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Presenter: Susan, Safley, Atlanta, United States
Authors: Susan A. Safley1, Norma S. Kenyon2, Dora M. Berman2, Antonello Pileggi2, Norman Kenyon2, Hong Cui1, Idelberto Badell1, Allan D. Kirk1, Robert W. Holdcraft3, Lawrence Gazda3, Camillo Ricordi2, Collin J. Weber1
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Function of microencapsulated adult porcine islet xenografts in streptozotocin-diabetic non-human primates
Susan A. Safley1, Norma S. Kenyon2, Dora M. Berman2, Antonello Pileggi2, Norman Kenyon2, Hong Cui1, Idelberto Badell1, Allan D. Kirk1, Robert W. Holdcraft3, Lawrence Gazda3, Camillo Ricordi2, Collin J. Weber1
1Surgery, Emory University, Atlanta, GA; 2Surgery, University of Miami, Miami, FL; 3Xenia Division, The Rogosin Institute, Xenia, OH; United States
We assessed the function of microencapsulated adult porcine islets (APIs) in immunosuppressed, streptozotocin (SZN) diabetic non-human primates (NHPs). NHPs (n=6) were transplanted i.p. with APIs (48,000 – 91,000 IEQ/kg) in barium-gelled 3.3% LVM alginate microcapsules and treated with CTLA4-Ig plus either LFA3-Ig and anti-LFA-1mAb (n=2), anti-CD40 mAb (n=1) or anti-CD154 mAb (n=3). In 5 NHPs, fasting blood glucose was normal on POD 1 without exogenous insulin and remained in the normal BG range for 2, 5, 8, 28, and 38 days, with lower HbA1c levels and insulin requirements 25-50% lower than pre-transplant. In 4 NHPs, porcine C-peptide values were 1.3-1.6 ng/ml on POD 3-11 but declined thereafter. All NHPs had post-prandial hyperglycemia with delayed clearance of glucose (and delayed porcine C-peptide release) compared to normal NHPs. At graft failure in 4-of-5 NHPs, we found clean free-floating capsules and relatively low levels of peritoneal cytokines and chemokines. Pre-existing anti-porcine and anti-Gal antibody levels did not rise post-transplant, but APIs in retrieved capsules stained positively for primate IgG. Explanted capsules from 2 NHPs corrected diabetes in STZ-diabetic nude mice, suggesting that some islets were still functional.
In one NHP given sub-optimal doses of CTLA4-Ig, porcine C-peptide values were 0.47 ng/ml on POD 14 and declined thereafter. At sacrifice, capsules were aggregated and surrounded by CD4+ and CD8+ T cells, CD19+ B cells, and CD68+ macrophages. Increased peritoneal cytokine and chemokine levels, plus elevated serum IgM and IgG, suggested a host cellular and humoral response. One NHP died on POD 1 with symptoms consistent with heavy metal toxicity.
We conclude that microencapsulation with adequate costimulatory blockade can inhibit host cellular responses to API xenografts in SZN-diabetic NHPs, but host humoral responses may contribute to graft failure. We predict that optimized capsules that exclude host IgG will promote longer-term graft survival.
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