Thalassemia Patients and Friends
Discussion Forums => Working Towards a Cure => Topic started by: Narendra on July 02, 2008, 02:08:17 PM
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May be we are on a breakthrough for spleen issues with thalassemia. Read below
From:- http://www.cooleysanemia.com/bodies/body407.php
Weill Cornell Study Examines Spleen in Thalassemia
May 22, 2008 - Researchers from Weill Cornell Medical College may have discovered the precise role of a gene in beta-thalassemia, which may help to prevent removal of the spleen in patients. The research is published in the latest online issue of the journal Blood, the official publication of the American Society of Hematology (ASH).
In thalassemia, hemoglobin -- the oxygen-carrying molecule on red blood cells -- is mutated and non-functioning, resulting in a low red-blood-cell count. Common symptoms include an enlarged spleen, called splenomegaly, caused by a buildup of malformed red blood cells within the body. The spleen works to filter out these unhealthy cells in order to protect the body from harm, such as in a stroke, but eventually the spleen becomes over-stuffed and is commonly surgically removed (splenectomy) in order to prevent a potentially fatal burst. Unfortunately, after the spleen is removed, patients are at a much greater risk for stroke and infections.
Dr. Stefano Rivella, the study's senior author and assistant professor of genetic medicine in pediatrics at Weill Cornell Medical College, in New York City, believes that he and his collaborators may have found a way around splenectomy. After giving mice with Cooley a compound called JAK2 inhibitor, the researchers found that the mice's spleens shrunk to normal sizes, and they began to produce normal red blood cells. The chemical (a similar compound is already in a Phase I clinical trial for myelodysplastic syndromes -- another blood disorder) blocks the activity of the JAK2 gene that is highly expressed in Cooley's anemia, and is believed to play a crucial role in the malformation of red blood cells.
After splenectomy, patients are considered immunocompromised, and so should be placed on lifelong prophylactic oral antibiotics. Patients should also be vaccinated against common viral infections, and should receive annual influenza vaccinations.
Researchers are still learning about the health effects that stem from years of living with reduced or deficient globin proteins. An emerging realization is that removal of the spleen can cause an increase in the risk of life-threatening blood clots. Splenectomy is common for thalassemia patients because their red blood cells are crippled or dead, so the spleen has to work overtime and can become enlarged.
Researchers disagree on the degree of risk associated with splenectomy. A study by Dr. M. Domenica Cappellini, a co-author of this research, found that 30 percent of splenectomized thalassemia intermedia patients developed clots. However, a recent study of 8,860 splenectomized patients with thalassemia major and thalassemia intermediate found that the rate of thrombolytic events was 1.75 percent.
Surgical technique has played a role in developing clots (thrombosis). A recent study found that patients who underwent open splenectomy had a 19 percent chance of developing life-threatening clots, whereas patients who had laparoscopic surgery had a 55 percent chance.
Researchers are only now discovering why splenectomy leads to clots. Injury of endothelial cells may lead to a coagulation cascade, involving the activation of endothelial adhesion proteins, monocytes, granulocytes and platelets. Alternatively, the splenectomy might result in an imbalance between coagulation factors and anticoagulation factors. Dr. Cappellini has recommended short-term anticoagulants such as heparin after surgery, and prophylactic anticoagulants any time thalassemic patients are exposed to thrombolytic risk factors such as surgery, prolonged immobilization or pregnancy. Oral contraceptives should be avoided because they carry their own risk of thrombosis.
This study was funded by grants from the National Institutes of Health (NIH), the Carlo and Micol Schejola Foundation, the Roche Foundation for Anemia Research (RoFAR), the Cooley's Anemia Foundation (CAF), the Children's Cancer and Blood Foundation (CCBF), the Associazione per la Lotta alla Talassemia di Rovigo (AVLT), and the American Portuguese Biomedical Fund.
