Fate of alphaGal +/+ pancreatic islet grafts after transplantation into alphaGal knockout mice.
BACKGROUND
Important phylogenetic differences between pig and human tissues prevent xenotransplantation from becoming a clinically feasible option. Humans lack the galactose-alpha1,3-galactose (alphaGal) epitope on endothelial cell surfaces and therefore have preformed anti-alphaGal antibodies. The role of these antibodies in rejection of non-vascular xenografts remains controversial. This study investigated the role of anti-alphaGal antibodies in rejection of non-vascularized alphaGal+/+ grafts in alphaGal -/- mice.


METHODS
alphaGal +/+ and alphaGal -/- pancreatic islets were transplanted under the renal capsule of streptozotocin-induced diabetic (1) alphaGal -/- mice and (2) alphaGal +/+ mice. alphaGal -/- recepients were immunized with rabbit red blood cell membranes (RRBCs) to produce elevated anti-alphaGal antibody levels.


RESULTS
Six of the 18 alphaGal -/- mice rejected the alphaGal +/+ grafts within 68 days whereas indefinite graft survival was achieved in the control groups. Animals with surviving islet grafts were challenged with alphaGal +/+ skin grafts. Although all alphaGal +/+ skin grafts were rejected within 58 days, the islet grafts remained intact. This observation correlated with the level of alphaGal expression (which was very low on islets compared to skin) rather than the actual titre of anti-alphaGal antibody.


CONCLUSIONS
The results suggest that the level of alphaGal expression plays an important role in graft survival. Therefore, its removal is important in the development of a pig islet donor for future clinical therapy.
Chandra
Abhilash P
AP
Centre for Transplant and Renal Research, Westmead Millenium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia.
Salvaris
Evelyn
E
Walters
Stacey N
SN
Murray-Segal
Lisa
L
Gock
Hilton
H
Lehnert
Anne M
AM
Wong
Jeffrey K W
JK
Cowan
Peter J
PJ
d'Apice
Anthony J F
AJ
O'Connell
Philip J
PJ
D000818:Animals; D000939:Epitopes / Q000276:immunology; D004910:Erythrocyte Membrane / Q000276:immunology; D000795:Fabry Disease; D017353:Gene Deletion; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007114:Immunization; D007075:Immunoglobulin M / Q000276:immunology; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D016038:Skin Transplantation / Q000276:immunology; D014180:Transplantation; D014184:Transplantation, Homologous; D000519:alpha-Galactosidase / Q000235:genetics / Q000276:immunology*
D000939:Epitopes; D007075:Immunoglobulin M; D000519:alpha-Galactosidase