Patients stem cell Q&A#1: can clinic injections cause GVHD?

Colonic_graft-versus-host_disease GVHD
H&E stained section showing Graft Versus Host Disease (GVHD) in the gut. Image credit Mark Ong, Creative Commons License.

People ask me questions about stem cells all the time so I decide to do a new blog series answering your questions.

Today’s post is  the first in this new stem cell Q&A series.

Colonic_graft-versus-host_disease GVHD
H&E stained section showing Graft Versus Host Disease (GVHD) in the gut. Dying intestinal cells are evident and can be a hallmark of GVHD. Image credit Mark Ong. Creative Commons License.

Past series have included my Elephant in the Lab series that provides some insights into the craziness that sometimes goes on in academic research with sometimes biting science humor. I’ve also gotten many great questions on my Reddit AMAs both about stem cells and CRISPR.

I’m focusing today on a question about a specific possible risk from getting stem cell injections at for-profit, unproven clinics.

Can stem cells injected by clinics cause graft versus host disease (GVHD)?

It’s an interesting question and not one that I have heard that often until the last couple years. Recently patients have brought it up more often.

GVHD is more typically a risk from allogeneic (donor-derived) bone marrow or hematopoietic stem cell transplantation, mostly in cancer patients who have received chemotherapy but also potentially for patients with other blood disorders who get transplants.

Injected immune cells from another person can potentially lead to a damaging or even fatal immune response of the transplant back against the recipient. In other words, the graft (the injected cells) attacks the host. You can see an example of dying gut cells (apparently in a human patient, but I’m not positive based on the image description) with GVHD in the image of a section of intestine stained with H&E above.From teaching histology what we’d expect to see in a healthy gut crypt or gland is a solid ring of cells around each lumen in the middle, but in this image we see some cells in the darker-staining outer rings are dying and disintegrating because of being attacked by immune cells.

This attack is possible because the graft in this case is either stem cells that can become immune cells or immune cells that are present in, for example, a bone marrow transplant. Especially in the absence of a perfect or near-perfect match between donor and recipient, the donor cells may view their new home (the recipient’s body) as foreign and attack.

In very rare cases, even simple blood transfusions can lead to transfusion-associated GVHD, which is usually fatal. This is extremely unusual, but based on the same principle and occurs more in immunocompromised patients.

So could GVHD happen to patients of stem cell clinics?

In most cases the probable risk of GVHD seems very low in this context, especially with use of autologous (one’s own) stem cells, but it can get tricky if allogeneic cells are used. Also, one of the complicating factors here is that transient or low-level GVHD could occur in some cases with negative consequences but be very hard to detect.

Here are some takes on the hypothetical potential for GVHD with specific types of stem cell injections at clinics, listed roughly in increasing order of risk. Note that I’m not a physician and this post is not medical advice.

Fat “stem cells”

Fat stem cell preparations such as stromal vascular fraction (SVF) apparently contain some immune cells, but only a minority of the overall cell population. Also SVF is nearly always an autologous transplant anyway so these cells are unlikely to view their new home after injection elsewhere in the body as foreign.

Lab culture or contamination of these cells before transplant may lead them to be eliminated from the body more quickly, but in theory shouldn’t present a high risk of GVHD. Most stem cell clinics do not grow the SVF cells prior to use anyway.

Still, we cannot entirely rule out other kinds of immune issues from SVF injections. These cells do not belong outside of adipose tissue so injecting them into the bloodstream or tissues where they don’t belong could trigger immune issues, most often leading to rejection of the transplanted cells.

Bone marrow injections

Minimally-manipulated, autologous injections of bone marrow cells given at unproven stem cell clinics to patients should present a very low risk, most often zero, for GVHD.

A hypothetical risk could arise if the bone marrow cells were cultured before injection and/or otherwise altered in such a way that they recognized some “self” tissue as non-self, but it seems unlikely and most clinics in the US do not grow bone marrow cells before use anyway. In addition, if bone marrow cells are just injected into defined spaces like joints, GVHD becomes even less likely.

