T-cell responses during pig-to-primate xenotransplantation.
Xenotransplantation using porcine organs may resolve a chronic shortage of donor organs for clinical transplantation if significant immunological barriers can be overcome. To determine the potential role of T lymphocytes in Xenograft (Xg) rejection, we transplanted transgenic hCD46 porcine hearts heterotopically into baboon recipients.


METHODS
Recipients were treated to deplete anti-Gal antibody with a non-antigenic alpha-Gal polyethylene glycol polymer (TPC) (n = 2), TPC plus rituximab (anti-CD20) (n = 1) or were untreated (n = 1). None of the recipients received T-cell immunosuppression.


RESULTS
All Xgs failed within 7 days and showed evidence of a mixed humoral and cellular rejection process. Cellular infiltration consisting primarily of CD4+ T cells and few CD8+ T cells. Proliferation and cytotoxicity assays showed sensitization of CD4+ and CD8+ T cells that reacted with porcine IFN-gamma (pIFN-gamma)-stimulated porcine aortic endothelial cells (PAEC). The CD4+ lymphocytes displayed greater cytotoxicity than CD8+ cells. An increased frequency of PAEC-specific interleukin (IL) 2 and IFN-gamma-secreting T cells was observed, suggesting a Th1 cytokine bias. An increase in the percentage of circulating CD4+CD28- cells was observed at the time of rejection and over 50% of the CD4+ cells recovered from residual pig tissue at necropsy lacked CD28 expression.


CONCLUSIONS
These findings show that lymphocytes are efficiently stimulated by PAEC antigens and can mediate direct tissue destruction. These studies (1) provide an insight into the potential of cellular-mediated cardiac Xg rejection, (2) show for the first time the induction of cytotoxic pig-specific CD4+CD28- lymphocytes and (3) provide a rational basis for determining different modes of immunosuppression to treat Xg rejection.
Davila
Eduardo
E
Department of Pediatrics, Louisiana State University Health Science Center, Stanley S. Scott Cancer Center, New Orleans, LA, USA.
Byrne
Guerard W
GW
LaBreche
Peter T
PT
McGregor
Hugh C J
HC
Schwab
Allison K
AK
Davies
William R
WR
Rao
Vinay P
VP
Oi
Keiji
K
Tazelaar
Henry D
HD
Logan
John S
JS
McGregor
Christopher G A
CG
D000818:Animals; D030801:Animals, Genetically Modified; D000911:Antibodies, Monoclonal / Q000276:immunology; D058846:Antibodies, Monoclonal, Murine-Derived; D000941:Antigens / Q000276:immunology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D010215:Papio; D000069283:Rituximab; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000941:Antigens; D000069283:Rituximab