HLA/DQ matching and embryo rejection?

jubileejune

2 Posts
Reply Posted on: May 15, 2013 at 4:00pm
Hello Dr. Braverman,

I have VERY mild PCOS and have had 3 miscarriages with IVF. In working with Dr. Sher, we were screened for HLA/DQ matches and had five partial-matches. Dr. Sher, recommends intralipid, steroids, and single embryo transfer for a 35% chance of success per viable embryo.

I have read some of your articles on HLA/DQ matching, NK cells, Tregs, etc. and am very interested in what you have to say. I am finding a lot of skepticism about the validity of alloimmune issues and treatments in the professional infertility community and am wondering what the data has to say about all of this.

I don't want to move forward with treatment if there is no data to prove that (1) there is any validity to HLA/DQ matching and RPL in the first place, and (2) there is no data to support that intralipid and steroids remedy the issue.

Of course, my one and only goal is to produce a live baby so I am looking to make an informed decision in making that happen, either through moving forward as I've done, moving forward with steroids/intralipid treatment, or moving on to a surrogate (which I have already).Any data you have is appreciated to either validate or invalidate this issue.

Thank you,
Andrea

Dr. Braverman

2026 Posts
RE: HLA/DQ matching and embryo rejection? Posted on: May 16, 2013 at 6:13am
Our extensive experience with HLA issues does not support DAalpha mathcing alone or "partial matches" in general. However it is very clear that you need disparity with your Husband on Key HLA components to generate T regulator cells and this is well supported in the literature. The role of HLA is quite complex(our blog tries to cover this) and there is quite a bit of analysis that needs to go into a "FULL" HLA complement from both partners as well as the genes that each carry individually which can also play a part. Most REs you speak with if not all will not understand HLA compatability issues as it is quite complex and even those of us int he field an those in transplant immunology where much of this data comes from still are trying to eclucidate the function of each of the HLA alleles.
I would be happy to help you understand whether you "actually" have an HLA issue(which is real and can be quite signiciant) or wether somehting all together is being missed. There is also no rational that I know of where a single embryo in the presence of HLA issues is of value in fact a good embryo that creates tolerance will actually help an embryo with poor combinations of HLA genes survive not the other way around.
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.

jubileejune

2 Posts
Reply RE: HLA/DQ matching and embryo rejection? Posted on: May 16, 2013 at 6:08pm
Thank you for your reply.

Again my primary goal is to have all the knowledge I need to make the best decision in moving forward. I have a few more questions and very much appreciate your expertise in this area:

1. As I mentioned, my husband and I were partial-matches for quite a few HLA and DQ genes, including HLA-A, HLA-C, DQBeta, DQAlpha, and HLADR-B1. These are all partial matches, no full matching. In your response, you said that partial matching does not warrant concern as a cause for RPL but that some disparity IS required in order to initiate the proper immunological response to protect the embryo. Does our particular case lie on the 'not enough matching to worry' side or the 'too much of a match' side?

I know, of course, this may require a lengthy answer. For example, HLA-C seems to be necessarily different from the mother in order to trigger a protective response. With that knowledge, and a partial match between us, will 50% of our embryos be terminated because of an HLA-C match?

2. I assume you would want to run further labs in order to develop a better sense of what may (or may not) be happening immunologically or genetically. If so, what further labs would you be looking to do? Of course I have had all the typical labs done (lupis, antipospholipid, anticardiolipin, etc.) after RPL, which have yielded normal results.

3. If we were to go out into the fertile population, would we indeed find that nearly all couples have this genetic disparity and that this issue is indeed isolated to couples with RPL?

4. In your publishings, you refute the specific role of NK cells in attacking the embryo, yet this is the primary focus of Dr. Sher's discussions, not to mention the aim of his treatments in suppressing them (or inhibiting their activation). I am very interested in your statement that Tregs are the necessary component in protecting the embryo. Under that assumption, what treatments do you pursue? Are you indeed trying to inhibit NK cell activation, as Dr. Sher aims to do, or are you looking to activate Tregs to keep the embryo safe? Do we even have any method that helps to activate Tregs or is that not yet developed?

5. Treatments supposedly attempt to calm the immunological responses, but will the treatments remedy the issue enough to accept ANY viable embryo, whether HLA-matched or not? This is a CRITICAL question to me, as I would much rather use a surrogate to produce LIVE babies (HLA matching or not), than to get pregnant with the disparity-embryos while essentially throwing away those embryos with too much matching. In other words, my own children are more important to me than my own pregnancy.

6. Are you saying that a good embryo may actually HELP the survival of an HLA-matching embryo or that, as Dr. Sher asserts, an HLA-matching embryo will cause the death of an otherwise viable embryo for my body.

7. I am currently about three weeks away from a frozen embryo transfer with my two remaining embryos from my initial IVF. As noted before, my current RE believes alloimmune issues to be invalidated by current findings. Is there ANYTHING that I can do with my current cycle and my current RE, using the knowledge we have of my particular case, to promote a healthy pregnancy (knowing, of course, that intralipids are not available to me at the moment).

Thank you so much for your time and I apologize for the length of this post.

Just as an FYI, I am going on 30, have PCO with pretty regular periods and very minimal symptoms otherwise, had many failed letrozole attempts, 3 failed IUIs, and my IVF produced 27 eggs, 22 fertilized with ICSI, and we ended with 8 fair-grade embryos. My husband is 32, with slightly low motility and low morphology (12-16%). I currently live in Hawaii.

Dr. Braverman

2026 Posts
RE: HLA/DQ matching and embryo rejection? Posted on: May 16, 2013 at 8:19pm
Yes this is not the forum to debate all of the philosophies on immune directed implantation. From what you have told me Im not sure there is a clear answer and hence a clear treatment that you require. After analysis of "ALL' of the correct immune testing , I could help you understand where the problem lies and what the best treatment is. I would ask your current RE to show you the literature that "invalidates" alloimmune issues Im going to guess you get nothing back if you do send it to me and Ill show you why it is not accurate(again I dont think you will get anything back) , and I also dont expect anyone outside of the field of reproductive immunology to have enough understanding of how tolerance is generated to comment on allo immune issues.
My recommendation would be to get the proper workup prior to placement of your last embryos. I would be happy to guide you , you would need to call the office and schedule a SKYPE or telelphone consultation.
Dr. Jeffrey Braverman MD FACOG
Medical Director
Braverman Reproductive Immunology P.C.