Allogeneic bone marrow injections, however, have substantial risk of GVHD. We just don’t see many clinics offering these.

Birth-related stem cells

Birth-related cells represent more a complex picture and at least a relatively higher risk of some kind of GVHD.

Amniotic or placental stem cells.

Let’s talk about amniotic and placental “stem cells” first since they’re simpler. They are used in an allogeneic fashion so in theory could lead to issues, but the cells are mostly not immune cells and so most of the cells cannot mount an immune response against a patient. The reason the risk is not entirely zero is that these cells/tissues have blood in them (placenta) or be contaminated with blood (amniotic) that is a mixture of baby’s and mom’s blood. There can also be some resident immune cells in the tissues. However, on a simple level it seems relatively unlikely there would be enough immune cell contamination to cause problems, but I’m not sure this has been studied.

The other potential risk-lowering factor here is that it appears that many preps of “stem cells” of this kind are actually dead cells or cell extracts. While this might be a good thing from a GVHD perspective, an IV infusion of a different person’s dead cells and debris could be problematic for the recipient in some ways including affecting the immune system.

It also means there’s little chance these preparations used at for-profit clinics could be effective for treating illnesses.

Umbilical cord cells.

The other main kind of perinatal “stem cells” that are popular these days at unproven clinics come from the umbilical cord. While Wharton’s Jelly cells are now sometimes used, mostly umbilical cord blood cells are the focus of clinic injections. Since these are immune cells from another person, they present some clear risk of GVHD, and there is a literature on this in PubMed.

In a for-profit unproven clinic setting there’s just not enough data to try to pin down the specifics of the risk here, but amongst the cells discussed in today’s post, these probably present the highest risk.

It’s also worth noting that many of the cells in unmatched allogeneic umbilical cord cell injections at clinics are likely to be killed by the recipient patient’s immune system lowering the chance of any actual benefit, although there is some debate about the possible immune stealthiness of these cells even in allogeneic setting.

Overall take-home

In a general sense, the relative risk of the cells in a stem cell injection turning against and attacking a patient’s cells and tissues leading to some kind of meaningful GVHD depends greatly on the type of cells being used and the care with which they were handled.

Disclaimer: this post is not meant as medical advice. Talk to your physician (I’m not an MD) before making medical decisions.

19 Comments

  1. Telomerase positive ectodermal stem cells, telomerase positive mesodermal stem cells, telomerase positive endodermal stem cells, and ALL telomerase negative stem cells contain cell surface markers that can distinguish self from non-self and those have the potential to induce a graft versus host response.

  2. Thanks for this Paul. It is important to weigh up the risks associated with a stem cell transplant, but even more important to recognize how little we know about GVHD in the stem cell treatment space and the requirement for more research.
    I think the section on UC cells need more context…this may not necessarily pose the greatest risk. If you are referring to umbilical cord blood and HLA matching donors with immune competent recipients- no data exists to suggest the risk of GVHD. Huge grey area in the literature with some studies suggesting low risks associated with lower HLA/no matching. Also…cord blood cells are immune privileged as you alluded to so the risks altogether are much lower. Generally, the biggest risks come from storing the cells and the cryopreservation chemicals.

    Also wanted to comment on the idea that the stem cells may be killed upon entry into the recipients body. This may not necessarily mean they have a lessened therapeutic effect. There has been lots of animal research to suggest that even when the cells are cleared (within hours-days), there is still time for the cells to have their effect. And this function in itself is beneficial with no concern for long-term immune alterations due to the cells lingering/engrafting etc.

    It is a shame that a lot of misinformation is carried around by the private clinics and this problem isn’t discussed more openly. Thank you for posting on this topic as i myself get asked questions about GVHD often, and more work needs to be done to uncover the real risks mostly with allo cells.

    • Yes, there are stem cells that may help prevent GVHD in patients such as those with blood cancers who’ve had chemo and bone marrow/HSC transplants. These are backed up by rigorous data from clinical trials.

        • Yep, such as work by Osiris and Mesoblast, which is encouraging and good news.