Dr. Rivella's co-authors and collaborators include Drs. Ilaria Libani, Ella Guy, Luca Melchiori, Raffaella Schiro, Pedro Ramos, Laura Breda, Amy Chadburn, YiFang Liu, Matteo Porotto, Patricia Giardina and Robert Grady -- all of Weill Cornell Medical College in New York City; Dr. M. Domenica Cappellini, as well as Dr. Libani, of Centro Anemie Congenite, the University of Milan; Dr. Maria de Sousa, as well as Dr. Ramos, of Iron Genes and Immune System (IRIS) Lab, Oporto University, Portugal; Drs. Thomas Scholzen, Margrit Kernbach, Bettina Baron-Luehr and Johannes Gerdes, of Research Center Borstel, Germany; Dr. Eliezer Rachmilewitz, of E. Wolfson Medical Centre, Israel; and Dr. John Hood, of TargeGen, Inc., San Diego.
About Weill Cornell Medical College
Weill Cornell Medical College -- Cornell University's Medical School located in New York City -- is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, AIDS, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. The Medical College -- in its commitment to global health and education -- has a strong presence in such places as Qatar, Tanzania, Haiti, Brazil, Austria, and Turkey. With the historic Weill Cornell Medical College in Qatar, the Medical School is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the world's first clinical trial for gene therapy for Parkinson's disease, and, most recently, the first indication of bone marrow's critical role in tumor growth. For more information, visit www.med.cornell.edu.
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Thanks Narendra! great sharing :)
This is impressive!
I hope this becomes a practical reality soon.
It would have a positive impact on all issues relating to missfunctioning spleen.
Hopefully something like this be found for the Stem cells in our BMT and make it work normally too
:pray
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Thanks for sharing.
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Awesome!!! I'm definately keeping my spleen for the time being now. Thanks. :hugfriend
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I had an interesting thought - which may or may not be of value, but I think it is worth considering.
I know of a case - in which a hemophiliac patient received a liver transplant (because his own liver was defective). A result of this transplant, which was not predicted, is that the transplanted liver now produces the factor he is missing therefore he no longer has hemophilia. His underlying disease has been cured.
In the same way, the spleen is capable of producing red blood cells - which is one of the reasons why it becomes enlarged in thalassemia (in hopes to increase its surface area to produce red blood cells - but the lack of beta genes makes it impossible for the spleen to do so). Would a spleen transplant - or even introducing spleen tissue or genes to a thal major patient's spleen possibly have a curative effect on thalassemia? Would it not be easier, perhaps safer than a bone marrow transplant or gene therapy targeting the bone marrow? Maybe this would decrease the need for chemotherapy in gene therapy (which is used for marrow ablation to make room for the corrected cells).
What do you think Andy? I have cooked this up in my own head I don't know if it makes any sense...
Sharmin
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Sharmin,
That is a very interesting idea, especially in light of what has been found with experiments using a spleen transplant as a way to increase tolerance of further transplants, such as other organs.
http://www.medicalnewstoday.com/articles/53021.php
...the induction of immunological tolerance is feasible through spleen transplantation...spleen transplantation in miniature swine...Spleen transplant recipients received a short course of immunosuppressive therapy, after which the transplanted spleen was accepted. The recipient became unresponsive towards the donor in vitro, allowing a kidney from the same donor to be accepted without immunosuppression. One of the possible mechanisms leading to tolerance though spleen transplantation, is the fact that hematopoietic stem cells from the donor spleen engraft in the recipients lymphoid organs, including the bone marrow, thereby teaching the immune system to consider the donor as "self".
What I find most interesting about this is that hematopoietic stem cells engraft in the patient's bone marrow. Hematopoietic stem cells are the precursors of all blood cells. In this study, the hematopoietic stem cells acted as the recipient's own stem cells. The application in thalassemia would depend on how well these stem cells reproduced and and their longevity. If the change is permanent, it may provide some real help to thalassemics.
Perhaps Dr Vichinsky can tell you if this could have some real application in thalassemia in the future.
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I will definitely mention this to Dr. Vichinsky.
Ever since I heard of the outcome for the hemophilia patient - I have been wondering about this. I know that the spleen is capable of extramedullary hemopoiesis - in addition the study you quoted mentions that the spleen causes engraftment in the host bone marrow. I wonder if a spleen transplant - or even engraftment of some spleen tissue could result in some benefit - or a potential cure for thalassemia. If the spleen can produce red blood cells - and the engrafted cells in the marrow also produce blood cells there may be potential.
If this does not cure thal, at the very least it can reduce complications in BMT - such as GVHD - and may increase survival rates.
We may be on to something Andy hmmmm :dunno :dunno...
