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Spleen's Role In Thal - Breakthrough under way? Introducing healthy cells into the spleen as a possible cure

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Sharmin:
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/

--- Quote ---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.
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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.
--- End quote ---

Sharmin:
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

Andy Battaglia:
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?"

Sharmin:
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:

--- Quote ---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.
--- End quote ---

http://eprints.bham.ac.uk/160/

Sharmin

Dori:
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

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