PBMC infusions

carnelian

14 Posts
Reply PBMC infusions Posted on: Nov 28, 2011 at 4:50pm
Dear Dr Braverman

I was wondering what you thought of this experimental treatment for repeat IVF implantation failure.

http://humrep.oxfordjournals.org/content/21/12/3290.long
http://www.jrijournal.org/article/S0165-0378(11)00278-6/abstract
http://www.jstage.jst.go.jp/article/jmor/26/3/122/_pdf
http://eshre2010.abstractsondemand.com/showabstract.php?congress=ESHRE2010&id=627
http://eshre2010.abstractsondemand.com/showabstract.php?congress=ESHRE2010&id=637

I am sure you have heard about it, but its where T, B and NK cells (PBMCs) from the IVF patient's own blood are incubated with HCG for 48 hours before being infused into the uterus 2 days before blastocyst transfer - these small studies seem to show quite a large increase in pregnancy rate for patients who have had several previous IVf failures. I was wondering

what the increase in pregnancy tells us about what cell communication might be missing in ladies who have repeat immune failures?
whether it helps to prove what you have been saying to us ladies on your forum about some level of local inflammation in the uterus being necessary to help implantation?
what the significance is of the observation that the PBMCs of ladies who failed to get pregnant following this treatment showed a big jump in the expression of IFN-g after incubation with HCG, which wasn't so often observed in the PBMCs of ladies who did get pregnant?
and, whether we'd expect the expression of IFN-g by uterine NK cells to be reduced/moderated after administration of neupogen or IVIG?

I gather that the Japanese researchers who did the first studies seem to think that infusing donor PBMCs from healthy pregnant ladies might be even more effective (but its hard to get ethical approval to do that in Japan - and I guess it might be similar in the US, given the situation with LIT?)

I know its asking a lot of someone who is so busy, but I find all this stuff really interesting (as well as being pretty desperate to get my 7th IVF to work!) and am quite excited to get your take on on what these PBMC infusion studies tell us.

Thanks v v v much!

Dr. Braverman

2026 Posts
Re: PBMC infusions Posted on: Nov 29, 2011 at 5:26am
we know that HCG has many immunosuppressive affects such as creating a higher volume of "tolerant" dendritic or messenger cells(there are HCG receptors on these cells, in fact they use this therapy to treat diabetes) and is one of its main immune regulatory functions. They are also responsible for the conversion of T regulator cellls. Both of these are important to help the embryo create immune tolerance and cells that continue to make INFgamma at high levels even after HCG show cells that may be refractory to this conversion and hence may predispose to pregnancy loss.
Neupogen has the same affect on dendritic cells without the invasiveness of transferring treated PBMCs. In fact there are also studies showing transfusing blood from patients PBMCs that are treated with neupogen then transferred back into the mother(studies taken from transplant literature)
so in answer to your question many "ladies" are not properly converting dendritic cells to their "tolerant" form and failing to then recruit in the necessary T regulator cells, instead making higher volumes of TH1 cells that produce INFgamma. this is not related to the recent article discussing need for local inflammation for implantation as this is only needed for a short time and if the INFgamma response can not be turned off then failure to imlplant ensues.

In the long run you are accomplishing the same with Neupogen or even IVIG(but neupogen better for this i.e. production of tolerant dendritic cells ).
I would be happy to help you with your losses, feel free to call and schedule a phone consultation with me.
Braverman Medical Team
Braverman Reproductive Immunology P.C.

carnelian

14 Posts
Reply Re: PBMC infusions Posted on: Nov 29, 2011 at 9:55am
I was thinking though, that although transferring autologous PBMCs from the blood to the uterine cavity seems invasive, because it used autologous cells, it doesn't have the (tiny) risk of blood product infection from ivig (and can be done for about $200, rather than $0,000s), and in some countries where it would be difficult to get ethical approval to use neupogen on pregnant ladies (due to its US cat C rating), PBMC might do some of the same job?

In your experiences, do ladies who fail to get pregnant with neupogen tend to show increases in IFNg when they are taking neupogen?

Would using HCG-treated autologous PBMCs be likely have any impact on ladies who have low blocking antibodies, or would that only be 'fixable' using IVIG/LIT? What I am trying to ask is whether, in the rare situation where IVF failure is due to low blocking antibodies, is it absolutely necessary to increase the number of blocking antibodies by getting them from donors (IVIG) or making more of your own (LIT), or would increasing the number of tolerant dendritic cells using neupogen/ivig sidestep the need for blocking antibodies?

thank you so much for all the time you spend informing us about these fascinating issues.

Dr. Braverman

2026 Posts
Re: PBMC infusions Posted on: Nov 30, 2011 at 4:05am
Low blocking antibodies are present so often its hard to use it as the sole diagnosis as most of the times its not the problem , its only after I have ruled out all else that I treat that and yes IVIG is the best along with LIT, not enough data with neupogen yet.
Yes patients who fail in our program are the ones who elevate their inflammatory cytokines and in this group we have started to add prednisone, no data on that yet.
yes Im not against the autologous infusion I agree with your thinking.
Braverman Medical Team
Braverman Reproductive Immunology P.C.

carnelian

14 Posts
Reply Re: PBMC infusions Posted on: Dec 1, 2011 at 7:58pm
If LIT can't be done (donor sperm etc), so I am relying on IVIG (and pbmc), does the IVIG actually supply the missing blocking antibodies? this is probably a stupid question, but if IVIG contains antibodies from large numbers of blood donors, and only ladies who've recently been pregnant have lots of blocking antibodies, would the number of recently pregnant blood donors, and therefore the amount of blocking antibodies in the IVIG, be high enough? or does ivig work in some other way to get round the missing blocking antibodies?

thank you!

Dr. Braverman

2026 Posts
Re: PBMC infusions Posted on: Dec 2, 2011 at 2:30am
blocking antibodies are a monovalent antibody, they have one defective end so therefore act as a shield. this is the same type of antibody thats in IVIG so it does simply replace the blocking antibody and does not come from previously pregnant women but pooled from many people. Its because of its use in this situation that I have rarely had to prescribe LIT, but now with the expense of IVIG and the better LIT therapies more patients are going to Mexico.
Braverman Medical Team
Braverman Reproductive Immunology P.C.