Prolonged survival of neonatal porcine islet xenografts in mice treated with a donor-specific transfusion and anti-CD154 antibody.
BACKGROUND
Combined treatment with a single donor-specific transfusion (DST) and a brief course of anti-mouse CD154 monoclonal antibody (mAb) to induce co-stimulation blockade leads to long-term murine islet allograft survival. The authors hypothesized that this protocol could also induce long-term survival of neonatal porcine islet cell clusters (NPCC) in chemically diabetic immunocompetent mice and allow their differentiation into functional insulin-producing cells.


METHODS
Pancreata from 1- to 3-day-old pigs were collagenase digested and cultured for 8 days. NPCC were recovered and transplanted into the renal subcapsular space. Recipients included chemically diabetic nonobese diabetic (NOD)-scid and C57BL/6 mice that were otherwise untreated, treated with anti-CD154 mAb alone, or treated with DST plus anti-CD154 mAb. Plasma glucose concentration and body weight were measured, and xenografts were examined histologically.


RESULTS
NPCC fully differentiated and restored normoglycemia in four of five diabetic NOD-scid recipients but were uniformly rejected by diabetic C57BL/6 recipients. Anti-CD154 mAb monotherapy restored normoglycemia in 4 of 10 (40%) NPCC-engrafted, chemically diabetic C57BL/6 mice, but combined treatment with DST and anti-CD154 mAb restored normoglycemia in 12 of 13 (92%) recipients. Reversal of diabetes required 5 to 12 weeks. Surviving grafts were essentially free of inflammatory infiltrates 15 weeks after transplantation.


CONCLUSIONS
Combination therapy with a single DST and a brief course of anti-mouse CD154 mAb without maintenance immunosuppression permits survival and differentiation of NPCC in diabetic C57BL/6 mice. Successful grafts were associated with durable restoration of normoglycemia and the absence of graft inflammation.
Appel
Michael C
MC
Department of Medicine, Division of Diabetes, University of Massachusetts Medical School, Worcester, MA 01605, USA. michael.appel@umassmed.edu
Banuelos
Scott J
SJ
Greiner
Dale L
DL
Shultz
Leonard D
LD
Mordes
John P
JP
Rossini
Aldo A
AA
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001786:Blood Glucose; D023201:CD40 Ligand / Q000276:immunology*; D002454:Cell Differentiation; D003131:Combined Modality Therapy; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D007121:Immunocompetence; D007515:Islets of Langerhans / Q000166:cytology; D016381:Islets of Langerhans Transplantation; D017708:Leukocyte Transfusion; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D023201:CD40 Ligand