Antibody absorbent materials - Apheresis

I had a crazy idea, and found that others had already thought of it: develop materials that soak up specific unwanted auto-antibodies in order to remove them from the body.

Apheresis is a procedure where blood is removed from the body, and a component of the blood is removed.
Immunoapheresis (AKA Immune Apheresis) is apheresis that removes unwanted antibodies.
The blood is passed through materials designed to absorb specific antibodies, and then the "clean" blood is replaced.
The procedure is currently being used to prevent organ transplant rejection.
In the study below, it is successfully used to treat autoimmune skin blisters:

www.ncbi.nlm.nih.gov/pubmed/20812992
J Dtsch Dermatol Ges. 2011 Jan;9(1):27-31. doi: 10.1111/j.1610-0387.2010.07500.x. Epub 2010 Aug 31.
Successful immunoapheresis of bullous autoimmune diseases: pemphigus vulgaris and pemphigoid gestationis.
BACKGROUND: Immunoapheresis/immunoadsorption is a specific tool to remove immunoglobulins and immune complexes from the circulation. Immunoapheresis is successfully used in various autoantibody-mediated diseases (such as autoimmune renal disease and others). In dermatology immunoapheresis is increasingly applied as an adjuvant treatment for severe autoimmune bullous diseases.
CONCLUSION: Immunoapheresis might represent an excellent therapy for certain patients with severe pemphigus vulgaris or pemphigoid gestationis, unresponsive to conventional treatment regimens. We observed rapid improvement of clinical symptoms and no notable side effects.

There is no reason I can imagine why immune apheresis could not be used to remove platelet antibodies, thrombopoietin antibodies and/or thrombopoietin receptor antibodies.

My crazy idea actually goes a step further: to develop molecules that act in the bloodstream as decoys and bind to unwanted antibodies, neutralizing them and allowing them to be removed by the liver. Or, tag the molecule with another antibody that causes the molecule/antibody to be removed by the immune system. As far as I know, nothing like this has been tried, but the concept is analogous to Rituxan using monoclonal antibodies to remove CD20+ B-cells, but removing unwanted antibodies rather than unwanted B-cells.

Any thoughts?

Actually, plasmapheresis has been tried for ITP. It doesn't work because the antibodies just keep coming. It's a very temporary solution, like a platelet transfusion.

My crazy idea actually goes a step further: to develop molecules that act in the bloodstream as decoys and bind to unwanted antibodies, neutralizing them and allowing them to be removed by the liver. Or, tag the molecule with another antibody that causes the molecule/antibody to be removed by the immune system.

I thought IVIG did something similar to this. Correct me if I'm wrong.

Rob, its Crazy-Fun to brainstorm

I dunno about how the liver works in destroying platelets.
DeJa Vue, wouldn't decoys need to be infused on a regular basis?
Isn't there like tens of thousands more antibodies than B cells circulating - making B cells a better target?

I think Rituxan destroys all (mature) B cells. And the reason why there are multiple Rituxan treatments is to kill off the maturing B cells. To ultimately wipe out at least one whole generation of B cells.

That part in your earlier post about ITP remissions not being the result of elimination of bad antibodies was very profound. I have to wonder if they can come up with a way to bring Treg cells into balance with Th cells and thus cause remission - as the paper described.

Perhaps just feeding odd/special constructed proteins to the immune system, via the CD20 Rituxan methodology, could modify the balance? Big question mark there.

Did you notice the funding disclosure at the end of the paper? Got to be some money going toward the next level with these ideas - right now.

If correcting the imbalance in ITP ever becomes a possibility, it seems reasonable that this technology could be extended to all the other autoimmune 'imbalances', eg SLE, RA, etc. Yes?

Ok, going off on a limb here. LOL, I'm going to quote Wikipedia. Don't beat me - I've read these quoted ideas in real research papers as well. Really, not lying.

en.wikipedia.org/wiki/Immunoglobulin_therapy#Mechanism_of_action
"
Other proposed mechanisms include the possibility that donor antibodies may bind directly with the abnormal host antibodies, stimulating their removal;
"
Yea, looks like your right Sandi. What Rob describes is similar to one of several theories on IVIG.

