[Discordant heart xenografts. Experimental study in pigs conditioned by total lymphoid irradiation and cyclosporine A].
The use of discordant xenografts may solve some of donor shortage problems. The beneficial effects of treatment with total lymphoid irradiation (TLI) and classical drugs on this discordant model of transplantation rejection was evaluated. Twenty-four lamb hearts were transplanted heterotopically in the abdomen of 24 pigs. Group I received no treatment (control). Group II received continuous intravenous medical treatment cyclosporin A (CyA) (5 mg/kg) and azathioprine (3 mg/kg) 3 days prior to transplantation. Group III received the same medical treatment and simultaneously 12 grays of irradiation in 5 equal fractions with a high rate (100 cGy/min) or a low rate (1.6 cGy/min) prior to transplantation. Group IV also received 12 grays in 5 fractions at a high rate followed by the medical treatment started 5 days after TLI and continued until the day of transplantation. Antibody and serum cyclosporine levels were monitored. Histology specimen were analyzed at the end of the experiment. Mean GST (graft survival time) in group I and II was 140 +/- 35 min and 117 +/- 27.4 min respectively. The histological features of these hearts suggested acute humoral rejection (hemorrhage, thrombosis, and edema) without cellular infiltration. In group III, one heart functioned 4.5 days with pathological features of cellular rejection and a second animal died at 6 hours with a functioning graft with no evidence of an acute rejection. Both had been treated with the low rate TLI protocol (1.6 cGy/min). The mean GST in this group was 1080 +/- 794 min. In Group IV, one graft functioned for 6.5 days and another for 3.25 days. Mean GST was significantly increased in this group to 4800 +/- 2647 min (p < 0.05). A cellular infiltration was seen in this two grafts. The remaining graft was rejected in 6 hours with histological lesions typical of acute humoral rejection. Antibodies levels at the time of transplantation were lowest (40%) in group IV and in the low rate irradiation group. The ability of TLI to induce tolerance and to prolong survival in a discordant xenograft model depends upon cumulative dose, rate of irradiation, delay between TLI and graft placement, and combined treatment with immunosuppressive drugs. A high rate of TLI and graft placement is delayed. Low rates of irradiation may be beneficial when there is a very short period between treatment and transplantation. These findings highlight the potential usefulness of TLI in combination with immunosuppressive drug therapy when antibody-mediated rejection occurs, such as with xenograft and in sensitized patient.
Tixier
D
D
Centre de Recherches Chirurgicales, CNRS URA 1431, Université Paris-XII, Créteil.
Levy
C
C
Le Bourgeois
J P
JP
Léandri
J
J
Loisance
D
D
D000818:Animals; D001379:Azathioprine / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use*; D016027:Heart Transplantation / Q000379:methods* / Q000401:mortality; D015182:Lymphatic Irradiation / Q000379:methods*; D008775:Methylprednisolone / Q000627:therapeutic use; D011300:Preoperative Care; D011829:Radiation Dosage; D012756:Sheep; D013552:Swine; D014183:Transplantation, Heterologous
D016572:Cyclosporine; D001379:Azathioprine; D008775:Methylprednisolone
Xénogreffes cardiaques discordantes. Etude expérimentale chez le porc conditionné par irradiation lymphoïde totale et ciclosporine A.