Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortalit y of allogeneic stem cell transplantation. Strategies to control GVHD while maintaining graft versus leukemia (GVL) include herpes simplex virus thymi dine kinase (HSV-tk) gene transduction of donor T cells followed by treatme nt with ganciclovir (GCV). Alternatively, GVHD and GVL may be mediated by d istinct processes. In this regard, whether cytokine polarization occurs and to what degrees various subsets of cytokine-producing T cells mediate GVHD or GVL has been an active area of research using cytokine or cytokine anti body infusion or genetically deficient mice. This study takes a different a pproach that allows simultaneous investigation into both the mechanisms und erlying GVHD reactions and the efficacy of HSV-tk suicide gene-based T-cell deletion. A source of donor T-cells, splenocytes from mice transgenic for HSV-tk controlled by elements of either the interleukin-2 (IL-2) or IL-4 pr omoters (IL-2-tk and IL-4-tk, respectively) Was used, thus allowing investi gation into the roles of T1 and T2 cells in ongoing GVHD reactions. To asse ss treatment rather than prevention of GVHD, GCV was started at peak diseas e. Remarkably, treatment at this late time point rescued mice from the clin ical effects of GVHD caused by T cells expressing either transgene. Thus, b oth T1 and T2 calls play an important role in clinical GVHD in a minor hist ocompatibility antigen-mismatched setting. In addition, because clinical di sease was reversible even at its maximum, these observations provide contro lled evidence that this strategy of treating ongoing GVHD could be effectiv e clinically. (Blood. 2001;98:3367-3375) (C) 2001 by The American Society o f Hematology.