Lewis rat pancreas, but not cardiac xenografts, are resistant to anti-gal antibody mediated hyperacute rejection.
BACKGROUND
The objective of this study was to evaluate the role of anti-Gal Abs and non-anti-Gal Abs in hyperacute rejection (HAR) of concordant pancreas xenografts compared with heart xenografts. In addition, we tested whether rejection of Lewis rat pancreas grafts was T-cell dependent and could be prevented by anti-T-cell treatment.


METHODS
To determine the role of anti-Gal Abs in the induction of HAR, Lewis rat pancreas and heart xenografts were transplanted into alpha1,3Galactosyltransferase knockout (GT-Ko) mice treated with normal human serum (NHS) or hyperimmune serum, or into presensitized GT-Ko mice. To investigate whether rejection of pancreas xenograft was mediated by a T-cell dependent response, Lewis rat pancreas grafts were transplanted into streptozotocin (STZ)-induced diabetic GT-Ko mice treated with FK506, anti-CD4 mAbs (GK1.5), and thymectomy. Antidonor-specific IgM and IgG and anti-Gal Abs were analyzed by flow cytometry. Rejected and long-term surviving pancreas xenografts were assessed by functional (blood glucose) and histopathological examination.


RESULTS
HAR of Lewis rat pancreas xenografts could not be induced by NHS (0.4 ml), whereas NHS (0.2 ml) resulted in HAR of Lewis heart xenografts. Infusion of Lewis rat-specific hyperimmune serum (0.2 ml) resulted in HAR of Lewis rat pancreas xenografts. In addition, second Lewis rat pancreas grafts were hyperacutely rejected by presensitized GT-Ko mice. Immunohistochemical staining showed a low expression of Galalpha1,3Gal antigen in the endocrine tissue compared with that in the cardiac grafts. The levels of anti-Gal Abs in pancreas xenograft transplantation did not increase in GT-Ko mice after pancreas xenograft transplantation that was significantly increased after heart transplantation. FK506 treatment induced long-term survival of Lewis pancreas xenografts (mean survival time (MST) >90 days). Anti-CD4 treatment delayed rejection of Lewis rat pancreas xenografts with MST of 34.3 days, whereas anti-CD4, in combination with thymectomy, synergistically prolonged survival of pancreas xenograft (MST=70.4 days).


CONCLUSIONS
Pancreas xenograft is resistant to anti-Gal Abs-induced HAR but is susceptible to anti-donor specific Abs. Rejection of Lewis pancreas xenograft in STZ-induced, diabetic, GT-Ko mice is T-cell dependent.
Yin
D P
DP
Department of General Surgery, Section of Transplantation, Rush-Presbyterian St. Luke's Medical Center, 1653 West Congress Parkway, Chicago, IL 60612, USA.
Sankary
H N
HN
Ma
L L
LL
Shen
J
J
Qin
Y
Y
Blinder
L
L
Williams
J W
JW
Chong
A S
AS
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D004187:Disaccharides / Q000276:immunology*; D004198:Disease Susceptibility; D005700:Galactosyltransferases / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation; D007106:Immune Sera / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D010179:Pancreas / Q000098:blood supply; D016035:Pancreas Transplantation; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D014019:Tissue Donors; D014183:Transplantation, Heterologous
D000906:Antibodies; D004187:Disaccharides; D007106:Immune Sera; D007166:Immunosuppressive Agents; C055075:galactosyl-(1-3)galactose; D005700:Galactosyltransferases; D016559:Tacrolimus