Teen Takes On Donor's Immune System

Leibel writes "The Australian ABC News is reporting that a 15-year-old Australian liver transplant patient has defied modern medicine by taking on her donor's immune system. Demi-Lee Brennan had a liver transplant. Nine months later, doctors at Sydney's Westmead Children's Hospital were amazed to find the teenager's blood group had changed to the donor's blood type. They were even more surprised when they found the girl's immune system had almost totally been replaced by that of the donor, meaning she no longer had to take anti-rejection drugs. 'Dr. Michael Stormon says his team is now trying to identify how the phenomenon happened and whether it can be replicated. "That's probably easier said than done... I think it's a long shot," he said. "I think it's a unique system of events whereby this happened. "We postulate there's a number of different issues - the type of liver failure that she had, some of the drugs that we use early on to suppress the immune system and also that she suffered an infection with a virus called CMV, or cytomegalovirus, which can also suppress the immune system."'"

Warring immune systems?

[KublaiKhan]

Sounds like carbosilicate amorph warfare to me...but then, who'dathunk that the Australians would go in for that schlock?

Actually, if memory serves, NPR had a short bit on a treatment for negating the need for anti-rejection drugs in kidney transplants--they not only transplanted the kidney, but also bone marrow from the donor, and 5 patients out of 6 were able to go off the anti-rejection drugs.

Article: Bone Marrow + organ = no rejection

[davidwr]

New Medical Technique Frees Transplant Patients From Lifetime Anti-Rejection Drugs January 24, 2008 9:32 a.m. EST [allheadlinenews.com]

Graft Versus Host Disease

[NIckGorton]

Yes, its called Graft Versus Host Disease (GVDH), and is a common complication of bone marrow transplantation. If it happens, it manifests as skin, liver, and gut problems mostly. Liver obviously isn't going to be a problem for her, and it sounds like from the original NEJM article I just read that she hasn't had any other manifestations of GVHD. If you are going to get bad GVHD its usually early on, so she's out of that woods, but there is always chronic GVHD manifestations that will show with time.

Though given a choice, I'd take the GVHD risk, lose the immunosuppressants, and never worry that my liver graft would fail. All in all she's a hella lucky kid.

Re:Warring immune systems?

[NIckGorton]

Except that both of her parents are also Rh negative. From the NEJM article: "Nine months after transplantation, a small-bowel obstruction developed, requiring surgical division of adhesions and resection of an ileal band. Routine preoperative blood grouping revealed that the patient's blood group had changed from O, RhD-negative, to O, RhD-positive (the donor's blood group), and a weakly positive direct antiglobulin test indicated coating of red blood cells with IgG antibodies. At that time, there was no evidence of spherocytosis on the blood film to suggest hemolysis; the hemoglobin level was 95 g per liter. This finding was confirmed by the Australian Red Cross Blood Service. Both parents had group O, RhD-negative blood with the phenotype ccdee, whereas their daughter's phenotype was now cDEe. However, serum samples showed mixed-field reactions with anti-D and anti-E typing."

Of course the parents genotype is no absolute guarantee, as it is always "momma's baby, daddy's maybe" but it sounds like they have this pretty well nailed down. She really did develop chimerism.

Re:Self-rejection?

[NIckGorton]

Nope. Its the boy's immune system now. From the NEJM article:

"The change in this patient from group O, RhD-negative blood to group O, RhD-positive blood suggested the development of chimerism by engraftment of the recipient marrow from passenger hematopoietic stem cells within the transplanted liver. Fluorescence in situ hybridization studies for the X and Y chromosomes were performed on a bone marrow aspirate and peripheral-blood lymphocytes 3 months after the onset of hemolysis (post-transplantation day 395).2 Analysis of cells from the marrow, sorted by means of flow cytometry, showed that they were male (XY) in myeloid, erythroid, and CD19+ B cells. Analysis of peripheral-blood aliquots revealed a predominantly male (donor) population: of 50 T cells, 94% were male and 6% were female; of 50 B cells, 98% were male and 2% were female; of 50 granulocytes, 100% were male; and of 50 natural killer cells, 100% were male"

And that was while she was still on an immune suppression regimen. After they found the results above, they made a decision: "These results suggested that the hemolysis was due to the production of antibodies by residual B lymphocytes in the recipient against engrafted erythroid cells from the donor. A choice between two therapeutic options was then considered: the use of rituximab, an anti-CD20 monoclonal antibody, which would deplete all B cells (both host and donor cells), or withdrawal of all immunosuppressive therapy to allow full engraftment. The decision was made to withdraw the immunosuppressive therapy." After which her immune system essentially became entirely that of the boy whose liver she received. Even to the point that since he hadn't gotten his MMR vaccine, she lost her immunity to measles, mumps, and rubella (which she regained when she was re-immunized.)

