KERATINOCYTE APOPTOSIS FOLLOWING BONE-MARROW TRANSPLANTATION - EVIDENCE FOR CTL-DEPENDENT AND CTL-INDEPENDENT PATHWAYS

Acute graft-versus-host disease (GVHD) is a complication of bone marro w transplantation (BMT), The histopathologic features used to diagnose GVHD are nonspecific, and may be secondary to chemotherapy or irradia tion given before BMT, The presence of apoptotic keratinocytes or acti vated CTL may distinguish GVHD from conditioning effects. This study i nvestigated the relationship in BMT recipients between keratinocyte ap optosis and the effects of conditioning regimens or immune-mediated GV HD. Inflammatory cells, apoptotic keratinocytes, and CTL expressing TI A-1 (a molecule associated with the lytic granules of CTL) were quanti tated in allogeneic and autologous recipients. Allogeneic recipients c ould exhibit keratinocyte apoptosis secondary to a combination of cond itioning effects and immune-mediated GVHD, In contrast, autologous rec ipients should show conditioning effects only. 'Capped' TIA-l-positive lymphocytes and apoptotic keratinocytes were much more frequent in th e allogeneic group than the autologous group (16.1% of total TIA-1 pos itive lymphocytes vs 4.5%, P=0.02; and 37.6/mm(2) vs 3.9/mm(2), P = 0. 005, respectively), although there was some overlap in their frequency . Among individual recipients of allogeneic BMT, the number of epiderm al lymphocytes or macrophages correlated with the number of apoptotic keratinocytes, A similar, but weaker, correlation was seen between the number of 'capped' TIA-l-positive lymphocytes and apoptotic keratinoc ytes, No such relationship was seen in autologous recipients. In allog eneic recipients, TIA-1 expressing CTL were seen in intimate contact w ith apoptotic keratinocytes, some of which also had detectable cytopla smic TIA-1, No CTL/keratinocyte interactions were identified in autolo gous recipients. Our results suggest that apoptotic keratinocytes aris e in the skin of BMT patients due to both GVHD and conditioning effect s, and that the keratinocyte damage in GVHD is mediated by both CTL-de pendent and -independent mechanisms. Increased numbers of apoptotic ke ratinocytes, in the presence of increased epidermal lymphocytes or 'ca pped' TIA-l-expressing lymphocytes, support a diagnosis of GVHD, but m ust be interpreted in the context of clinical information and other hi stopathologic findings.