          There seems to be an immunosuppressive function. However, this is probably not useful to patients receiving MSC injections who have not had an allogeneic marrow transplant previously or who do not have an autoimmune disease. In fact, in that context massive culture-amplified MSC infusion could make such patients more susceptible to illnesses or cancer via immunosuppression. Fortunately, short term studies suggest this is not a common side effect, but more data is needed especially long term.

              • I’m not a stem cell scientist so I don’t have an opinion. The highest clinic claim I’ve heard is 300 million but I think it’s pretty clear these days that many products claiming to have live stem cells of whatever type in them, actually contain very few, if any, live cells.

  3. What will be even more helpful is when someone steps up and removes “amniotic and umbilical cord blood products” from the LIVING stem cell language since both University and private testing has Proven that these amniotic and umbilical cord blood products do Not contain any living stem cells at all!
    In fact, the only way that physicians peddling these illegal amniotic and cord blood products sell them is by telling their patients that they do contain actual living stem cells. After all, who would buy dead, non- viable cellular debris from someone else’s body if the truth is told? Having purchased this load of balls
    “amniotic and cord blood bait and switch” sales gambit, I can tell you, firsthand, this Is how it is being sold.
    Furthermore, these amniotic and cord blood products often sold at chiropractic clinics are only 361 FDA Registered HCT/Ps and the FDA states that 361 Registered products cannot contain any living stem cells or the need for a 351 FDA Approved Drug is required.
    The FDA/CDC MMWR 2018 about the amniotic and cord blood products marketed and sold by Genetech/Liveyon, LLC, the CDC clearly states that There Is No Known Method of Sterilization for these amniotic and cord blood products, which is also why they are illegal.
    The Florida Department of Health, in conjunction with the CDC, sent out letters to physicians who had purchased the Genetech/Liveyon, LLC amniotic and umbilical cord blood products to notify these physicians and their clinics that the physicians needed to notify the patients that they had injected with the Liveyon, LLC amniotic and cord blood products to be tested for at least 8 communicable diseases including West Nile, Zika,Syphillis, Cytomegalovirus, Human T-lymphotrophic virus I/II, HIV, Hepatitis B and C. ( No, the chiropractic physician and the injecting MD did not notify us- we had to get that information from another doctor, contact the Florida Department of Health and our family did end up with some of what is listed post injections of Genetech/ Liveyon amniotic and cord blood)
    Jim Hardy, the former Compliance Director for Genetech/Liveyon, LLC, stated on documents made public, whereby he told Liveyon that the product was “Not intended to be used therapeutically in humans,” and that unmatched amniotic and cord blood products do cause GVHD and can manifest from skin irritations, severe infections to organ failure and death.
    As a matter of documented medical fact, one of our elder family members who was given 2 IVs of the Genetech/Liveyon, LLC’s amniotic and cord blood products did experience multiple gastrointestinal ruptures ( perhaps like what is pictured above as we did report to the FDA Medwatch) that required multiple emergency surgeries, as well as severe systemic infection and severe skin rashes and sores so requiring even an amputation.
    These amniotic and cord blood products are a method of spreading disease and there is no known method of sterilization, they do not contain any living stem cells, cause GVHD and other diseases and the physicians that sell and market them do so by deliberately misleading their patients using NLP ( neurolinguistic programming) based sales skills originally used by psychiatric doctors in hypnotic therapy to achieve desired behaviors. Let us all not be relegated to being deep hypnotic trance subjects.

  4. Stella,

    Your timely response is precisely what is needed for us (you and I) to illustrate the expertly crafted “confusion” that is happening now that is so detrimental to the field of ortho-biologics.

    Understanding what is being said before writing is very important so as not to deliberately or unintentionally create unnecessary confusion is very important as many people are experiencing fraud and illness from these tactics.

    If you read the entire post, then you know that I am speaking about 361 FDA Registered only amniotic and cord blood HCT/Ps that are being sold to patients unlawfully per the FDA/CDC MMWR September 2018;

    https://www.cdc.gov/mmwr/volumes/67/wr/pdfs/mm6750a5-H.pdf

    Some physicians are telling patients that these 361 FDA Registered HCT/Ps contain living stem cells when they do not and these products not only do not contain any living stem cells, but also have no known method of sterilization, cause GVHD and per the Genetech/Liveyon former compliance director, were never intended to be used therapeutically in humans, but were and are still being unlawfully marketed and sold.

