Reduced Immunogenicity of First-Trimester Human Fetal Pancreas
- Kerstin Brands1,
- Emily Colvin1,
- Lindy J. Williams1,
- Rennian Wang2,
- Richard B. Lock3 and
- Bernard E. Tuch1
- 1Diabetes Transplant Unit, The Prince of Wales Hospital and The University of New South Wales, Sydney, Australia
- 2Departments of Physiology & Pharmacology and Medicine, University of Western Ontario, London, Canada
- 3Leukaemia Biology Program, Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, Australia
- Address correspondence and reprint requests to Bernard E. Tuch, Diabetes Transplant Unit, The Prince of Wales Hospital and The University of New South Wales, Sydney, New South Wales 2031, Australia. E-mail: b.tuch{at}unsw.edu.au
Abstract
OBJECTIVE—The use of human fetal pancreatic tissue may provide a potential source of transplantable β-cells as a therapy for type 1 diabetes. Human fetal pancreas has a remarkable capacity to grow and differentiate in vivo and has been shown to reverse diabetes in rodents. However, it is known that human fetal pancreas obtained from the second trimester of gestation is immunogenic and is rejected after transplantation. Tissue obtained from earlier stages might prove to be immune privileged, as has been shown for other tissues.
RESEARCH DESIGN AND METHODS—In this study, we determined the immunogenicity of human fetal pancreatic tissue obtained from the first trimester of gestation in a humanized mouse model. A microarray study of immunoregulatory gene expression in first- and second-trimester human fetal pancreas was also undertaken.
RESULTS—The analysis of transplanted human fetal pancreata revealed a significantly decreased immunogenicity of the first-trimester tissue. The first-trimester grafts showed only limited cellular infiltration and contained numerous insulin-positive cells, whereas second-trimester tissue was completely infiltrated and rejected. Furthermore an analysis of immunoregulatory genes expressed in first- and second-trimester human fetal pancreas by microarray demonstrated the upregulation of several key immunoregulatory genes in the second-trimester tissue. This might account for the reduced immunogenicity of the younger tissue.
CONCLUSIONS—Our results provide the first indication that the use of first-trimester human fetal pancreas for transplantation might increase the survival of the grafts and might decrease the requirement for immunosuppressive drugs.
- APC, allophycocyanin
- BGL, blood glucose level
- cRNA, complimentary RNA
- FACS, fluorescence-activated cell sorting
- FITC, fluorescein isothiocyanate
- H-E, hematoxylin-eosin
- MHC, major histocompatibility complex
- PBMC, peripheral blood mononuclear cell
- PE, phycoethrin
- RMA, robust multichip analysis
- TNF, tumor necrosis factor
- TRAIL, TNF-related apoptosis-inducing ligand
- UNSW, University of New South Wales
Footnotes
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Published ahead of print at http://diabetes.diabetesjournals.org on 7 December 2007. DOI: 10.2337/db07-0720a.
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K.B. and E.C. contributed equally to this work.
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Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0720a.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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See accompanying commentary, p. 525.
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- Accepted November 23, 2007.
- Received May 27, 2007.
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