Sharmin :biggrin
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Sharmin, You're a genius!! :thumbs
:stars
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Oh my God,
Great idea Sharmin :hi5girls
This site is full of geniuses,i think i am the only dumb one :heehee
ZAINI.
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Thanks Sajid and Zaini :blush ,
Andy is our genius, I'm just a mom thinking up crazy ideas and bouncing them off of poor Andy - hoping that something makes sense. You are right Zaini, this site is full of some very intelligent and knowledgeable people including you! Isn't it amazing how much we can learn when we need to for our children!
I will mention this to Dr. Vichinsky to see if this has been looked into previously.
I hope our appointment goes well,
Sharmin
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Hey Guys / Sharmin
Any news on this.?
Actually I had no idea that spleen can produce RBC's, I was only aware that spleen just protects the body and destroys the unwanted stuff in human body. Therefore it cannot distinguish the thal rbc's to the normal rbc's as thal rbc's are not normally shaped.
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Sharmin, did you ask him about this subject???
manal
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Hi guys,
I did mention this during my July visit. I did not have a chance to see Dr. Vichinsky at the time but I mentioned it to his associate. He said that he had not heard of anyone attempting to transplant cells into the spleen. He said that he would give it some thought, I have not heard back. I think they were more concerned with getting my son's antibodies and iron levels under control at the time. I will definitely bring it up again.
My son's doctor however, (and he is the best doctor in our city) thought that the idea had potential especially in light of the surprising results they had in hemophilia and engraftment of liver tissue. The spleen is definitely capable of extramedullary hemopoiesis. Remember with thalassemia we just need some benefit, if certain cells in the body can make red blood cells it may be enough. Also, considering that when cells are transplanted to the spleen some are also engrafted into the bone marrow. If the spleen has already accepted these cells gvhd should not occur. Of more benefit would be to target the spleen in gene therapy and then to attempt an autologous introduction of cells into the spleen. It would be much better than having to ablate the marrow with chemotherapy.
OH no there I go again making up my own science!!
Let's see what the experts say!
Sharmin
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Andy,
Has there been any discussion at the conference along these lines?
Sharmin
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I wish I could say that there was a lot of new material at the conference, but when I see an article presented that I downloaded long ago and see the same presentations twice by different doctors, I can't honestly say that this conference had enough new material. That isn't to say that there weren't some really good presentations, particularly those from the top doctors, Wood, Piga, Porter, etc. Wood's presentation on the treatment of heart failure in thals should be the gold standard for every thal treating hospital in the world. I will talk more about this later. For me, the conference was very successful and I accomplished a great deal, but that is due to my own efforts. More to come.
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Over the years I have thought about this idea, I entertain it for a while and then wonder if it has any merit. Several years ago, a hemophilia patient - following a liver transplant found himself cured of hemophilia because the liver was able to produce the clotting factor which he lacked.
This lead me to think whether the spleen, which is capable of extramedullary hematopoiesis may be helpful in the same way. In fact, there may be two ways that it may be helpful. Firstly, introducing donor cells into the spleen may create enough red blood cell production to reduce if not eliminate the requirement for transfusions. Cells from the spleen often engraft in the bone marrow, where they would continue to create more red blood cells. Also, the spleen being a significant part of the immune system, having accepted the donor cells would largely eliminate chances of the rest of the body rejecting donor cells. This tendency brings me to the second way in which introduction of cells into the spleen may have some benefit. If the spleen has accepted the donor cells, but the hematopoiesis is not adequate to resolve the anemia completely - at that time a bone marrow transplant from the same donor (donor of spleen cells) may be more successful because the spleen and immune system have already accepted this donor as 'self'. My hope being that the bmt not be required, and the tissue transplant to the spleen would be enough.... Sometimes I wonder if a spleen transplant would be helpful.
I know that the spleen is not a vital organ for survival, which is why spleen transplants have not been investigated but in thalassemia and sickle cell anemia it could be beneficial in more ways than one...the faulty, enlarged spleen would be removed - an healthy, donor spleen would be transplanted possibly restoring normal immune function to the recipient, reducing the risk of clots and destruction of red blood cells and possibly resolving their thalassemia or sickle cell anemia....
Am I the only one who is able to see the potential in this?
