Suppression of T cells results in long-term survival of mouse heart xenografts in C6-deficient rats.
The present study aimed to investigate the role of cellular immune response in the absence of membrane attack complex (MAC) formation in the concordant mouse-to-rat heart xenografting. Hearts from BALB/c mice were transplanted into the neck vessels of C6-competent (C6(+)) and C6-deficient (C6(-)) PVG rats. Liposome-encapsulated dichloro-methylene diphosphonate (Lip-Cl2MDP) was administered at a dose of 10 ml/kg 2 days before transplantation and every 5 days thereafter. Cyclosporine (CsA) was administered intramuscularly (i.m.) at a dose of 15 mg/kg per day. The heart xenografts were harvested for immuno-histological analysis at the time of rejection and the functioning grafts were removed at 70 days after transplantation. In untreated C6(+) rats, xeno-grafts survived for 2.3 +/- 0.5 days. Treatment with CsA or Lip-Cl(2)MDP in C6(+) rats did not significantly affect graft survival (2.5 +/- 0.6 and 2.3 +/- 0.4 days, respectively). In untreated C6(-) rats, xenografts survived for 5.0 +/- 0.6 days. However, Lip-Cl(2)MDP in C6(-) rats resulted in a prolongation of graft survival to 11 +/- 2.3 days (P < 0.05 vs. untreated C6(-) rats), while treatment with CsA alone in these rats led to more than 70 days' survival in four out of six grafts (61 +/- 16 days). In untreated C6(+) rats, immunohistology showed a severe myocardial necrosis and thrombosis with a scarce cellular infiltrate in the rejected xenografts. By contrast, in untreated C6(-) rats, xenografts were heavily infiltrated by macrophages and T cells. The number of macrophages, but not T cells, was markedly reduced in Lip-Cl(2)MDP-treated rats. In CsA-treated C6(-) rats, the grafts harvested at 70 days after transplantation had a normal morphology, with a minimal cellular infiltrate. Our data indicate that MAC-mediated injury plays an essential role in concordant xenograft rejection. Once this mechanism has been prevented, suppression of T cells allows for long-term xenograft survival.
Wu
G
G
Department of Transplantation Surgery, Huddinge Hospital, Karolinska Institute, Stockholm, Sweden. guoshengwu@hotmail.com
Korsgren
O
O
van Rooijen
N
N
Tibell
A
A
D000818:Animals; D030801:Animals, Genetically Modified; D004002:Clodronic Acid / Q000494:pharmacology; D003176:Complement C3 / Q000032:analysis; D003183:Complement C6 / Q000172:deficiency* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D008081:Liposomes; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009200:Myocardial Contraction; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D051381:Rats; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology*; D016042:Transplantation, Heterotopic
D003176:Complement C3; D003183:Complement C6; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D008081:Liposomes; D004002:Clodronic Acid; D016572:Cyclosporine