WOFIE augments the immunosuppressive potency of FK-506

Bidirectional recognition of donor- and recipient-derived immunocompetent c ells has been proven to play a pivotal role for the induction of long-term unresponsiveness to allogeneic grafts. This study investigated the fate of heterotopic heart grafts with respect to the timing of subtherapeutic doses of FK-506 and with respect to the time point and type of donor antigen app lication, leaving space for mutual adaptation of alloreactive lymphocytes, designated as the 'WOFIE-concept' (window of opportunity for immunological engagement), originally described by R Calne. Methods. Heterotropic heart transplantation was performed using male DA (RT 1.(a)) donor and LEW (RT1.(1)) recipient rats in the following groups (n = 6). FK-506 was applied intramuscularly (i.m.) using doses of 2 mg/kg x body weight per day. Donor antigen application was performed either by DA blood transfusion, 2 mi intravenously (i.v.), or by i.v. transfusion of 5 x 10(7 ) DA splenocytes. (i) LEW --> LEW, untreated; (ii) DA --> LEW, untreated; ( iii) DA --> LEW, FK-506 days 0, 4-7; (iv) DA --> LEW. FK-506 as group (iii) plus 2 mi of DA blood 6 h post-Tx; (v) same as group (iv) but DA blood tra nsfusion 24 h post-Tx (vi) DA --> LEW, FK-506 as group (iii) plus DA spleno cytes 6 h post-Tx; (vii) same as group (vi) but DA splenocyte transfusion 2 4 h post-Tx; (viii) DA --> LEW, FK-506 days 0-4 and (ix) DA --> LEW, FK-506 as group (viii) plus DA blood 6 h post-Tx. Immunohistochemical stainings ( APAAP-method) of the allografts and flow cytometric analysis of recipient s pleens were performed electively 3, 7 and 14 days after organ reperfusion. fusion. Results. The mean graft survival differed significantly between groups and comprised (mean +/- SD days): (i) >100, (ii) 6.5 +/- 1.0, (iii) 31.6 +/- 12 .1, (iv) 44.8 +/- 10.1, (v) 29.5 +/- 14.2, (vi) 27.2 +/- 4.7, (vii) 14.6 +/ - 4.2, 17.5 +/- 4.2, (viii) 17.5 i 4.2 and (ix) 18.8 +/- 2.8 days. Prolonga tion of graft survival and long-term unresponsiveness (group iv) revealed a substantially different pattern of graft infiltration. Conclusions. Effective treatment with unspecific immunosuppressants like FK -506 can be substantially improved if (i) mutual antigen recognition betwee n donor and recipient immunocompetent cells is warranted, (ii) donor-derive d blood-borne antigens are given immediately after graft reperfusion, and ( iii) the type of inoculated donor antigen has a strong impact on graft surv ival as splenocytes which contain a large population of professional antige n-presenting cells failed to prolong graft survival after interrupted FK-50 6 treatment.