Sharmin
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Sharmin
Correct me if I am wrong . What I know is that the spleen enlarges in thal because it is ""eating"" the muted red blood of patients dealing with them as if they are microbs. So how is the spleen producing blood too?
Is it doing two opposite functions?..
Manal
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Hi Manal,
The spleen does actually serves two functions - one is an immune function and the other is extramedullary hematopoiesis. The spleen increases it's surface area for either purpose. While serving its immune function it increases in surface area (enlarges) in order to be more effective in removing debris and old red blood cells from circulation in the plasma. In a non thalassemia individual this would not be a problem as they would quickly produce more blood cells. In a thalassemia patient this is a problem because the red blood cells are not being replaced.
Another function of the spleen is actually extramedullary hematopoiesis. In thalassemia the spleen often increases its surface area in response to anemia - and by expanding its surface area - much like bone marrow - it 'hopes' to increase red blood production. In thalassemia these efforts are futile - therefore the larger surface area in fact becomes 'too efficient' in its first function (the immune function) thereby quickly recycling red blood cells and exacerbates the anemia. I can see how these two functions can seem contradictory to one another - yet in a non thal individual they work well - in thalassemia they can become problematic.
Because the spleen serves these two functions - immune and red blood cell production - I do think that there may be some potential in investigating the spleen in thalassemia and sickle cell anemia.
Does that make sense? lol I tend to get a wordy when trying to explain :wink
Sharmin
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Very confusing and overlaping jobs,but I understood your explanation.
Hope a doctor can answer these possibilities even on a theoretical basis
Just thinking.....
What could be a source for these transplants? Would donors give part of their spleens as in liver transplant, is this medically possible?
Is the mechanism of producing blood by spleen is the same as in the bone marrow? Would engrafment be easy without getting rid of the old marrow?
Manal
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Shall I ask this in Antayla? I do dare to ask this. May I post it on my wall or pass it on to others?
May I print this out (deleting names and any personal information) to put it under some doctors nose?
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Yes Dore,
You are more than welcome to ask about this at the conference. Thank you!
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1570552/
Immunologic Benefits of Spleen Transplantation in the Absence of Graft-Versus-Host Disease
Frank J. M. F. Dor, MD* and David K. C. Cooper, MD, PhD, FRCS†
*Department of Surgery; Erasmus MC; Rotterdam, The Netherlands†Thomas E. Starzl Transplantation Institute; University of Pittsburgh Medical Center; Pittsburgh, PA
This article has been cited by other articles in PMC.
Other Sections▼
To the Editor:
With interest we read the paper by Tzakis et al, recently published in your journal,1 that summarizes the evolution and current status of clinical multivisceral transplantation. One of the conclusions of the authors is that a multivisceral graft seems to facilitate engraftment of organs, suggesting that this procedure offers a degree of immunologic advantage. As the authors state in their discussion, this advantage could be partly attributed to the inclusion of the spleen in the graft, and they referred to a previous study of ours relating to spleen transplantation.2
We would like to comment on some of the immunologic aspects of spleen transplantation, particularly with regard to its effect in inducing a state of donor-specific unresponsiveness, the lack of associated graft-versus-host-disease (GVHD), and the incidence of posttransplantation lymphoproliferative disease (PTLD) (as discussed in the panel discussions on pages 491–493).1
Following an extensive review of the literature of spleen transplantation, mainly in rodent models,3 we and colleagues carried out spleen allotransplantation across minor-mismatch, MHC class 1 and MHC full-mismatch barriers in a preclinical miniature swine model.4–6 Recipient pigs of MHC-mismatched grafts received induction therapy consisting of a low dose of whole body irradiation (100 cGy on day −2), which is nonmyeloablative,6 and thymic irradiation (700 cGy on day −1); maintenance immunosuppression consisted of cyclosporine monotherapy for 45 days only.
