Anti-LFA-1 Improves Pig Islet Xenograft Function in Diabetic Mice When Long-Term Acceptance Is Induced by CTLA4Ig/Anti-CD40L

Kumagai‐Braesch, Makiko; Ekberg, Henrik; Wang, Rui; Österholm, Cecilia; Ehrnfelt, Cecilia; Sharma, Amit; Lindeborg, Ellinor; Holgersson, Jan; Corbascio, Matthias

doi:10.1097/01.tp.0000261722.02697.75

Cited by 16 publications

(20 citation statements)

References 31 publications

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“…We also experienced that STZ-diabetic mouse recipients accepted porcine xenograft for as long as 180 days when treated with costimulation blockade reagents, i.e. anti CD154, CTLA4Ig with/without anti LFA-1 [22], while, with the same treatment, some of ALX-diabetic mouse rejected rat xenografts at around 100 days [23].…”

Section: Discussionmentioning

confidence: 96%

Immunotoxicological effects of streptozotocin and alloxan: In vitro and in vivo studies

et al. 2015

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Section: Discussionmentioning

confidence: 96%

Immunotoxicological effects of streptozotocin and alloxan: In vitro and in vivo studies

et al. 2015

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“…A few studies have claimed permanent acceptance and donor specific tolerance after short treatment with costimulatory blockade agents (29,31,39,40), while more commonly, this protocol was shown to induce prolonged engraftment without establishment of tolerance (41–50). This discrepancy could be attributed, in part, to strain or species differences investigated in the different studies reported, as well as to the different assays used to define rejection (32,51).…”

Section: Discussionmentioning

confidence: 99%

Pig Embryonic Pancreatic Tissue as a Source for Transplantation in Diabetes

et al. 2009

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OBJECTIVEDefining an optimal costimulatory blockade–based immune suppression protocol enabling engraftment and functional development of E42 pig embryonic pancreatic tissue in mice.RESEARCH DESIGN AND METHODSConsidering that anti-CD40L was found to be thrombotic in humans, we sought to test alternative costimulatory blockade agents already in clinical use, including CTLA4-Ig, anti-LFA1, and anti-CD48. These agents were tested in conjunction with T-cell debulking by anti-CD4 and anti-CD8 antibodies or with conventional immunosuppressive drugs. Engraftment and functional development of E42 pig pancreatic tissue was monitored by immunohistology and by measuring pig insulin blood levels.RESULTSFetal pig pancreatic tissue harvested at E42, or even as early as at E28, was fiercely rejected in C57BL/6 mice and in Lewis rats. A novel immune suppression comprising anti-LFA1, anti-CD48, and FTY720 afforded optimal growth and functional development. Cessation of treatment with anti-LFA1 and anti-CD48 at 3 months posttransplant did not lead to graft rejection, and graft maintenance could be achieved for >8 months with twice-weekly low-dose FTY720 treatment. These grafts exhibited normal morphology and were functional, as revealed by the high pig insulin blood levels in the transplanted mice and by the ability of the recipients to resist alloxan induced diabetes.CONCLUSIONSThis novel protocol, comprising agents that simulate those approved for clinical use, offer an attractive approach for embryonic xenogeneic transplantation. Further studies in nonhuman primates are warranted.

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“…This therapy has also been shown to induce the permanent acceptance of porcine islet grafts transplanted into wildtype diabetic mice. These recipients were treated only during the first week after transplantation and followed up for 5 months (Kumagai-Braesch et al 2007). …”

Section: Tolerance Induction Towards Hescmentioning

confidence: 99%

Immunogenicity of human embryonic stem cells

et al. 2007

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Human embryonic stem cells (HESC) are pluripotent stem cells isolated from the inner cell mass of human blastocysts. With the first successful culturing of HESC, a new era of regenerative medicine was born. HESC can differentiate into almost any cell type and, in the future, might replace solid organ transplantation and even be used to treat progressive degenerative diseases such as Parkinson's disease. Although this sounds promising, certain obstacles remain with regard to their clinical use, such as culturing HESC under well-defined conditions without exposure to animal proteins, the risk of teratoma development and finally the avoidance of immune rejection. In this review, we discuss the immunological properties of HESC and various strategic solutions to circumvent immune rejection, such as stem cell banking, somatic cell nuclear transfer and the induction of tolerance by co-stimulation blockade and mixed chimerism.

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Anti-LFA-1 Improves Pig Islet Xenograft Function in Diabetic Mice When Long-Term Acceptance Is Induced by CTLA4Ig/Anti-CD40L

Abstract: CTLA4Ig/anti-CD40L/anti-LFA-1-treated recipients had superior islet function compared with CTLA4Ig/anti-CD40L-treated recipients. However, both costimulation blockade regimens led to islet graft acceptance up to 5 months after a 1-week treatment.

Cited by 16 publications

References 31 publications

Immunotoxicological effects of streptozotocin and alloxan: In vitro and in vivo studies

Immunotoxicological effects of streptozotocin and alloxan: In vitro and in vivo studies

Pig Embryonic Pancreatic Tissue as a Source for Transplantation in Diabetes

Immunogenicity of human embryonic stem cells

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