Monday, November 11, 2013

Bone marrow transplants to cure food allergies?

Let me get this out of the way from the get-go, bone marrow transplants (BMTs) to cure food allergies are not really a question up for debate - this is NOT a good treatment option for your typical food allergic individual. There I've said it - the disappointing part. More on WHY I say this further in the post where I will discuss exactly what a BMT is. Let's just say the potential life-threatening risks of a BMT (among a few other factors, such as cost) far outweigh the potential benefits of a food allergy cure - even for those of us dealing with the risk of life-threatening anaphylaxis.

So where did this business of BMTs curing food allergies even come from? This week, clinicians presented a case-study at the annual #ACAAI (American College of Asthma Allergy and Immunology) scientific meeting, that a 10-year-old boy with both leukemia and a life-threatening peanut allergy was likely cured of his peanut allergy following a BMT to treat his leukemia (Link to press coverage of the case study) [1]. First off, I cannot even imagine dealing with a life-threatening food allergy and then discovering cancer on top it. Needless to say, this family has endured a lot. The really good news is that as far as I can read in the scientific abstract from the meeting, the boy is cancer-free and peanut-allergy free! Below I am giving you the details that are given in the abstract, which inquiring minds may want to know (Meeting abstracts are published in the 2013 November Supplement to the Annals of Allergy, Asthma and Immunology).

 

Details of the boy's peanut allergy PRIOR to leukemia

  • 2003 (15 months old) - the boy had anaphylaxis to peanut.  Allergy was confirmed with additional testing (skin-prick test and ImmunoCap).
  • The boy followed up yearly with his doctor, continued to avoid peanuts, and had no further anaphylaxis.

 

Details of the leukemia (Cancer of the white blood cells)

  •  2006 (4 years old) - Diagnosed with Acute Lymphoblastic Leukemia (ALL) - the pre-B lymphocyte variant
  • Over the next several years, he had several rounds of chemotherapy. After each round, the cancer relapsed.
  • 2010 (8 years old) -Bone marrow transplant - it involved myeloablative conditioning (completely wiped out the immune cells in the bone marrow prior to transplant), and the transplant was allogeneic (coming from a tissue-matched bone marrow donor who had no known allergies).
  • 2010-2011 (8-9 years old) - Took immunosuppressive drugs for one year following BMT (transplant of donor tissue runs the risk of an immune response against your own body.

 

Details of the boy's peanut allergy POST leukemia diagnosis

  • 2007 (5 years old) - Peanut ImmunoCap test:  0.87 kUA/L
  • 2011 (9 years old) - ImmunoCap and skin-prick test to peanut were negative
  • 2012 (10 years old) - Passed a peanut oral food challenge! 

 

What is going on biologically?

First of all, both leukemia and food allergies involve the cells of the immune system.  In this boy's form of leukemia, a type of white blood cell - the precursor (progenitor) of the mature B lymphocyte - became cancerous.  By the way, healthy, mature B lymphocytes are the cells that make the antibodies that protect us from those nasty pathogens we've already encountered or have been vaccinated against!  And yes, B lymphocytes also happen to be the little IgE-antibody factories in people who have IgE-mediated allergies.
The lineage of blood cells.  I have added in red text to highlight cells that are discussed in the blog post.  Source:  http://en.wikipedia.org/wiki/File:Hematopoiesis_simple.svg

In this boy's form of leukemia, these cancerous progenitor B cells propagated like madness in the bone marrow, crowding out the normal progenitor/stem cells that ultimately give birth to all blood cells, red and white.  The marrow (the spongy insides of many of our larger bones) is the location in our body where we manufacture blood cells for the duration of a lifetime.  If left untreated, this cancer is deadly fast.  We can't survive without a functional immune system (white blood cells) and we can't survive without red blood cells to shuttle oxygen to and fro in our bodies.   Treatments typically start with chemotherapy - injections of nasty drugs to kill off cancer cells while trying to avoid killing off healthy cells.  It truly is a delicate balance, and chemotherapy typically has nasty side effects as a result.

This little boy underwent multiple attempts at chemotherapy, followed by a relapse of leukemia.  These treatments were not enough to kill all the cancerous cells, which can lurk in little nooks and crannies and evade the chemotherapy drugs.  If any cancerous cells remain after treatment ends, they begin propagating like gang-busters and you are back to square one.  They needed to up the ante and try more desperate measures to rid this boy of cancer - a bone marrow transplant.

 

What is a bone marrow transplant (BMT), and what are the risks?

This particular boy received the form of BMT that involved myeloablative conditioning.  This means that prior to the transplant, chemotherapy (possibly combined with radiation therapy) was given to remove the cancerous cells along with other cells of the immune system.  In a sense, this procedure annihilates the immune system.  At this point, a person receiving the treatment is incredibly vulnerable to infection (very few immune system cells to fight off pathogens!).  Subsequently, a patient will be given the donor bone marrow intravenously.  Then, those precursor blood cells (stem cells from the bone marrow) need to find their way to the patient's bone marrow and take up residence (this is called a graft).  The best case is that this process happens seamlessly.  However, a real possibility is that the transplant could completely fail and the patient is left without those stem cells required to generate all the new blood cells your body needs.  This is life-threatening. Furthermore, in a strange twist, the donor immune cells can recognize the recipient's body as "foreign" and begin a full-on onslaught against the recipient's tissues (graft versus host disease).  This, too, can be life-threatening.  Immunosuppressant drugs are given to mitigate graft versus host disease, but it still happens all too frequently.  Because of this, the person is quite vulnerable to infection for many months to a year or more.  For these reasons, bone marrow transplants really are reserved for cases when all other options have run out - remember, this little boy had multiple rounds of chemotherapy before they opted to do a BMT. (Summary of various side effects of stem cell transplants from the American Cancer Society).