In all recipients of successful spleen grafts, multilineage chimerism was detected in the blood for periods up to 6 months,6 and donor cells were identified in the bone marrow and thymus. In vitro assays, such as mixed leukocyte reactivity and cell-mediated lympholysis, indicated that donor-specific T-cell reactivity was suppressed while third-party responses were maintained intact.6 In 2 recipients of spleen transplants, kidney transplantation was subsequently performed from a pig MHC-matched to the original spleen donor, without exogenous immunosuppression. Although these grafts eventually failed from uncertain cause (although not from classic rejection) after >4 and >7 months, respectively, this was in great contrast to kidney grafts in control asplenic nonimmunosuppressed recipients that were rejected within 4 and 15 days, respectively.6
A very mild, transient, and self-limiting form of cutaneous GVHD was observed in a minority of recipients, but no serious manifestations of this condition were seen even in pigs that demonstrated >50% donor T-cell chimerism.4,6
Although none of the patients with a spleen as part of their multivisceral transplant developed PTLD in the series reported by Tzakis et al,1 we observed 2 cases in pigs with spleen transplants, but only when the levels of cyclosporine therapy had been excessively high.7
In conclusion, we agree with the authors of this paper in believing that a spleen allograft has immunologic benefits and has the potential to induce a state of unresponsiveness not only to itself but also to other donor-specific organs. Using the regimen we followed, even when the level of chimerism was high, GVHD was not a problem, and PTLD could be avoided by careful monitoring of immunosuppressive drug levels. We think that spleen transplantation has considerable potential as a means of inducing a state of tolerance to other donor-specific organs and is worthy of further investigation.
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Possibly also worth consideration,
Because cells from the transplanted spleen settle into the bone marrow - the blood cell production could occur in the spleen and in the bone marrow...I wonder if this could lead to any clinical benefits for thalassemia and sickle cell anemia.
I wonder if there is any potential benefit for our children and millions of others, if this could be an avenue of research...
Sharmin
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I have merged these two topics so we can keep all the posts organized in one place. I have found this very interesting when first discussed, but have found no information on spleen transplants for the sake of the spleen alone.
A very good question to ask at the TIF conference is "Why are spleen transplants not considered in thalassemia?"
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http://www.spiritindia.com/health-care-news-articles-5203.html
not that I am keen on the idea of transplant from swine.....but the general idea is there.
see also:
Transplantation of embryonic spleen tissue reveals a role for adult non-lymphoid cells in initiating lymphoid tissue organization
Glanville, S.H and Bekiaris, V and Jenkinson, E.J and Lane, P.J.L and Anderson, G and Withers, D.R (2009) Transplantation of embryonic spleen tissue reveals a role for adult non-lymphoid cells in initiating lymphoid tissue organization. European Journal of Immunology, 39 (1). pp. 280-289. ISSN 0014-2980
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URL of Published Version: http://www3.interscience.wiley.com/cgi-bin/fulltext/121571421/PDFSTART
Identification Number/DOI: 10.1002/eji.200838724
Abstract
In this report we describe a transplantation system where embryonic spleens are grafted into adult hosts. This model can be used to analyze the cellular and molecular requirements for the development and organization of splenic microenvironments.Whole embryonic day 15 (ED15) spleens, grafted under the kidney capsule of adult mice, were colonized by host-derived lymphocytes and DC and developed normal splenic architecture. Grafts were also able to form germinal centers in response to T-dependent antigen. Using this system we demonstrated that adult host-derived lymphotoxin (LT) a was sufficient for the development of ED15 LTa/ grafts. Grafting of ED15 LTa/ spleens into RAG/ hosts followed by transfer of LT a/ splenocytes revealed no requirement for lymphocyte-derived LT a in the induction of CCL21 or the development of T-zone stroma. These data suggest that interactions between adult lymphoid-tissue inducer-like cells and embryonic stromal cells initiated T-zone development. Furthermore,adult lymphoid tissue inducer-like cells were shown to develop from bone marrow-derived progenitors. The model described here demonstrates a method of transferring whole splenic microenvironments and dissecting the stromal and hematopoietic signals involved in spleen development and organization.
http://eprints.bham.ac.uk/160/
Sharmin
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I am very sorry to tell you that I did not ask this at the conference. To my own suprise I only asked one question and that was it. I did not, and a feel sorry for that, grab to mic and ask them all about PKD. I have only talked about that with a English doctor with (possible) Turkish roots. I wanted to check the forums but I never made it too.
My well meant apologies for this misser. I will, however, put this thing in my long term memory, and ask this question to a doctor when I see a good one. Not sure when that will been, but I will promote this idea.
At the end of June I plan to pick up all my medication activities again. Will you remind me of this thing by that time? I must email a few doctors about some other stuff (all PKD related, but..).
-D