CLINICAL CONSEQUENCES OF SENSITIZATION TO MINOR HISTOCOMPATIBILITY ANTIGENS BEFORE ALLOGENEIC BONE-MARROW TRANSPLANTATION

To study sensitisation to minor histocompatibility antigens (mHag) bef ore and after BMT, we measured antidonor CTL activity in five patients who had rejected their graft, and in a control group of 10 leukemic p atients who engrafted without complications. All patients were transpl anted with marrow from an HLA-identical sibling. Fourteen patients wer e conditioned with cyclophosphamide (120 mg/kg) and TBI (1350 cGy) and received a T cell-depleted graft, while one patient with aplastic ana emia received cyclophosphamide alone and unmanipulated marrow. Before transplantation, anti-donor CTL activity was detected in two of the 15 patients. These patients rejected their grafts at days 21 and 58, res pectively. In the other three patients who rejected their grafts at da ys 41, 60 and 250, CTL activity was found only after transplantation. In contrast, no anti-donor CTLs could be detected at any time in the 1 0 patients who engrafted permanently. We have identified some of the m Hags recognised during graft rejection by cloning and subsequent speci ficity analysis of the recipient CTLs, In the patient who rejected at day 41 without detectable immunisation before BMT, the response was di rected against HA-1, a minor antigen known to play a role in GVHD. In the other combinations, a significant part of the CTL activity was dir ected against the male antigen H-Y. In the patient who rejected the ma rrow of her HLA-identical brother at day 250, two clones recognised H- Y, while five others recognised at least three distinct autosomal mHag s. This patient had an HLA-identical sister who expressed only one aut osomal mHag that had been recognised by one single T cell clone. After re-transplantation with the marrow of this second donor, the CTL acti vity could no longer be detected and the patient engrafted without fur ther complications.