I kinda like the following theory about IVIG as well. I think it would work in conjunction/concurrently with the above theory as well.
"
and the ability of immunoglobulin to block the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis.
"

Read all the threads here.

All Greek to me...lol
Just would love to ask here

What are the tests to be done to know the reasons for ITP
(Sorry for this dumb question)

Sandi,

For the benefit of the readers, let me first point out that plasmapheresis and immune apheresis are similar but different. Plasmapheresis removes the patient's plasma and replaces it with donor plasma. Immune apheresis removes only the offending antibodies, and the patient's plasma is returned to the body, so no foreign tissue is introduced, and no donor plasma is required.

Drew Provan, et al, in the 2010 International Consensus Report, state that no ITP patients have shown a response to plasmapheresis. The citation used to support that claim says just the opposite. This is the second time I have found that a citation used by Provan, et al contradicts their statement. Odd.

www.bloodjournal.org/content/115/2/168
International consensus report on the investigation and management of primary immune thrombocytopenia
Drew Provan, Roberto Stasi, Adrian C. Newland, Victor S. Blanchette, Paula Bolton-Maggs, James B. Bussel, Beng H. Chong, Douglas B. Cines, Terry B. Gernsheimer, Bertrand Godeau, John Grainger, Ian Greer, Beverley J. Hunt, Paul A. Imbach, Gordon Lyons, Robert McMillan, Francesco Rodeghiero, Miguel A. Sanz, Michael Tarantino, Shirley Watson, Joan Young and David J. Kuter
Blood 2010 115:168-186; doi: doi.org/10.1182/blood-2009-06-225565
Plasmapheresis has been studied in small cohorts of ITP patients, some of whom had acute ITP. No patients with chronic ITP showed a response⁶⁶ (evidence level III).
66. ↵ Masseau A, Guitton C, Bretonniere C, et al. [Plasma exchanges as treatment of severe acute immune thrombocytopenic purpura]. Rev Med Interne 2005;26(10):824-826.

www.ncbi.nlm.nih.gov/pubmed/16084628 Rev Med Interne. 2005 Oct;26(10):824-6. Epub 2005 Aug 9.
Plasma exchanges as treatment of severe acute immune thrombocytopenic purpura
Masseau A1, Guitton C, Bretonnière C, Renard B, Villers D, Hamidou M.
High dose steroids and intravenous immunoglobulins are the gold treatment of acute immune thrombocytopenic purpura, before splenectomy for severe and refractory forms of the disease. Authors report two cases of severe acute refractory immune thombocytopenia with a dramatic response to plasma exchanges.

A 1989 article from Russia also showed plasmapheresis to be effective with ITP. Unfortunately, the abstract does not reveal the sample size. It is poorly translated from Russian, and is amusing if read with a Russian accent.

Immunocorrective treatment of idiopathic thrombocytopenic purpura by plasmapheresis
Gematol Transfuziol. 1989 Feb;34(2):9-12.Kovaleva LG, Reshetnikova ME, Kalinin NN, Petrova VI, Iakovleva ON.
Abstract
Patients with idiopathic thrombocytopenic purpura (ITP) tolerated well plasmapheresis. In no cases hemorrhage intensification was observed. An immediate clinical effect was recorded in all patients that correlated with the immunological parameters improvement in most of them. The platelet count significantly rose only in one patient immediately after the plasmapheresis course. The follow-up of the patients during 11-20 months has enabled revealing not only immediate clinical but also late hematological effect of plasmapheresis, that was manifest in a delayed rise of the platelet levels in most patients, and abolished resistance to glucocorticoids in one of them. It has been concluded that plasmapheresis produces immunocorrecting effect and could be used for the treatment of ITP patients.

It appears that plasmapheresis works in the ER setting, but like you said, Sandi, the result may be temporary, and who wants to go through plasmapheresis on a weekly (or whatever) basis?

The pemphigus vulgaris patient in the original article of this thread received immune apheresis followed by Rituxan, for a 12 month remission. This possibility of a one-two punch sounds interesting, perhaps analogous to combining high-dose dexamethasone with Rituxan.