Re:2 questions

[Henry V .009]

If the blood type were AB to begin with, it could probably handle a liver from A, B or O.

Re:2 questions

[Stooshie]

True to a certain extent. AB could probably handle O, but AB couldn't handle A or B (just the same as A couldn't handle B or vice versa). Having the A markers yourself, as an AB, doesn't neutralise the problems with the B vs A clashwith your B markers and their A markers).

Certainly, when reciving blood, if she was AB positive, she can be a universal recipient. But that would be for an emergency blood transfusion. In an organ transplant situation it would be too risky.

Just as a side note. The problems with different blood types in blood transfusions is less to do with rejection by the immune system and more to do with the blood cells co-aggulating. With a transplant the problem is more to do with rejection by the immune system.

Re:2 questions

[Grym]

If her immune system has been replaced by her donors, won't her other organs/tissues (her own) be rejected by her new (her donor's) immune system?

A better article [yourguide.com.au] on this case described her original blood group to be Type O negative(-) with her new blood group being Type O positive(+).

In this special instance, there would be no reaction. Simply stated, anti-bodies can only be generated for antigens. Thus, you cannot have a humeral immune response based upon a lack of an antigen. This, incidentally, is the same reason why a type AB positive(+) person can receive blood transfusions from any blood group.

They gave her a liver from someone with a different blood type?!? I know other markers as well as blood type are taken into account (and in hepatic Tx urgency is another factor), but I thought a blood type match was the minimum requirement.

This is a good point. I can only guess that because the recipient's blood type was rare (approximately 9% of the population in Australia, according to wikipedia) and that the donors blood type was close (and perhaps their major histocompatibility was good too), other factors like urgency might have taken precedence over the ideal hope of a "perfect match."

-Grym

Re:2 questions

[rnws]

From what I can tell of from extracts from their paper the donor was the same blood type (O) with a different rhesus group.

A person with group O can receive blood only from another group O person (but can donate to almost everyone else). RhD negative people who don't have anti-RhD antibodies can receive one transfusion of RhD positive blood then become sensitised to the RhD antigen.
On the flipside, RhD positive people don't react to RhD negative blood.

It's important to realise that the ABO and RhD+/- systems are only the most important parts of the system - there are 29 blood group systems and over 600 known antigens relating to blood type.

Re:The implications are much more profound than th

[Grym]

Imagine if they could take a sample of your DNA, correct inherited defects, and then re-implant you with stem cells carrying the corrected sequence.

We effectively already do this. They're called bone marrow transplants [wikipedia.org], and it's been used to treat a number of blood-based or auto-immune diseases for years.

The risk of this procedure aside, one problem is that bone marrow transplants aren't perfect. Take leukemia or sickle cell anemia for instance. Unless every single hemopoietic stem cell is eradicated (unlikely), there is a risk that the original cell populations will reproduce and the disease will eventually come back.

It would mean hope for victims of all kinds of diseases like Tay-Sachs or Kreuzfeld-Jacob.

Umm... no.

Tay-Sachs disease [wikipedia.org] is a lysosomal storage disease [wikipedia.org] which becomes most problematic in the nerve cells of the brain. For obvious reasons, unlike a bone marrow transplant, you can't remove/replace all of the nerve cells of the brain without killing the patient.

Creutzfeldt-Jakob disease [wikipedia.org] is, to put it simply, mediated by a prion (a malfolded protein that induces normally folded proteins to also misfold) which can be either genetic in origin or acquired. Even in the case of genetic CJD, the protein would is expressed in every cell of the body, so a bone marrow transplant would not address the problem. Furthermore, even in the best case scenario where you could replace the entire defective genome without killing the patient, because the defective prion is self-replicating in nature, unless you ALSO replaced every protein in their body too (which, if you could do that, you effectively just be making a whole new body for the person--a cure for all diseases) you'd be in the unique situation of having treated the genetic form of CJD, only to be effectively left with the acquired (and still deadly) form.

At the very least, the promise of being able to transfer immunological memory on the marrow level potentially means that all we have to do is find the one person whose immune system wipes out HIV, say, and we can all receive that same immunity.

Yeah sure. If you're willing to inflict one of the most invasive, riskiest, and painful procedures in medicine upon the entire world's population just for immunity to one disease, I guess you could [/sarcasm].

-Grym

Re:2 questions

[Anonymous Coward]

Nope, a blood-type match is not required. I was a live liver donor two years ago,
my blood type is O+, the recipient is A+.