My interpretation of the case study with a side of additional scientific data:

First off, just to be slightly obnoxious, I don't think you can assume that the BMT caused a reversal in the boy's allergy. Based on the abstract, there does seem to be a possibility that the boy's allergy resolved on its own. That being said, I do not think this is the most likely explanation given the procedure done, which essentially replaced an immune system, combined with the fact that a very low percentage (~20%) of peanut allergies are outgrown. Nonetheless, I throw that out there as a possibility to consider.

If the BMT did in fact cause a reversal in the allergy, it is not entirely surprising! After all, the immune system was essentially replaced with a new immune system from a donor who was not allergic. I view it as hitting the reset button on allergies. Remember, these new cells contain all of the DNA (genetic instructions and predispositions) from the donor, and not the allergic recipient. In some ways, this case implies that the susceptibility lies within the immune system bone marrow stem cells. I would argue, though, that drawing too many conclusions based on one case study is dangerous. There are too many unknowns and uncontrolled variables. This case is fascinating, nonetheless. It raises many questions and provides possible clues in order to do controlled studies. By the way, I did find one other case in the literature where allergy resolved after BMT [2]!

Even more interesting is that the reverse seems to be true as well - BMTs from allergic donors to non-allergic recipients overwhelmingly transfer that same allergy/atopic disorder to the recipient. One particular study did a long-term follow-up a cohort of BMT recipients (14 years later) and found that more often than not, the allergy persisted and often new allergies were added [3]. This really seems to imply that those stem cells in the bone marrow are genetically susceptible in atopic individuals.Furthermore , there are many instances reported where non-allergic individuals receiving an organ transplant (i.e. liver [4], lung [5]) develop the allergy that their donor had. However, in all cases I found, those allergies were transient. They tended to persist for a few months and then went away. The possible explanation here is that many of those immune cells from the allergic donor certainly were present in the transplanted organ (e.g. - cells that make the allergic antibodies, progenitors of cells that make the allergic antibodies, T-cells that direct the allergic phenotype, etc.). The transferred allergies were likely short-lived because eventually those donor "allergic" cells got replaced by the recipients' own immune cells from their own bone marrow stem cells. The combination of all of these studies suggests that blood stem cells in the bone marrow are critically important for the allergic phenotype. Is this where the genetic susceptibility to allergy lies? Future studies will tell!

The take-away
Bone marrow transplants will not be a treatment for allergic individuals anytime soon. I just don't think there is enough evidence at this point to justify the very real, life-threatening risks of a BMT. That being said, I'm not a medical doctor! Perhaps there are cases where individuals are so severely allergic that their life is in very real danger and the risk could be justified. This case study, combined with other previous evidence implies the bone marrow stem cells are critically important determinants of allergies.

Selected References  

Note - I did not incorporate all possible references. I tried to give a few examples where publications were freely available on the web and had many references to previous scientific studies.

1. Luo Y, Weiss SJ (2013) Cure of peanut allergy after bone marrow transplantation for acute lymphocytic leukemia (ALL). Presentation at the ACAAI meeting, Baltimore, MD. (Link - on pg. 51 of the pdf)

2. Hourihane JO, Rhodes HL, Jones AM, Veys P, Connett GJ (2005) Resolution of peanut allergy following bone marrow transplantation for primary immunodeficiency. Allergy 60: 536-537.

3. Hallstrand TS, Sprenger JD, Agosti JM, Longton GM, Witherspoon RP, et al. (2004) Long-term acquisition of allergen-specific IgE and asthma following allogeneic bone marrow transplantation from allergic donors. Blood 104: 3086-3090.

4. Dewachter P, Vezinet C, Nicaise-Roland P, Chollet-Martin S, Eyraud D, et al. (2011) Passive transient transfer of peanut allergy by liver transplantation. Am J Transplant 11: 1531-1534.

5. Bhinder S, Heffer MJ, Lee JK, Chaparro C, Tarlo SM (2011) Development of transient peanut allergy following lung transplantation: a case report. Can Respir J 18: 154-156.


12 comments:

  1. Thank you for a excellent breakdown!

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  2. When my food allergic son was born, we banked his cord blood. With this case in mind, do you think it might be possible that someday his cord blood may be used to help treat his food allergies?

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    1. There is still so much we don't know when it comes to stem cells and viable therapies. Potential is always there, which is why stem cells are a big area of research right now! I honestly don't know the answer to your question. The beauty of treating with your own stem cells is that there should be no adverse immune response (it's your own tissue!). The pitfall that I see with treating with your own cells in the case of allergic disorders is that the genetic susceptibility of allergies is still present (nothing about your DNA has changed). Until we know what those genetic predispositions are and how to avoid turning on the triggers, I would worry about allergies all over again. Again, risky procedure with so many unknowns yet.

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    2. It would have to be a unrelated donor or a sibling match that does not carry the same IgE mediated response.
      Using the cord blood from your own self would do nothing.

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  3. When I read the original news story, I assumed that bone marrow transplant would never be a practical treatment for food allergies, but that the case might lead to some new lines of research. I had previously read news articles about patients who had acquired food allergies after organ transplants, but didn't know that most of them went away again, which really does make the marrow seem even more important. Thanks so much for digging through the literature and writing this up!

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