    I AM aware that the FDA states that only 351 FDA Approved drugs can contain living stem cells and that a 361 FDA Registered HCT/P claiming that it’s product can treat or cure disease triggers the need for a 351 FDA Drug Approval.

    The last link that you posted from the FDA website states verbatim, “Cord blood stored for use by a patient Unrelated to the donor meets the legal definitions of both a “drug” and a “biological product.” Cord blood in this category must meet additional requirements and be licensed under a biologics license application, or be the subject of an investigational new drug application before use. The FDA requirements help to ensure that these products are safe and effective for their intended use….Be skeptical of claims that cord blood is a miracle cure-it is not… But remember that, currently, the only approved use of cord blood is for treatment of blood-related illnesses.”

    The point is that the only FDA Approved use for these cord blood 351 Approved Drugs is in blood to blood transfers, which seems a lot like a correctly donor/host matched blood transfusion. My family was not going to the local chiropractic office for a blood transfusion, nor were we donor matched.

    This is a black and white issue. There is no gray area. For the purposes of additional clarification, perhaps what can be said is that the sale of 361 FDA Registered amniotic and cord blood HCT/P products that are not donor/host matched, claiming that their products contain living stem cells that are a panacea for everything from orthopedic issues to neurological issues and autoimmune diseases and more, triggers the need for a 351 FDA Drug Approval. Though these unmatched donor to host amniotic and cord blood products companies that simply go online and register their company products as 361 FDA Registered products, they are classified as an Unapproved drug according to CBER, PHSA and FDA/CDC. The Genetech/Liveyon amniotic and cord blood products used on my family had/has no 351 FDA Approval to be marketed and sold legally.

    Dr. Centeno, who has been instrumental in educating the public on these unlawfully marketed and sold fraudulent products, as well as the Niche and Paul, did post a magnificent blog today about this “confusion” between 361 FDA Registered amniotic and cord blood products vs the 351 FDA Approved Drug cord blood.

    This creatively concocted “confusion,” is part of the sales based language and sales technique used to profit from the unlawful marketing and sale of the 361 FDA Registered HCT/Ps as if they are 351 FDA Approved Drugs.

    avoidthestemcellscam.com is an information only website that my family created based on our own experience and ongoing events where we collectively invested $30K on these fraudulent, unsterile, contaminated and Unproven (and Unapproved drugs per the FDA/CDC) amniotic and cord blood products unlawfully being marketed, sold and injected by learned physicians who went to medical school and know that any cell transplant requires donor/host matching, as well as what constitutes a 351 FDA Approved Drug.

    • “If you read the entire post, then you know that I am speaking about 361 FDA Registered only amniotic and cord blood HCT/Ps…” In your post you said, “both University and private testing has Proven that these amniotic and umbilical cord blood products do Not contain any living stem cells at all!” But cord blood contains HSCs or do you think this is not true? Furthermore some 361 HCT/Ps that meet the criteria in 21 CFR 1271.10(a) contain stem cells but you say they do not.

      I am well aware that you have had a bad experience and that you believe you were sold a compliant HCT/P and you believe it contained no stem cells, but this does not mean that all umbilical cord blood products contian no stem cells, which is what you wrote. Maybe you are referring to only the cases where some con artist is selling a product that contains no stem cells– well that’s an issue for the law, but does not alter the validity of other purveyors of FDA compliant products.

      You speak about “confusion” created to push sales of non-compliant products – yes it’s bad, but there’s also the confusion spread by posts like yours that appear to state that all products are bad because one is bad. I understand that is not your aim, but in reading your posts there are many generalized statements that are simply untrue.

      I work with a team refining cord blood based cell therapies to treat GVHD. It is funded by a charitable organization and donations are falling because of the bad news being spouted by uninformed bloggers – a lot of which is likely a result of a singular bad experience.