My "crazy idea" of creating injectable decoys to remove offending antibodies presents the possibility of treatment being similar to Nplate treatment: a weekly injection. This would be much less cumbersome than plasmapheresis.

There are many contradictory articles out there.

As far as removing 'offending antibodies', it would have to be tailored to target the patient's specific antibodies, unless all of them were included for every patient. Science hasn't gotten that far yet. And yes, it would have to be an on-going treatment. It's similar to some that we already have, such as Rituxan which targets the cell that produces the antibodies in the first place.

Plasmapheresis or to give it it's politically correct term Therapeutic Plasma Exchange (TPE) is a daily, aggressive, invasive procedure used for attempting to remove antibodies. I have performed this treatment countless times.

Patient plasma is removed and replaced replaced with 4.5% solution of Human Albumin (HAS 4.5%). Usually patients undergo 10 treatments.

HAS does not replace the calcium removed requiring IV calcium replacement each treatment ( not without risk)

Nor does it replace the essential clotting factors removed necessitating the patient undergoing a cross matched human donated Plasma transfusion post each treatment.

It has been effective in treating auto immune diseases affecting the kidneys such as Weighers and Goodpastures. Upon my ITP diagnosis the first question I asked was can I have TPE?

No was the immediate response. It rarely works and isn't worth the risks involved.

Badami, if I understand your question.
In Rob's recent thread announcing this paper
www.bloodjournal.org/content/128/22/2548

notice this sentence in the paper
"
Samples were tested for circulating antibodies against TPO or cMpl using newly developed enzyme immunoassays (EIAs) and for antibodies against platelet glycoproteins (GPIIb/IIIa and GPIb/IX) using the antigen capture assay.
"

Does that help?

mrsb04 wrote: Plasmapheresis or to give it it's politically correct term Therapeutic Plasma Exchange (TPE) is a daily, aggressive, invasive procedure used for attempting to remove antibodies. I have performed tis treatment countless times.

Patient plasma is removed and replaced replaced with 4.5% solution of Human Albumin (HAS 4.5%). Usually patients undergo 10 treatments.
... It rarely works and isn't worth the risks involved.

My understanding is that immune apheresis of the sort discussed in this paper is not TPE because there is no plasma exchange. I agree that TPE would not be desirable, even if it might work.
My impression is that immune apheresis would be more like dialysis (which is still not a treat!). I have no idea how often or how long it would be given, only that it shows promise with other autoimmune diseases.

Sandi wrote: As far as removing 'offending antibodies', it would have to be tailored to target the patient's specific antibodies, unless all of them were included for every patient. Science hasn't gotten that far yet. And yes, it would have to be an on-going treatment. It's similar to some that we already have, such as Rituxan which targets the cell that produces the antibodies in the first place.

There are apparently only four antibodies: one antibody each for TPO and TPO-receptors plus two antibodies for GPIIb/IIIa and GPIb/IX antigens. Whether they would test and tailor the treatment or use a shotgun approach and treat for all antibodies is an interesting question. My guess is that the new assays for TPO and TPO receptor antibodies are still some time away from FDA approval.

Rob, I just realized. Since TPO receptors never go to the spleen, would that be the reason why IVIG doesn't work for them - thus ~25% of folks that don't respond to IVIG probably have TPO receptor issue?

My question was....
Which tests would I need to conduct for me to know the the antibodies present that have resulted in my son having ITP.

Also if the antibodies are then known.....can something be done to either remove them frim my sons system or treat them in a manner other than the normal prednisone; promacta;mycophenolate etc etc

Hal, your reasoning makes sense. Don't forget when you are reasoning this stuff out, though, that there is also the issue of antibody regulation w... which is way over my head.

Badami, there are the two platelet antibody tests which are not generally used, and the two new assays, for TPO antibodies and TPO receptor antibodies, that are not even available except for research. Right now, the information might not be very useful, anyway, because little is known which treatments are best for a particular set of antibodies.

Badami, I dunno. Wish I knew these things myself.

My experience is asking the right questions is the key to technological advances. From what I'm reading, scientists are doing much better in doing just that for ITP.

Rob, I think many of us will be looking forward to reading papers about antibody regulation, as new discoveries are made, in the near future.