Efficacy of immunosuppressive drugs in islet xenotransplantation: leflunomide in combination with cyclosporine and mycophenolate mofetil prevents islet xenograft rejection in the pig-to-rat model.
BACKGROUND
Morphological characteristics of islet xenograft rejection differ from those of islet allograft rejection. Therefore, prevention of islet xenograft rejection probably requires a different type of immunosuppression from that used in allogeneic transplantation.


METHODS
Fetal porcine islet-like cell clusters (ICC) were transplanted into the renal subcapsular space of rats treated with different immunosuppressive protocols. The existence of a cellular infiltrate or deposits of antibodies and complement in the grafts was evaluated at different times after transplantation using immunohistochemistry.


RESULTS
Treatment with leflunomide (LEF), cyclosporine (CsA), mycophenolate mofetil (MMF), 15-deoxyspergualin, and rapamycin alone or in combination had an insufficient inhibitory effect on ICC xenograft rejection. However, in animals treated with LEF+CsA, the rejection process was markedly inhibited. However, some macrophages and T cells were still present, and at 24 days, the xenografts were destroyed. In LEF+CsA-treated animals that were given sera containing an excessive amount of rat anti-porcine xenoreactive antibodies, marked deposits of IgG, and to some extent C3 as well, were detected along the border between intact ICC, and the xenografts were surrounded by macrophages. However, almost no cells infiltrated the grafts, and there were many intact ICC. In animals treated with LEF+CsA+MMF, only occasional infiltrating cells were seen at 12 and 24 days after transplantation, and the endocrine tissue was completely intact.


CONCLUSIONS
LEF+CsA+MMF prevented rejection of porcine ICC xenografts in the rat for up to 24 days after transplantation.
Wennberg
L
L
Department of Transplantation Surgery, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden.
Karlsson-Parra
A
A
Sundberg
B
B
Rafael
E
E
Liu
J
J
Zhu
S
S
Groth
C G
CG
Korsgren
O
O
D000818:Animals; D000906:Antibodies / Q000097:blood / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D016572:Cyclosporine / Q000627:therapeutic use*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007555:Isoxazoles / Q000627:therapeutic use*; D000077339:Leflunomide; D008297:Male; D051379:Mice; D011247:Pregnancy; D051381:Rats; D013552:Swine; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*; D014529:Uridine / Q000494:pharmacology
D000906:Antibodies; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D016572:Cyclosporine; D003165:Complement System Proteins; D000077339:Leflunomide; D014529:Uridine