  5. SS,

    Aren’t U a Riot? A word “Salad Spinner.” Why are you deliberately trying to create confusion here for people to read?
    Remember, “mediocrity is self- inflicted, Genius is self-bestowed.” It is good that bloggers are becoming more self-bestowing, coming out with the truth, asking questions and sharing their outcomes with both scientists and physicians because some of the amniotic and cord blood products that are legally regulated as drugs and/or biological products according to FDA & 21 CFR 1271.3(d) are simply going online and completing a 361 FDA Registration in order to bypass the IND and 351 FDA Drug Approval process and are therefore selling and injecting into patients, Unapproved Drugs.
    Are you openly stating that you, as someone who works “with a team refining cord blood based cell therapies to treat GVHD,” think these unlawfully marketed, unsterile and unscreened products and activity in the amniotic and cord blood space is acceptable?

    Maybe it is your approach that needs changing. It has been noted that “selling is a transference of emotion” which you need in order to procure your funding. Your “transference” smacks of desperation and your disposition is seriously self-inflicting.
    Blaming bloggers for your lack of funding is easier than accountability and is also obsolete and futile.

    https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=1271

    https://www.cdc.gov/mmwr/volumes/67/wr/pdfs/mm6750a5-H.pdf

    https://www.fda.gov/news-events/press-announcements/fda-sends-warning-companies

    Furthermore, we were far from being sold a compliant HCT/P that was for Homologous use only! If a product is regulated as a drug and decides to by- pass the 351 FDA Approval process and just does a simple online 361 FDA Registration, does not make it a compliant HCT/P!
    Our PRP was MIXED in with the Genetech/Liveyon product, put into syringes and then injected into us via both blind trigger point injections and IV’s. We know that is Not “minimally manipulated.”
    The effect is systemic and these products are regulated “under the FD&C Act and/or section 351 of the PHS Act and applicable regulations.”

    My family is comprised of 3 vulnerable, elder and disabled adults who were exploited, lied to by physicians,frauded, injected with an Unapproved Drug, made ill and are still suffering the consequences. At least 12 more people are on the CDC MMWR as of September 2018 while 5 more were added shortly thereafter and 4 more recently in Nebraska.
    These events constitute many more lives than your obviously incorrect assumption of a singular event.

    The link below is from Paul/ the Niche concerning the unlawful sale of these amniotic and cord blood products that are Unapproved Drugs.

    https://ipscell.com/?s=amniotic+and+cord+blood

    • Well, sorry if I hit a nerve – my interest is in facts and in your posts there is a hodge-podge of opinions.
      So once again I ask you to answer these:
      1. do you really think that ALL purveyors of cord blood stem cell products are acting illegally?
      2. do you believe that ALL 361 HCT/Ps that meet the criteria in 21 CFR 1271.10(a) should not contain stem cells?

      When you reread what you have written then your answer to both is yes, but in reality neither is true. I suggest you sort out the facts and stop confusing people by throwing the baby out with the bathwater.

      Anyways, wish you luck with your campaign.

      • @Stella,
        Some of these things are hard to answer flat-out “yes” or “no” because the circumstances matter, but I get your points.
        My impression is that some products marketed as “umbilical cord stem cells” actually do contain living stem cells or at least living cells of some kind, regardless of how the producer describes them or what they should be doing/saying according to the FDA.
        Other products probably do not contain living cells despite how they are marketed.

        “Umbilical cord stem cell” products that actually are living cells and are not used autologously (or in first-degree relatives) probably are drugs that require premarket approval. Furthermore, such products are often marketed for non-homologous use because there aren’t many homologous uses of these cells, making them potential drugs on another level.

        These issues impact whether the marketing and use is legal or not.

        But since umbilical cord cells are approved by the FDA, off-label use can come into play which complicates things from a compliance perspective, rigth?
        Clearly some 361s do have living stem cells in them. E.g. I think minimally manipulated bone marrow aspirates/cells generally are both 361s and contain living stem cells.

