PERINATAL INDUCTION OF IMMUNOTOLERANCE TO CARDIAC AND PULMONARY ALLOGRAFTS

Objectives: Tolerance appears to be more easily induced in the fetus b efore full immunocompetence is established, but elucidation of this pr ocess is needed, A model of perinatal tolerance induction to neonatal skin allografts followed by cardiac and pulmonary allografts is descri bed, Methods: Sixty Lewis (RT1(l)) rat fetuses were inoculated intrape ritoneally at IS days' gestation, with 1 x 10(7) ACI (RT1(a)) rat feta l liver cells (group I); 20 Lewis fetuses were inoculated with 2 x 10( 7) ACI fetal liver cells (group II), Control groups consisted of Lewis fetuses inoculated with saline solution (It = 25, group III) and fetu ses that were not inoculated (n = 25, group IV). Twenty-five of the 50 surviving group I rats received ACI skin (<24 hours old) and heart (8 to 10 weeks old) allografts (group IA); the remaining 25 rats receive d only ACI heart grafts (group IB), Groups II, LII, and IV received AC I skin and cardiac allografts, Recipients tolerant to both skin and ca rdiac grafts received orthotopic ACI lung grafts and third-party skin grafts, Tolerance was indicated by graft survival for more than 100 da ys, Limiting dilution and flow cytometric analyses were performed, Res ults: Abortion rates in groups I, II, III, and IV were 17% (10/60), 65 % (13/20), 8% (2/25), and 4% (1/25), respectively. Specific tolerance to skin, cardiac, and lung allografts was observed in seven of 25 grou p IA recipients (28%) and seven of seven group II recipients (100%) co mpared with no tolerance in any group IB, III, or IV recipients (fl = 0.03, chi(2) test), A 100-fold reduction of precursor cytotoxic T lymp hocytes and significant splenocyte and bone marrow chimerism in tolera nt versus nontolerant rats were noted (p = 0.0001, Student's t test), Conclusions: Using donor-strain fetal liver cells and neonatal skin gr afts, we achieved higher frequencies of tolerance to solid organ graft s in adulthood with lower cell inocula and abortion rates than previou sly described, Chimerism and depressed precursor cytotoxic T lymphocyt e frequencies in tolerant recipients suggest that hematopoietic stem c ell engraftment and clonal deletion/anergy are involved in induction o f perinatal tolerance.