neuritis and encephalomyelitis (confirmed by CT and MRI) and treated by methylprednisolone. The treatment was successful and patient regained consciousness.

Acute optic neuritis and encephalomyelitis in a young person, such as our patient, that developed 6 hours after the third injection of MSC suggests a causal relationship. This may be one of the first reports of a multiple sclerosis (MS)-like disorder following bone marrow transplantation.

The authors conclude:

MSC possess immunosuppressive potential and are proposed as a tool for cell therapy; however, under certain circumstances, they could change to become immunostimulating. It is therefore important to better understand the immune plasticity of MSC.

The commentary to this case report warns us about caution of possible severe immunomodulatory reactions in MSC-based clinical trials:

This is possibly the first report of a neuroinflammatory exacerbation after MSC therapy…
While these studies pave the way for future randomised controlled trials, serious adverse events are likely. The main concern has been the malignant potential of MSC…
However, the following case report in this journal raises another serious concern – the potential for immunomodulation in the wrong direction.

Well, I’m not sure if the authors used true MSC, since they didn’t propagate it in culture, but rather incubate for a day to remove non-adherent cells. I’d suspect that in this case, the “product” could be contaminated by monocytes.

What these reports have in common? The diagnosis of encephalomyelitis, young women, relation to adult stem cell therapy, abnormal immune status before treatment, intrathecal route of transplantation. Although patients had slightly different diagnoses (diffuse fulminant encephalomyelitis and acute disseminated encephalomyelitis (ADEM)), both had developed it as massive immune reaction to neural tissue antigents shortly after stem cell treatment.

Since both patients had pre-existing neuroinflammatory condition, we should probably look at reported safety of MS trials. The most recent review of results all MS trials, involved MSC transplantation, didn’t indicate any severe adverse events related to cells. Interestingly, development of severe neuroinflammation de novo, namely multiple sclerosis, was describe as an anecdotal case in leukemic patient after autologous hematopoietic stem cell transplantation. The first case of ADEM after autologous hematopoietic stem cell transplantation was described in lymphoma patient in 1999.

As the authors of the first report noticed:

This report suggests that it is unnecessary for the immune system to be primed against nervous system antigens prior to stem cell transplantation for this complication to occur.

So, I don’t think demyelinating encephalomyelitis cases linked to particular cell type. It could be hematopoietic stem/ progenitor cells or MSC or monocytes or lymphocytes – we don’t know. Also, based on 2 leukemic cases, neuroinflammation is not obligate condition for development of this complication. It could be any immune system abnormality. If it’s true, it makes things even worse.

What can we learn from these cases? I think, at list 3 important things:

  • Cell trialists must be aware about these cases and add it in the list of possible severe complications.
  • Pre-existing severe neuroinflammation (or other abnormal immune conditions) could predispose patients to such acute reactions.
  • We have to understand better immunomodlatory properties of MSC and learn more about exogenous cells immunogenicity in abnormal immune environment.

{ 2 comments… read them below or add one }

Henry E. Young PhD December 13, 2012 at 12:41 pm

One of my biggest “rubs” I have with peers in the adult stem cell arena is their lack of characterizing what they have before they try any type of treatment, be it in an animal or, heaven forbid, human. Mesenchymal stem cells, by their very name, are mesodermally-derived cells and will form multiple cell types, but only of the mesodermal lineage. If investigators, clinicians, etc. had worked with clones of cells derived from a single cell, they would/should have known this. Mesodermal cells should not be used for any type of neuronal therapies – that is bottom line. Only cells that have the potential to form neuronal cell types should be used, i.e., neuroectodermal stem cells, ectodermal stem cells, pluripotent stem cells or totipotent stem cells (and with respect to the last two I am referring to endogenous populations of adult cells, not induced populations).

Now with respect to the immunomodulatory properties of MSCs, I would suggest that the studies in which this was shown to occur used mixed populations of cells NOT pure populations of cell clones. Osiris performed phase-I clinical trials that suggested an immunomodulatory affect of their MSCs. However, their phase-II trial failed when they had to adhere to the isolation scheme in their patent.

We have addressed flow cytometric analyses of pre- and post-induced clones of MSCs (mesodermal, 8-10 microns), ELSCs (pluripotent, 6-8 microns) and BLSCs (totipotent, 0.2 – 2.0 microns) stem cells using 58 CD markers. Pre- treated MSCs display the MHC Class-I marker and were rejected either pre or post induction when transplanted into an animal. Pre-ELSCs do NOT display the MHC Class-I marker before transplantation and were not rejected as long as they maintained an undifferentiated state. However, once the cells differentiated and displayed the MHC Class-I marker they were rejected. Pre-BLSCs do NOT display the MHC Class-I marker in the undifferentiated state and if transplanted were not rejected. Post-BLSCs, if induced outside the individual they expressed the MHC Class-I marker and were rejected when implanted. The strange data we have, and it has been repeated by at least 3 of our collaborators, is that if pre-BLSCs are implanted in the naive form they are not rejected (same as above), however, if they are induced in situ after transplantation , they still were NOT rejected. We would hypothesize that the BLSCs somehow tolerized the recipient to accept them as self. The BLSCs are extremely small, 0.2 to 2.0 microns in size, and can be easily overlooked in mixed cultures of cells. Bottom line, individuals performing stem cell transplants ABSOLUTELY and POSITIVELY need to know what cells they are working with before any attempt at transplantation is made. We have used “fingerprinting” with CD markers, selection with CD markers, differential-centrifugation based on specific cell properties, zeta potential, and other techniques to isolate individual populations of cells prior to transplant. But our transplantation studies were preceded by 20+ years of cell characterization studies first.

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Amy P December 14, 2012 at 12:19 am

I was awed by the video of the little girl with leukemia featured on this blog who got her life back through regenerative medicine but almost lost it through a reaction. Because of the way the procedure was documented step by step they were able to identify the protein that was over expressing and deliver the gift of life they intended for that young child. Maybe if that same diligence could be initiated with human stem cell treatment that presently falls into unregulated territory there would be multiplied progress, less risk and excellent scientific publications so others could replicate what works for the benefit of human kind

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