Hematopoiesis-specific T-cells may contribute to GVHD reactivity by induction of collateral damage to non-hematopoietic tissues during an ongoing profound GVL reaction

      Following HLA-matched allogeneic stem cell transplantation (alloSCT) donor T-cells recognizing minor histocompatibility antigens (MiHA) specifically expressed on recipient hematopoietic cells are hypothesized to mediate specific graft-versus-leukemia (GvL) activity without inducing graft-versus-host-disease (GvHD), whereas T-cells recognizing ubiquitously expressed MiHA may induce both GvL and GvHD reactivity. However, clinical observations suggest that overt GvL reactivity, associated with expansion of T-cells specific for hematopoiesis-restricted MiHA, is often associated with GvHD reactivity. It is, however, impossible to draw definite causal conclusions on this relation in the clinical setting since the immune responses occurring after alloSCT are never of single specificity. Therefore, we developed in-vitro models to investigate whether allo-reactive T-cells recognizing hematopoiesis-restricted MiHA induce collateral damage to surrounding non-hematopoietic tissues. We stimulated MiHA-specific T-cells with MiHA-positive hematopoietic targets and analyzed whether this resulted in lysis of surrounding MiHA-negative primary human fibroblasts. CD4 and CD8 MiHA-specific T-cells activated by MiHA-positive hematopoietic stimulator cells induced 60–100% bystander cytotoxicity to the surrounding fibroblasts and increased strength of T-cell activation was correlated with increased severity of collateral damage. Moreover, we showed that T-cell activation in a cell-free system using PHA or antiCD3/CD28 beads resulted in induction of collateral damage to surrounding fibroblasts, illustrating that the MiHA-negative fibroblasts are not attacked due to cross-presentation of HLA/peptide complexes from apoptotic hematopoietic cells. We demonstrated that collateral damage to MiHA-negative fibroblasts was induced by misdirection of cytotoxic granules released from locally activated MiHA-specific T-cells resulting in induction of classical apoptosis pathways in the adjacent fibroblasts by granzyme-B released from the activated T-cells. Direct contact between the activated T-cell and the fibroblast appeared to be a prerequisite for this collateral damage to occur. In conclusion, these data suggest that hematopoiesis-restricted T-cells actively participating in an overt GvL response may contribute to GvHD via induction of collateral damage to MiHA-negative non-hematopoietic targets.
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