Fetal porcine islet-like cell clusters transplanted to cynomolgus monkeys: an immunohistochemical study.
BACKGROUND
The mechanism(s) involved in acute cellular xenograft rejection have hitherto been generated in vitro or in different experimental models, with pig tissue being transplanted to rodents. There is an urgent need to validate these results in a clinically more relevant combination of species.


METHODS
Fetal porcine islet-like cell clusters (ICC) were transplanted under the kidney capsule in cynomolgus monkeys, either untreated or given immunosuppression with cyclosporine (CsA; 10 mg/kg body weight, intramuscularly) and 15-deoxyspergualin (DSG; 5 mg/kg body weight, intramuscularly). ICC xenografts were examined at 1, 3, 6, or 10-12 days after transplantation, using immunohistochemical techniques. Serum levels of xenoreactive antibodies were measured with ELISA.


RESULTS
No deposits of IgM, IgG, Clq, or C3 were detected within the ICC xenograft in any of the monkeys. Likewise, no significant increase in the levels of xenoreactive antibodies were found after transplantation. In untreated animals, a few N-Elastase-positive cells (neutrophil granulocytes) were seen in the xenograft at day 1. A few mononuclear cells were present in the adjacent renal parenchyma, but they did not infiltrate the xenograft. At this time (day 1), early signs of necrosis were observed in the central parts of the graft. On day 3, the graft had a large, central necrotic area that contained polymorphonuclear cells; the remaining parts of the xenograft showed severe infiltration with CD8+ T cells. Occasional CD68+ cells (macrophages) were seen on days 1 and 3. On day 6, large numbers of macrophages were found infiltrating the entire graft. A few CD20+ B cells, accumulated as small clusters, were also found. Only a few natural killer cells (CD56+) were detected. The CsA/DSG-treated monkeys showed markedly fewer CD2+/CD8+ T cells on day 6 than the untreated monkeys, and the ICC graft was clearly better preserved. However, the number of CD8+ and CD68+ cells had increased considerably at 12 days after transplantation and diffusely infiltrated the whole ICC xenograft.


CONCLUSIONS
Porcine ICC transplanted under the kidney capsule in cynomolgus monkeys were rejected by an acute cell-mediated rejection progressing during the first 6 days after transplantation. The process was not dependent on host Ig or C3 binding to the graft. Although the rejection of porcine ICC was significantly delayed in CsA/DSG-treated monkeys, the ICC xenografts were almost completely destroyed 12 days after transplantation.
Söderlund
J
J
Immunopathology Laboratory, Karolinska Institute, Stockholm, Sweden.
Wennberg
L
L
Castaños-Velez
E
E
Biberfeld
P
P
Zhu
S
S
Tibell
A
A
Groth
C G
CG
Korsgren
O
O
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D019002:CD56 Antigen / Q000032:analysis; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D005333:Fetus; D006084:Graft Rejection; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D008297:Male; D011247:Pregnancy; D011817:Rabbits; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D019002:CD56 Antigen; D016572:Cyclosporine; D006146:Guanidines; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C037258:gusperimus