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Review
. 2012 Dec;61(12):3046-55.
doi: 10.2337/db12-0033.

Clinical islet xenotransplantation: how close are we?

Dirk J van der Windt  1 , Rita Bottino, Goutham Kumar, Martin Wijkstrom, Hidetaka Hara, Mohamed Ezzelarab, Burcin Ekser, Carol Phelps, Noriko Murase, Anna Casu, David Ayares, Fadi G Lakkis, Massimo Trucco, David K C Cooper
Affiliations
Review

Clinical islet xenotransplantation: how close are we?

Dirk J van der Windt et al. Diabetes. 2012 Dec.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Schematic overview of the instant blood-mediated inflammatory response. Tissue factor expression and antibody binding to non-Gal antigens (as well as to Gal on neonatal pig islets) activate coagulation and complement cascades, leading to clotting, direct cellular membrane damage through the membrane attack complex (MAC), and recruitment of macrophages and monocytes through the chemoattractants C3a and C5a. TF, tissue factor.
FIG. 2.
FIG. 2.
Histology of the pancreas of a GTKO/hCD46/hTFPIIns/pCTLA4-IgIns/hCD39Ins pig. hCD46 is expressed throughout the pancreas (green fluorescence). Insulin, hTFPI, pCTLA4-Ig, and hCD39 are expressed exclusively in the islets of Langerhans (green fluorescence). (A high-quality digital representation of this figure is available in the online issue.)
FIG. 3.
FIG. 3.
A: Functional survival of pig islets with a single genetic modification, that is, the transgenic expression of a human complement regulatory protein (hCD46), after transplantation in a cohort of five diabetic cynomolgus monkey recipients. Immunosuppression consisted of induction with antithymocyte globulin and was maintained with an anti-CD154 mAb and mycophenolate mofetil. All experiments were electively terminated; all monkeys were healthy when they were killed. Partial graft function (white bars) and full graft function (insulin independence) (black bars) are shown. Arrowheads indicate retransplantation. B: Serum acute C-peptide responses (ACR) of monkey C-peptide (white bars) and pig C-peptide (black bars) in nanograms per milliliter after a metabolic challenge with intravenous glucose (glu) during follow-up of case 5. The ACR was calculated as the mean of postchallenge C-peptide values obtained at 5 and 15 min minus the corresponding prechallenge value. Pre, the acute monkey C-peptide response before diabetes induction; post, the average of acute monkey C-peptide responses during follow-up after transplantation, monitored until day 372. C: Blood glucose values and insulin requirements in a monkey transplanted with pig islets carrying four genetic modifications—GTKO/hCD46/hTFPIIns/pCTLA4-IgIns. The monkey is currently insulin independent for >150 days. Immunosuppression is identical to the regimen in A.
FIG. 4.
FIG. 4.
Fasting blood glucose and C-peptide levels in humans, cynomolgus monkeys (cyno), and pigs. Data are presented as mean ± SE. Adapted from Casu et al. (48).
FIG. 5.
FIG. 5.
A: Absence of islet amyloid polypeptide deposition in pig islets >1 year after transplantation into the liver of a cynomolgus monkey. B:Native islets from a deceased, nondiabetic adult human in which there is significant amyloid deposition (red immunofluorescence). Blue, cell nuclei; green, insulin. (A high-quality digital representation of this figure is available in the online issue.)
See this image and copyright information in PMC

References

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    1. Collaborative Islet Transplant Registry. Sixth Annual Report. 1 November 2009. Available from http://www.citregistry.com/ Accessed 29 July 2011
    1. Shapiro AM. State of the art of clinical islet transplantation and novel protocols of immunosuppression. Curr Diab Rep 2011;11:345–354 - PubMed
    1. Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation 2011;91:373–378 - PubMed
    1. US Department of Health & Human Services. Organ Procurement and Transplantation Network. Available from http://optn.transplant.hrsa.gov/latestData/step2.asp? Accessed 29July 2011

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