THE EFFECT OF BURSECTOMY ON NATURAL XENOREACTIVE ANTIBODIES AND VASCULARIZED RAT CARDIAC XENOGRAFT REJECTION IN THE CHICKEN

The clinical application of xenotransplantation between distantly rela ted species is currently prevented by the occurrence of hyperacute rej ection (HAR). Controversy exists over the importance of natural xenore active antibody (NAb)-mediated activation of the classical complement pathway vs. direct activation of the alternative C pathway in this pro cess. In order to evaluate HAR of xenografts (Xgs) in the absence of N Ab, this study utilized K strain leghorn chickens that were bursectomi zed (Bx) on day 17 in ovo (n=18) to prevent B cell development and pro duction of NAb. Aged-matched untreated siblings served as controls (n= 13). Based on pretransplant antibody levels, the Bx chickens were divi ded into two groups: totally Bx (Total Bx, n=9) and partially Bx (Part Bx, n=9). Chickens then underwent heterotopic cardiac xenotransplanta tion using PVG rats as donors, where the Xg was connected to the circu lation of the chicken recipient utilizing cannulae. For the control gr oup, Xg survival was 28+/-3 min (mean+/-SEM), while Part Bx prolonged survival to 80+/-15 min. Total Bx extended rat Xg survival to 102+/-11 min, with 5 of 9 Xgs functioning well at the time of termination of t he study (90-120 min). Three chickens in the Total Bx group with rat c ardiac Xgs that were functioning at 120 min were given a 1 ml i.v. inj ection of heat inactivated control chicken serum. This led to loss of Xg function within 10 min, confirming the important role for NAb in HA R in this species combination. Histologic examination of the Xgs follo wing perfusion revealed significant arterial endothelial injury in the control and Part Bx groups but not in the Total Bx group. Conversely, Xgs from the Total Bx group showed marked venous congestion, which wa s not seen in the other two groups. This study demonstrates that (1) B x effectively eliminates NAb; (2) Xg survival is significantly prolong ed in the absence of NAb in this rat-to-chicken xenogeneic combination ; (3) the presence of NAb is associated with arterial endothelial inju ry; and (4) in the absence of NAb, marked venous congestion and injury occurs, which is possibly mediated by alternative C pathway activatio n or other humoral mechanisms.