GvHD after small bowel transplantation: the role of caspases, FAS-L, and galectin-1

Abstract

IN small bowel transplantation, graft-versus-host disease (GvHD) can play a potential risk factor if the recipient organism is unable to counteract donor-derived immunocompetent cells (eg, in a semiallogeneic setting). Previously, we demonstrated that host-derived natural killer (NK) cells can prevent lethal GvHD if the F1-hybrid recipient’s NK cell population is preactivated prior to transplantation of parental small bowel, an immune mechanism also referred to as allogeneic lymphocyte cytotoxicity (ALS). The molecular mechanisms contributing to the lytic machinery of cytotoxic T lymphocytes and natural killer cells in the context of GvHD are presumed to include the interaction between Fas and Fas-ligand, one of the most potent signal transducers involved in the process of activation-induced cell death (AICD), or apoptosis. In this context, it is noteworthy that new groups of cytoplasmic proteins, such as cysteine proteases (caspases) like interleukin-converting enzyme (ICE) and the polypeptide cysteine protease-P32 (CPP-32), have been characterized as important intracellular transmitters of apoptotic signaling via the Fas pathway. CPP-32 serves as a substrate for ICE and generates enzymatically active ICE-like proteases from the inactive proenzymes. Beside the Fas/Fas-L pathway, galectin-1, a member of the family of b-galactoside binding proteins with immunomodulatory properties, has been shown to induce apoptosis of alloreactive T cells, a mechanism that could be blocked by anti-CD45 antibodies. The present study was conducted to investigate the impact of various apoptotic signal events in the context of GvHD with respect to the activation status of the F1 recipient’s NK activity prior to parental small bowel transplantation (SBTx).