  6. Dear Paul,
    Yes there are products that are not in line with the 361 HCT/Ps regulations and may not even contains stem cells – bad guys. There are others that meet the criteria in 21 CFR 1271.10(a) and contain stem cells, such as peripheral and umbilical cord blood stem cells – good guys.

    But some want to paint all as bad guys through some personal experience, which although I am sympathetic, is simply wrong. Nobody has proven that “umbilical cord blood products do not contain any living stem cells at all” This is a flat-out “no” for me but maybe there was some context missing. Let´s move on.

  7. Paul,
    Thank you for restating your comments and for your kind patience! The articles that you have written do provide that exact information that you mention which is why I reference them frequently with links to them when posting. My hope is to help others avoid making the mistakes that my family did by believing a pair of physicians who sold an unlawfully marketed (and possibly unlawfully procured) product that takes their money and leaves them ill and needing multiple life saving surgeries after the injections when never having been hospitalized before as in our case.
    It is amazing how far back the Niche posts on the fraudulent amniotic and umbilical cord blood products that are seriously compromising the integrity of science, physicians, Ph.d’s, court rooms and potential patient’s health go and even more disheartening that it has gotten worse! That is why we flog to your blog!
    It seems that we can all appreciate your breakdown on the” stem-cell” products that are most likely to cause GVHD and it seems to be particularly helpful for non­ scientists and non-physicians who might be vulnerable to exploitation by the unlawfully marketed and sold amniotic and cord blood products that both the FDA and the CDC, as well as the Niche, FDA compliant physicians , CBER , PHSA , CFR
    and scientists have warned to avoid the distribution of Unapproved Drugs that do cause GVHD , products for which there is no known method of sterilization, nor donor testing for diseases or donor/ host matching and per the Florida Department of Health, cause at least 8 other communicable diseases. Please see the link:

    https://stemcellorthopedic.com/more-bad-news-about-cord-blood/

    Since there are only a handful of 351 FDA Approved Drugs and uses for blood to blood transfers for amniotic and umbilical cord blood, it seems like further refining the classification for distinction of amniotic and cord blood products claiming live stem cells with only a 361 FDA Registration when these products are both used exogenously and massed produced( and procured?) For mass distribution into non-related hosts is about as much of a Hindenburg red flag as well as the questionable purveying of such amniotic and cord blood products that the FDA and CDC have already stated are unlawful.
    For example, the Genetech/ Liveyon product sold to our family by both a MD and a DC claiming that they contain actual living stem cells and are therefore claiming that the Genetech/ Liveyon amniotic and umbilical cord blood products are 351 FDA Approved Drugs, produced in a sterile environment , sterile , donor screened and also claiming that there was no need to donor/ host match because their amniotic and umbilical cord blood products were immune privileged and did not need to be donor matched, as well as being “for homologous use only,”per the Liveyon Product Application Guide, but being applied for orthopedic, neurological and other diseases, obviously not being used homologously and all of which claims have been proven to be false. Here is both the Liveyon Product Application Guide and the FDA stating the truth about Liveyon:

    http://integrativepracticesolutions.com/wp-content/uploads/2017/07/5-LIVEYON-PRODUCT-GUIDE.pdf

    https://www .fda.gov/news-events/press-announcements/fda -sends-wa rning­ companies-offering-unapproved-umbilical-cord-blood-products-may-put-patients­ risk

    So, Stella, Please, tell us:
    Exactly WHO are ” All purveyors of cord blood” that are “acting illegally?”

    The FDA states that the regulations 21 CFR Part 1271 do not apply if a product that is 361 Registered claims to contain living stem cells and is therefore regulated as a drug and/ or biological product under the FD&C Act and/or section 351 of the PHS Act and applicable regulations. Please see the links below:

    https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/fdaregulation-human-cells-tissues-and-cellular-and-tissue-based-products-hctps­-product-list

    https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=1271&showFR=1

  8. Hi Paul, thank you for your post today. As the post is on injection, it might not be a right place to ask but it actually reminded me of once being suggested to take GHK-Cu instead of transplant. Do you have any comments on their effectiveness?

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