Costimulation blockade in pig artery patch xenotransplantation - a simple model to monitor the adaptive immune response in nonhuman primates.
BACKGROUND
CD154 blockade-based immunosuppression successfully prevents both humoral and cellular adaptive immune responses in baboons receiving α1,3-galactosyltransferase gene-knockout (GTKO) pig organs. Using a GTKO pig artery transplantation model in baboons, we evaluated the efficacy of CD28/B7 costimulatory pathway blockade in comparison with CD154 blockade.


METHODS
Baboons received artery patch grafts from GTKO pigs, with no (Group1), anti-CD154mAb-based (Group2), or CTLA4-Ig-based (Group3) immunosuppressive therapy. Anti-pig IgM and IgG antibody and cellular responses were monitored. Xenografts were immunohistologically evaluated for antibody and complement deposition, and cellular infiltration.


RESULTS
Group1 baboons developed increased IgM and IgG antibody and cellular responses against GTKO antigens. In Group2, anti-CD154mAb alone prevented the development of both IgM and IgG antibody and cellular responses,but not cellular infiltration of the graft. In the single baboon that received anti-thymocyte globulin (ATG) + mycophenolate mofetil (MMF) + anti-CD154mAb, cellular infiltration of the graft was not seen. In Group3, CTLA4-Ig with ATG + MMF inhibited the cellular proliferative response to pig antigens but did not prevent the IgG response or cellular infiltration.


CONCLUSIONS
(i) Artery patch transplantation is a simple model to monitor the adaptive immune response to xenografts; (ii) anti-CD154mAb prevents sensitization but not cellular infiltration (but, without anticoagulation, may result in early thrombosis of a pig xenograft); (iii) although in only one baboon, the addition of ATG and MMF prevents cellular infiltration and (iv) replacement of anti-CD154mAb by CTLA4-Ig (at the doses used), even in combination with ATG and MMF, prevents the cellular proliferative response to GTKO pig antigens but is insufficient to prevent the development of anti-pig antibodies.
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Mohamed B
MB
Ezzelarab
Burcin
B
Ekser
Gabriel
G
Echeverri
Hidetaka
H
Hara
Corin
C
Ezzelarab
Cassandra
C
Long
Pietro
P
Bajona
Bertha
B
Garcia
Noriko
N
Murase
David
D
Ayares
David K C
DK
Cooper
D056704:Adaptive Immunity; D000818:Animals; D015478:Antigens, Heterophile / Q000276:immunology; D001158:Arteries / Q000637:transplantation; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D005700:Galactosyltransferases / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D055786:Gene Knockout Techniques; D007113:Immunity, Innate; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D023421:Models, Animal; D018448:Models, Immunological; D010215:Papio / Q000276:immunology; D013552:Swine / Q000235:genetics / Q000276:immunology; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology
D015478:Antigens, Heterophile; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase