Purified Allogeneic Hematopoietic Stem Cell Transplantation Blocks Diabetes Pathogenesis in NOD Mice

Beilhack, Georg F.; Scheffold, Yolanda C.; Taylor, C. V.; Jerabek, Libuse; Burge, Mary; Masek, Anna; Shizuru, Judith A.

doi:10.2337/diabetes.52.1.59

Cited by 119 publications

(155 citation statements)

References 36 publications

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“…Interestingly, however, pancreatic isoantigens were previously detected in rabbits [54]. Hence, split tolerance is potentially relevant to chimerism strategies in islet [55] or pancreas transplantation that is currently used to treat type-1 diabetes. Supporting this possibility, we recently found that mixed chimerism generated in pre-diabetic NOD mice does lead to split tolerance, with donor islets being rapidly rejected (Chan et al, manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

Luo¹,

Chan²,

Shapiro³

et al. 2007

Eur J Immunol

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Stable mixed chimerism has been considered the most robust tolerance strategy. However, rejection of solid donor tissues by chimeras has been observed, a state termed split tolerance. Since new non-myeloablative mixed chimerism approaches are being actively pursued, we sought to determine whether they lead to full tolerance or split tolerance and to define the mechanisms involved. Fully mismatched mixed chimeras generated by induction with various lymphocyte-depleting antibodies along with either low-dose irradiation or busulfan and temporary sirolimus, maintained stable mixed chimerism but nevertheless rejected donor skin grafts. Generation of stable mixed chimerism using antibody targeting CD40L, but not depleting antibodies to CD4 and CD8, could prevent split tolerance when skin grafts were given together with donor bone marrow. Minor antigen matching abrogated the ability of effector T cells to reject donor skin grafts. A CFSE killing assay indicated that chimeras were both directly and indirectly tolerant of donor hematopoietic cell antigens, suggesting that minor mismatches triggered a tissue-specific response. Thus, split tolerance due to tissuerestricted polymorphic antigens prevents full tolerance in a number of nonmyeloablative mixed chimerism protocols and a 'tolerizing' agent is required to overcome split tolerance. A model of the requirements for split tolerance is presented.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/36938_s.pdf IntroductionMuch of the effort to develop donor-specific transplantation tolerance has been focused on inducing peripheral tolerance through costimulation blockade. While initially promising, with more extensive tests of this approach the success has been somewhat limited, particularly when translated to larger animal models and to the clinic [1]. In hindsight this may not be surprising given that tolerance naturally occurs primarily in the thymus and only secondarily in the periphery [2]. In contrast, the approach of generating hematopoietic chimerism via bone marrow transplantation (BMT) takes advantage of the thymic central tolerance mechanisms, and is considered the most robust method of inducing donor-specific tolerance [3][4][5][6]. The chimer- ism approach is limited clinically by the harsh recipient conditioning needed to establish chimerism and the possibility of graft-vs.-host disease [7]. More recently less toxic strategies have been developed that establish mixed allogeneic chimerism, where substantial levels of donor and recipient hematopoietic cells co-exist in the recipient, and have raised hope that robust transplantation tolerance will soon be routine clinically [6]. Mixed chimerism has been considered to induce tolerance to all other donor tissues. If true, mixed chimerism could be a solution for both solid organ transplantation and cellular transplants, such as allogeneic islets used to treat type-1 diabetes. However, studies in full chimeras, where virtually all hematopoietic cells in the recipien...

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Section: Discussionmentioning

confidence: 99%

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

Luo¹,

Chan²,

Shapiro³

et al. 2007

Eur J Immunol

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“…And Judy Shizuru and I showed that C57BL-to-BALB/c chimeras had better minor histocompatibility T cell restriction to donor H2 b MHC than to thymic host (H2 d ) MHC, apparently contradicting the rules for MHC restriction established previously (15). Finally, we have shown that tolerance induction by HSCs from donors genetically resistant to diabetes and lupus can end the autoimmune components of these diseases in mice (18)(19)(20).…”

Section: Introductionmentioning

confidence: 97%

How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

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I started research in high school, experimenting on immunological tolerance to transplantation antigens. This led to studies of the thymus as the site of maturation of T cells, which led to the discovery, isolation, and clinical transplantation of purified hematopoietic stem cells (HSCs). The induction of immune tolerance with HSCs has led to isolation of other tissue-specific stem cells for regenerative medicine. Our studies of circulating competing germline stem cells in colonial protochordates led us to document competing HSCs. In human acute myelogenous leukemia we showed that all preleukemic mutations occur in HSCs, and determined their order; the final mutations occur in a multipotent progenitor derived from the preleukemic HSC clone. With these, we discovered that CD47 is an upregulated gene in all human cancers and is a “don't eat me” signal; blocking it with antibodies leads to cancer cell phagocytosis. CD47 is the first known gene common to all cancers and is a target for cancer immunotherapy.

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“…We can measure and visualize proteins in amounts that were unimaginable 10 years ago. Numerous studies utilized GFP to track cell fate following bone marrow transplantation, local injection or promoter specific expression [3][4][5][6][7][8][9][10]. While a variety of groups showed that GFP-expressing bone marrow cells are able to seed many tissues and *corresponding author ztoth@mail.nih.gov, mezeye@mail.nih.gov, NIH, NIDCR, Bldg 49, Rm 5A-76, 49 Convent Drive, Bethesda, Md 20892, T: (301) 435-5635, F: (301) 496-1339 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication.…”

Section: Introductionmentioning

confidence: 99%

Sensitive detection of GFP utilizing tyramide signal amplification to overcome gene silencing

Tóth

Shahar

Leker

et al. 2007

Experimental Cell Research

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The green fluorescent protein (GFP) is among the most commonly used expression markers in biology. GFP-tagged cells have played a particularly important role in studies of cell lineage. Sensitive detection of GFP is crucially important for such studies to be successful, and problems with detection may account for discrepancies in the literature regarding the possible fate choices of stem cells. Here we describe a very sensitive technique for visualization of GFP. Using it we can detect about 90% of cells of donor origin while we could only see about 50% of these cells when we employ the methods that are in general use in other laboratories. In addition, we provide evidence that some cells permanently silence GFP expression. In the case of the progeny of bone marrow stem cells, it appears that the more distantly related they are to their precursors, the more likely it is that they will turn off the lineage marker.

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Purified Allogeneic Hematopoietic Stem Cell Transplantation Blocks Diabetes Pathogenesis in NOD Mice

Cited by 119 publications

References 36 publications

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

Non‐myeloablative mixed chimerism approaches and tolerance, a split decision

How One Thing Led to Another

Sensitive detection of GFP utilizing tyramide signal amplification to overcome gene silencing

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